Prevalence and Incidence of Rare Diseases: Bibliographic Data

Home , Achalasia microcephaly, Acrocallosal syndrome, Boomerang dysplasia, CADASIL, Carpenter syndrome, Cherubism

Number 1 | January 2019

Prevalence and incidence of rare diseases:

Bibliographic data Prevalence, incidence or number of published cases listed by diseases (in alphabetical order)

www.orpha.net www.orphadata.org

If a range of national data is available, the average is

Methodology calculated to estimate the worldwide or European prevalence or incidence. When a range of data sources is available, the most Orphanet carries out a systematic survey of literature in recent data source that meets a certain number of quality order to estimate the prevalence and incidence of rare criteria is favoured (registries, meta-analyses, diseases. This study aims to collect new data regarding population-based studies, large cohorts studies). point prevalence, birth prevalence and incidence, and to update already published data according to new For congenital diseases, the prevalence is estimated, so scientific studies or other available data. that: Prevalence = birth prevalence x (patient life This data is presented in the following reports published expectancy/general population life expectancy). biannually: When only incidence data is documented, the prevalence is estimated when possible, so that : • Prevalence, incidence or number of published cases listed by diseases (in alphabetical order); Prevalence = incidence x disease mean duration.

• Diseases listed by decreasing prevalence, incidence When neither prevalence nor incidence data is available, or number of published cases; which is the case for very rare diseases, the number of cases or families documented in the medical literature is Data collection provided.

A number of different sources are used : Limitations of the study

• Registries (RARECARE, EUROCAT, etc) ; The prevalence and incidence data presented in this report are only estimations and cannot be considered to • National/international health institutes and agencies be absolutely correct. (Institut National de Veille Sanitaire (French Institute of Health Surveillance); American Center of Disease The average values presented in this report do not take Control and Prevention, American National Cancer into account the heterogeneous nature of the Institute, European Medicines Agency, World Health methodologies employed by the studies considered in the Organization etc) ; literature survey.

• Medline is consulted using the following search The validity and exactitude of raw data sources is taken algorithm : «Disease names» AND for granted and have not been verified. Thus, confusion Epidemiology[MeSH:NoExp] OR between terms such as incidence and prevalence and/or Incidence[Title/abstract] OR Prevalence[Title/ abstract] OR Epidemiology[Title/abstract]; birth prevalence is possible due to the interchangeable use of these terms in certain sources. • Medical texts, grey literature and reports from It is possible that prevalence is overestimated in some experts; cases as epidemiological studies are generally based on hospital data in regions with higher prevalence. • Orphanet collaborating experts Data presentation Data characteristics Without specification, published figures are worldwide. The data published in this document are worldwide An asterisk * indicates European data. estimations, or European estimations if a worldwide P indicates prevalence data estimation is not available. I indicates incidence data. BP indicates birth prevalence The published data is raw collected data or extrapolations of raw data at worldwide or European Please note that this is just a selection of Orphanet's rare level when no genetic founder effect is suspected as a disease epidemiological data. Currently 5949 rare cause of a disease. diseases are annotated with prevalence or incidence

Without specification, published figures are worldwide. An asterisk * indicates European data. P indicates prevalence data, I indicates incidence data and BP indicates birth prevalence Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - January 2019 - Number 1 http://www.orpha.net/orphacom/cahiers/docs/GB/Prevalence_of_rare_diseases_by_alphabetical_list.pdf 2

information in the Orphanet database. To access the complete data sets visit Orphadata (www.orphadata.org).

Estimated Number of Prevalence, incidence or number of ORPHA Disease prevalence/ published published cases listed by diseases (in Number or Group of diseases incidence cases or (/100,000) families alphabetical order) 10 48,XXYY syndrome 1.9 BP * 99329 48,XYYY syndrome 10 Cases

96264 49,XXXXY syndrome 0.55 BP * Estimated Number of ORPHA Disease prevalence/ published 261534 49,XXXYY syndrome 2 Cases Number or Group of diseases incidence cases or 99330 49,XYYYY syndrome 8 Cases (/100,000) families 293948 1p21.3 microdeletion syndrome 9 Cases 79154 2-aminoadipic 2-oxoadipic aciduria 20 Cases 401986 1p31p32 microdeletion syndrome 5 Cases 2-methylbutyryl-CoA 79157 30 Cases dehydrogenase deficiency 456298 1p35.2 microdeletion syndrome 2 Cases 3-hydroxy-3-methylglutaryl-CoA 35701 9 Cases 250994 1q21.1 microduplication syndrome 46 Cases synthase deficiency 238769 1q44 microdeletion syndrome 100 Cases 939 3-hydroxyisobutyric aciduria 13 Cases 3-methylcrotonyl-CoA carboxylase 363680 2p13.2 microdeletion syndrome 2 Cases 6 2.65 BP * deficiency 261349 2p15p16.1 microdeletion syndrome 11 Cases 67046 3-methylglutaconic aciduria type 1 20 Cases 163693 2p21 microdeletion syndrome 7 Cases 445038 3-methylglutaconic aciduria type 7 22 Cases 2p21 microdeletion syndrome 369881 2 Cases 505208 3-methylglutaconic aciduria type 8 9 Cases without cystinuria 228402 2q23.1 microdeletion syndrome 18 Cases 505216 3-methylglutaconic aciduria type 9 4 Cases 3-phosphoglycerate dehydrogenase 313947 2q23.1 microduplication syndrome 2 Cases 79351 15 Cases deficiency, infantile/juvenile form 1617 2q24 microdeletion syndrome 23 Cases 3-phosphoserine phosphatase 79350 8 Cases deficiency 251019 2q32q33 microdeletion syndrome 25 Cases 7 3C syndrome 25 Cases 251028 2q33.1 microdeletion syndrome 20 Cases 2616 3M syndrome 200 Cases 1001 2q37 microdeletion syndrome 115 Cases 293843 3MC syndrome 32 Cases 435638 3p25.3 microdeletion syndrome 8 Cases 217064 5-fluorouracil poisoning 2.0 P * 1621 3q13 microdeletion syndrome 42 Cases 33572 5-oxoprolinase deficiency 8 Cases 96095 3q26 microduplication syndrome 100 Cases 46,XX disorder of sex development- 356947 3q26q27 microdeletion syndrome 4 Cases 2975 2 Cases skeletal anomalies syndrome 397695 3q27.3 microdeletion syndrome 7 Cases 46,XX ovarian dysgenesis-short 444048 3 Cases stature syndrome 238750 4q21 microdeletion syndrome 14 Cases 46,XX ovotesticular disorder of sex 2138 2.5 BP 502437 4q25 proximal deletion syndrome 3 Cases development 46,XX testicular disorder of sex 329802 5p13 microduplication syndrome 7 Cases 393 2.5 P development 228384 5q14.3 microdeletion syndrome 40 Cases 46,XY disorder of sex development 753 due to 5-alpha-reductase 2 50 Families 228415 5q35 microduplication syndrome 30 Cases deficiency 251046 6p22 microdeletion syndrome 19 Cases 46,XY disorder of sex development 90796 due to isolated 17,20-lyase 15 Cases 75857 6q terminal deletion syndrome 19 Cases deficiency 171829 6q16 deletion syndrome 12 Cases 46,XY disorder of sex development 251056 6q25 microdeletion syndrome 4 Cases 443087 due to testicular 17,20-desmolase 2 Families deficiency 314034 7p22.1 microduplication syndrome 5 Cases 46,XY disorder of sex development- 7q11.23 microduplication 96121 163 Cases 168558 adrenal insufficiency due to 9 Cases syndrome CYP11A1 deficiency 251061 7q31 microdeletion syndrome 20 Cases 46,XY gonadal dysgenesis-motor 168563 5 Cases 8p inverted duplication/deletion and sensory neuropathy syndrome 96092 3.9 BP * syndrome 8 47,XYY syndrome 50.0 BP * 251066 8p11.2 deletion syndrome 3 Cases 96263 48,XXXY syndrome 1.0 BP * 251076 8p23.1 duplication syndrome 1.72 P

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families 17q11.2 microduplication 228399 8q12 microduplication syndrome 4 Cases 139474 7 Cases syndrome 284160 8q21.11 microdeletion syndrome 13 Cases 261265 17q12 microdeletion syndrome 103 Cases 178303 8q22.1 microdeletion syndrome 6 Cases 261272 17q12 microduplication syndrome 118 Cases 508488 8q24.3 deletion syndrome 2 Cases 363958 17q21.31 microdeletion syndrome 6.25 P * 324313 9p13 microdeletion syndrome 4 Cases 17q23.1q23.2 microdeletion 261279 7 Cases 9q31.1q31.3 microdeletion syndrome 401923 2 Cases syndrome 254346 19p13.12 microdeletion syndrome 6 Cases 9q33.3q34.11 microdeletion 495818 4 Cases syndrome 357001 19p13.13 microdeletion syndrome 7 Cases 11p15.4 microduplication 19p13.3 microduplication 300305 1 Family 447980 6 Cases syndrome syndrome 11q22.2q22.3 microdeletion 444002 5 Cases 217346 19q13.11 microdeletion syndrome 12 Cases syndrome 261295 20p12.3 microdeletion syndrome 3 Cases 313884 12p12.1 microdeletion syndrome 6 Cases 313781 20p13 microdeletion syndrome 4 Cases 94063 12q14 microdeletion syndrome 22 Cases 12q15q21.1 microdeletion 444051 20q11.2 microdeletion syndrome 11 Cases 289513 6 Cases syndrome 21q22.11q22.12 microdeletion 261323 12 Cases syndrome 412035 13q12.3 microdeletion syndrome 3 Cases 567 22q11.2 deletion syndrome 37.5 BP 261120 14q11.2 microdeletion syndrome 3 Cases 14q11.2 microduplication 439232 AApoAIV amyloidosis 2 Cases 261229 7 Cases syndrome 915 Aarskog-Scott syndrome 0.5 BP * 261144 14q12 microdeletion syndrome 3 Cases 916 Aase-Smith syndrome 10 Cases 264200 14q22q23 microdeletion syndrome 5 Cases 324723 ABeta amyloidosis, Arctic type 1 Family 14q24.1q24.3 microdeletion 401935 3 Cases 100006 ABeta amyloidosis, Dutch type 250 Cases syndrome 488280 14q32 duplication syndrome 33 Cases 324708 ABeta amyloidosis, Iowa type 2 Families 314585 15q overgrowth syndrome 12 Cases 324713 ABeta amyloidosis, Italian type 7 Families 261183 15q11.2 microdeletion syndrome 200 Cases 324718 ABetaA21G amyloidosis 2 Families 15q11q13 microduplication 324703 ABetaL34V amyloidosis 1 Family 238446 30 Cases syndrome Ablepharon macrostomia 920 16 Cases 199318 15q13.3 microdeletion syndrome 246 Cases syndrome 261190 15q14 microdeletion syndrome 9 Cases 921 Abruzzo-Erickson syndrome 4 Cases Absence deformity of leg-cataract 94065 15q24 microdeletion syndrome 30 Cases 2310 2 Cases syndrome 16p11.2p12.2 microdeletion Absence of fingerprints-congenital 261211 8 Cases 1658 10 Families syndrome milia syndrome 16p11.2p12.2 microduplication 261204 7 Cases 980 Absence of the pulmonary artery 0.5 I * syndrome Absent radius-anogenital 485405 16p12.1p12.3 triplication syndrome 3 Cases 3016 2 Cases anomalies syndrome 261236 16p13.11 microdeletion syndrome 7.0 BP Absent thumb-short stature- 2951 3 Cases 16p13.11 microduplication immunodeficiency syndrome 261243 162 Cases Absent tibia-polydactyly-arachnoid syndrome 3328 3 Cases cyst syndrome 500055 16p13.2 microdeletion syndrome 6 Cases 67043 1.0 P * 16p13.3 microduplication Acanthamoeba keratitis 96078 27 Cases syndrome Acanthosis nigricans-insulin 90301 resistance-muscle cramps-acral 5 Cases 352629 16q24.1 microdeletion syndrome 42 Cases enlargement syndrome 261250 16q24.3 microdeletion syndrome 27 Cases 926 Acatalasemia 3.2 P * 17p13.3 microduplication 217385 50 Cases syndrome 48818 Aceruloplasminemia 0.09 P 97685 17q11 microdeletion syndrome 170 Cases 929 Achalasia-microcephaly syndrome 7 Cases

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families 15 Achondroplasia 4.0 BP 39 Acromelanosis 10 Cases 49382 Achromatopsia 2.7 P 1827 Acromelic frontonasal dysplasia 22 Cases Acromesomelic dysplasia, Hunter- 424046 Acinar cell carcinoma of pancreas 0.02 I * 968 10 Cases Thompson type 40366 26 Cases Acitretin/etretinate embryopathy Acromesomelic dysplasia, 40 50 Cases Acquired aneurysmal subarachnoid 90065 10.0 P * Maroteaux type hemorrhage 969 Acromicric dysplasia 60 Cases 91385 Acquired angioedema 200 Cases 955 Acroosteolysis dominant type 100 Cases 46487 Acquired epidermolysis bullosa 0.03 I * Acroosteolysis-keloid-like lesions- 363665 5 Cases 79086 Acquired generalized lipodystrophy 1.0 P * premature aging syndrome 85203 Acropectoral syndrome 25 Cases 73274 Acquired hemophilia 0.1 P * 957 Acropectorovertebral dysplasia 30 Cases 73274 Acquired hemophilia 0.08 I 971 Acrorenal syndrome 20 Cases 2221 Acquired hypertrichosis lanuginosa 60 Cases Acquired idiopathic sideroblastic ACTH-dependent Cushing 75564 0.09 I * 99892 0.55 I anemia syndrome Action myoclonus-renal failure 464453 Acquired methemoglobinemia 242 Cases 163696 38 Cases syndrome Acquired monoclonal Ig light chain- 91136 100 Cases 397596 Activated PI3K-delta syndrome 18 Cases associated Fanconi syndrome 284460 Acute annular outer retinopathy 12 Cases 79087 Acquired partial lipodystrophy 1.0 P * Acquired pseudoxanthoma Acute disseminated 228247 20 Cases 83597 0.6 I * elasticum encephalomyelitis Acute encephalopathy with 99147 Acquired von Willebrand syndrome 300 Cases 363549 biphasic seizures and late reduced 283 Cases Acral dystrophic epidermolysis diffusion 158673 10 Families bullosa Acute generalized exanthematous 293173 0.3 I 263534 Acral peeling skin syndrome 40 Cases pustulosis Acute infantile liver failure due to 281127 Acral self-healing collodion baby 2 Cases 217371 synthesis defect of mtDNA-encoded 19 Cases 958 Acro-renal-mandibular syndrome 10 Cases proteins Acute infantile liver failure- 959 Acro-renal-ocular syndrome 20 Families 466794 cerebellar ataxia-peripheral sensory 3 Cases 36 Acrocallosal syndrome 38 Cases motor neuropathy syndrome 2008 Acrocardiofacial syndrome 9 Cases Acute infantile liver failure- 370088 multisystemic involvement 6 Cases 221054 Acrocephalopolydactyly 8 Cases syndrome Acute inflammatory demyelinating 949 Acrocraniofacial dysostosis 2 Cases 98916 3.1 P * polyradiculoneuropathy 950 Acrodysostosis 80 Cases 79276 Acute intermittent porphyria 0.54 P * Acrodysostosis with multiple 280651 40 Cases hormone resistance 79276 Acute intermittent porphyria 0.013 I * 2956 Acrodysplasia scoliosis 2 Cases 79126 Acute interstitial pneumonia 3.8 P * 1786 Acrofacial dysostosis, Catania type 2 Families 90062 Acute liver failure 20.0 P * Acrofacial dysostosis, Kennedy- 64542 2 Cases 178320 Acute lung injury 25.0 I * Teebi type 513 Acute lymphoblastic leukemia 11.0 P * Acrofacial dysostosis, Palagonia 1787 4 Cases type 513 Acute lymphoblastic leukemia 2.75 I * Acrofacial dysostosis, Rodríguez 1788 13 Cases 488239 Acute macular neuroretinopathy 101 Cases type 518 Acute megakaryoblastic leukemia 0.02 I * 1784 Acrofrontofacionasal dysostosis 12 Cases Acromegaloid facial appearance 514 Acute monoblastic leukemia 0.13 I * 965 23 Cases syndrome Acute myeloblastic leukemia with 98834 0.02 I * 963 Acromegaly 5.5 P maturation Acute myeloblastic leukemia 963 Acromegaly 0.35 I 98833 0.01 I * without maturation

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families 519 Acute myeloid leukemia 2.5 I 978 ADULT syndrome 50 Cases Acute myeloid leukemia with 98832 0.01 I * 86875 Adult T-cell leukemia/lymphoma 3.0 P * minimal differentiation Adult-onset autosomal dominant Acute myeloid leukemia with 99027 20 Families 98277 0.11 I * leukodystrophy recurrent genetic anomaly Adult-onset autosomal recessive 284289 14 Cases 517 Acute myelomonocytic leukemia 0.17 I * cerebellar ataxia Acute panmyelosis with Adult-onset autosomal recessive 86843 0.06 I * 255132 2 Cases myelofibrosis sideroblastic anemia Adult-onset cervical dystonia, 90064 Acute peripheral arterial occlusion 16.0 P * 420492 2 Families DYT23 type 520 Acute promyelocytic leukemia 0.11 I * Adult-onset distal myopathy due to 329478 9 Cases Acute sensorineural hearing loss by VCP mutation acute acoustic trauma or sudden 90059 37.0 P * 199351 Adult-onset dystonia-parkinsonism 14 Cases deafness or surgery induced acoustic trauma 183669 Agammaglobulinemia 0.13 P * 139417 Acute transverse myelitis 1.6 I Agammaglobulinemia- 83617 microcephaly-craniosynostosis- 3 Cases Acute zonal occult outer 284454 150 Cases severe dermatitis syndrome retinopathy Acyl-CoA dehydrogenase 9 85448 AGel amyloidosis 475 Cases 99901 23 Cases deficiency 98850 Aggressive systemic mastocytosis 0.33 P * 100008 ACys amyloidosis 9 Families 442582 AH amyloidosis 12 Cases 55881 Adamantinoma 0.01 I * AHDC1-related intellectual 974 Adams-Oliver syndrome 398 Cases 412069 disability-obstructive sleep apnea- 4 Cases mild dysmorphism syndrome 85138 Addison disease 12.5 P * 250977 AICA-ribosiduria 1 Case Adducted thumbs-arthrogryposis 2952 9 Cases syndrome, Christian type 51 Aicardi-Goutières syndrome 10.0 P * 213504 Adenocarcinoma of ovary 5.97 I * 90081 AIDS wasting syndrome 20.0 P * AKT2-related familial partial 424016 Adenocarcinoma of the anal canal 0.26 I * 79085 1 Family lipodystrophy 213772 Adenocarcinoma of the cervix uteri 1.01 I * 85443 AL amyloidosis 11.0 P * 99976 Adenocarcinoma of the esophagus 0.7 I Alacrimia-choreoathetosis-liver 404454 8 Cases Adenocarcinoma of the gallbladder 424991 2.62 I * dysfunction syndrome and extrahepatic biliary tract 52 Alagille syndrome 0.8 BP * Adenocarcinoma of the liver and 424943 0.21 I * intrahepatic biliary tract 178333 Åland Islands eye disease 5 Families Adenocarcinoma of the small Alar cartilages hypoplasia- 104075 0.57 I * 2007 2 Cases instestine coloboma-telecanthus syndrome Adenosine monophosphate 45 100 Cases 53 Albers-Schönberg osteopetrosis 1.0 P deaminase deficiency Adenovirus infection in 998 Albinism-deafness syndrome 1 Family 91127 18.0 P * ALDH18A1-related De Barsy immunocompromised patients 35664 32 Cases syndrome 46 Adenylosuccinate lyase deficiency 56 Cases Adenylosuccinate synthetase-like 79327 ALG1-CDG 57 Cases 482601 19 Cases 1-related distal myopathy 79326 ALG2-CDG 1 Case 404448 ADNP syndrome 10 Cases 79321 ALG3-CDG 15 Cases 1501 Adrenocortical carcinoma 0.75 P * 79320 ALG6-CDG 54 Cases 1501 Adrenocortical carcinoma 0.03 I * 79325 ALG8-CDG 15 Cases 977 Adrenomyodystrophy 2 Cases 79328 ALG9-CDG 12 Cases Adult familial nephronophthisis- 2666 2 Cases 280071 ALG11-CDG 8 Cases spastic quadriparesia syndrome 178487 Adult intestinal botulism 19 Cases 79324 ALG12-CDG 11 Cases 206583 Adult polyglucosan body disease 50 Cases 324422 ALG13-CDG 1 Case

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families 502444 Alkaline ceramidase 3 deficiency 2 Cases 803 Amyotrophic lateral sclerosis 3.85 P 59 Allan-Herndon-Dudley syndrome 320 Cases 803 Amyotrophic lateral sclerosis 1.35 I 1006 Alopecia antibody deficiency 3 Cases 357043 Amyotrophic lateral sclerosis type 4 70 Cases 700 Alopecia totalis 10.5 P * 228113 Anal fistula 23.0 P * 701 Alopecia universalis 25.0 P * 98841 Anaplastic large cell lymphoma 2.0 P * Alopecia-contractures-dwarfism- 1005 5 Cases 251630 Anaplastic oligodendroglioma 0.09 I * intellectual disability syndrome Alopecia-epilepsy-pyorrhea- 142 Anaplastic thyroid carcinoma 0.1 P * 1008 12 Cases intellectual disability syndrome 142 Anaplastic thyroid carcinoma 0.17 I * Alopecia-intellectual disability 2850 15 Families 93347 Anauxetic dysplasia 10 Cases syndrome Alopecia-intellectual disability- 37553 Andersen-Tawil syndrome 0.1 I * 1014 hypergonadotropic hypogonadism 2 Cases 157954 ANE syndrome 5 Cases syndrome 726 Alpers-Huttenlocher syndrome 0.07 P * 284984 Aneurysm-osteoarthritis syndrome 45 Cases Angel-shaped phalango-epiphyseal 726 Alpers-Huttenlocher syndrome 0.7 BP * 63442 20 Cases dysplasia 60 Alpha-1-antitrypsin deficiency 20.0 P * 72 Angelman syndrome 7.5 P Alpha-B crystallin-related late- 399058 17 Cases 72 Angelman syndrome 1.3 BP * onset myopathy 100025 Alpha-heavy chain disease 400 Cases 251671 Angiocentric glioma 52 Cases 61 Alpha-mannosidosis 0.1 P * 2346 Angioosteohypertrophic syndrome 0.8 BP * Alpha-N-acetylgalactosaminidase 370039 Angora hair nevus 2 Cases 3137 20 Cases deficiency Anhidrotic ectodermal dysplasia- Alpha-N-acetylgalactosaminidase 69088 immunodeficiency-osteopetrosis- 2 Cases 79279 10 Cases deficiency type 1 lymphedema syndrome Alpha-N-acetylgalactosaminidase 79280 10 Cases 1069 Aniridia-absent patella syndrome 3 Cases deficiency type 2 Aniridia-cerebellar ataxia- Alpha-N-acetylgalactosaminidase 1065 22 Families 79281 10 Cases intellectual disability syndrome deficiency type 3 Aniridia-intellectual disability Alpha-thalassemia-intellectual 1068 2 Cases syndrome 98791 disability syndrome linked to 20 Cases Aniridia-ptosis-intellectual chromosome 16 1067 3 Cases disability-familial obesity syndrome Alpha-thalassemia-myelodysplastic 231401 80 Cases Aniridia-renal agenesis- syndrome 1064 2 Cases psychomotor retardation syndrome Alpha-thalassemia-X-linked 847 200 Cases intellectual disability syndrome 1070 Anisakiasis 0.32 I ANK3-related intellectual disability- 63 Alport syndrome 2.0 P * 356996 3 Cases sleep disturbance syndrome Alport syndrome-intellectual 86818 disability-midface hypoplasia- 2 Families Ankyloblepharon filiforme elliptocytosis syndrome 1074 adnatum-imperforate anus 3 Families syndrome 64 Alström syndrome 950 Cases Ankylosing vertebral hyperostosis 2206 8 Cases 284 Alveolar echinococcosis 0.16 I * with tylosis 169095 Alymphoid cystic thymic dysgenesis 9 Cases 254411 Annular atrophic lichen planus 10 Cases 93561 ALys amyloidosis 7 Families 281139 Annular epidermolytic ichthyosis 7 Families Amaurosis-hypertrichosis 675 Annular pancreas 1.8 BP * 1021 2 Cases syndrome Anonychia with flexural 69125 3 Cases 314422 Ameloblastic carcinoma 40 Cases pigmentation Ameloonychohypohidrotic 1094 Anonychia-microcephaly syndrome 4 Cases 1028 2 Cases syndrome Anonychia-onychodystrophy 90390 14 Cases Aminopterin/methotrexate 1908 17 Cases syndrome embryofetopathy 1104 Anophthalmia plus syndrome 17 Cases 319635 Amyloidosis cutis dyschromia 27 Cases

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families Anophthalmia-megalocornea- Arterial dissection-lentiginosis 1682 4 Cases 1101 cardiopathy-skeletal anomalies 3 Cases syndrome syndrome 3342 Arterial tortuosity syndrome 102 Cases Anophthalmia/microphthalmia- 77298 30 Cases esophageal atresia syndrome 1037 Arthrogryposis multiplex congenita 5.7 BP * Arthrogryposis multiplex 93976 Anotia 0.028 BP * 1150 10 Cases congenita-whistling face syndrome 2987 Antecubital pterygium syndrome 11 Cases Arthrogryposis-ectodermal 90079 Anthracycline extravasation 0.3 P * 3200 dysplasia-other anomalies 2 Cases syndrome Anti-glomerular basement 375 0.08 I * Arthrogryposis-hyperkeratosis membrane disease 1485 2 Cases syndrome, lethal form 454710 Anti-p200 pemphigoid 50 Cases Arthrogryposis-like hand anomaly- 1144 1 Family 81 Antisynthetase syndrome 3.5 P sensorineural deafness syndrome Arthrogryposis-renal dysfunction- 83 Antley-Bixler syndrome 34 Cases 2697 100 Cases cholestasis syndrome 1457 Aorta coarctation 35.6 BP * Arthrogryposis-severe scoliosis 65720 2 Families Aortic arch anomaly-facial syndrome 1110 dysmorphism-intellectual disability 4 Cases 1253 Ascher syndrome 50 Cases syndrome 137686 Asherman syndrome 44.0 P * 2299 Aortic arch interruption 0.3 BP * 85175 Astley-Kendall dysplasia 5 Cases 3400 Aorto-ventricular tunnel 130 Cases 251679 Astroblastoma 0.02 I * Aphalangy-hemivertebrae- 1112 urogenital-intestinal dysgenesis 3 Cases 94 Astrocytoma 2.5 P * syndrome 94 Astrocytoma 4.8 I * Aphalangy-syndactyly- 1113 5 Cases microcephaly syndrome 96 Ataxia with vitamin E deficiency 0.33 P * Aphonia-deafness-retinal Ataxia-deafness-intellectual 1188 8 Cases 324540 dystrophy-bifid halluces-intellectual 2 Cases disability syndrome disability syndrome Ataxia-intellectual disability- 1114 Aplasia cutis congenita 10.0 BP 370022 oculomotor apraxia-cerebellar cysts 7 Cases syndrome Aplasia cutis congenita-intestinal 1116 3 Cases lymphangiectasia syndrome 459033 Ataxia-oculomotor apraxia type 4 12 Cases Ataxia-photosensitivity-short 1117 Aplasia cutis-myopia syndrome 4 Cases 1184 2 Cases stature syndrome 99981 Apnea of prematurity 8.5 P * 100 Ataxia-telangiectasia 0.49 P * 425 Apolipoprotein A-I deficiency 30 Families 1190 Atelosteogenesis type I 12 Cases Aprosencephaly cerebellar 1126 2 Cases dysgenesis 56304 Atelosteogenesis type II 25 Cases Arachnodactyly-abnormal 56305 Atelosteogenesis type III 25 Cases 1129 ossification-intellectual disability 5 Cases Athabaskan brainstem dysgenesis syndrome 69739 13 Cases syndrome Arachnodactyly-intellectual 1130 3 Cases Atherosclerosis-deafness-diabetes- disability-dysmorphism syndrome 1192 2 Cases epilepsy-nephropathy syndrome 1133 AREDYLD syndrome 3 Cases 95713 Athyreosis 3.5 P * 23 Argininosuccinic aciduria 1.0 P * 1193 Atkin-Flaitz syndrome 14 Cases 23 Argininosuccinic aciduria 0.46 BP 163934 Atopic keratoconjunctivitis 15.0 P * 91 Aromatase deficiency 38 Cases ATP13A2-related juvenile neuronal 314632 4 Cases 178345 Aromatase excess syndrome 30 Cases ceroid lipofuscinosis Aromatic L-amino acid 1201 Atresia of small intestine 16.0 BP * 35708 100 Cases decarboxylase deficiency Atrial septal defect-atrioventricular 1479 11 Cases Arrhinia-choanal atresia- conduction defects syndrome 1135 4 Cases microphthalmia syndrome Atrioventricular defect- Arrhythmogenic right ventricular 1352 blepharophimosis-radial and anal 2 Cases 247 20.0 P cardiomyopathy defect syndrome

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families Attenuated Chédiak-Higashi Autoimmune pulmonary alveolar 352723 100 Cases 747 0.5 P syndrome proteinosis Autoimmune pulmonary alveolar 1456 Atypical coarctation of aorta 0.17 BP * 747 0.04 I proteinosis Atypical dentin dysplasia due to 314721 4 Cases Autoinflammation-PLCG2- SMOC2 deficiency 324530 associated antibody deficiency- 2 Cases 289863 Atypical glycine encephalopathy 20 Cases immune dysregulation Atypical hemolytic-uremic Autoinflammatory syndrome with 2134 1.0 P * syndrome 329173 pyogenic bacterial infection and 3 Cases Atypical hemolytic-uremic amylopectinosis 357008 13 Cases syndrome with DGKE deficiency 33110 Autosomal agammaglobulinemia 100 Cases Atypical hypotonia-cystinuria 238523 2 Cases Autosomal dominant adult-onset syndrome 209335 0.1 P * proximal spinal muscular atrophy 391411 Atypical juvenile parkinsonism 6 Families Autosomal dominant aplasia and 314399 6 Cases 86797 Atypical lichen myxedematosus 20 Cases myelodysplasia Autosomal dominant cerebellar 99 2.7 P 314466 Atypical Meigs syndrome 9 Cases ataxia Auricular abnormalities-cleft lip Autosomal dominant cerebellar 77300 with or without cleft palate-ocular 2 Cases 314404 ataxia-deafness-narcolepsy 24 Cases abnormalities syndrome syndrome 137888 Auriculocondylar syndrome 50 Cases Autosomal dominant Charcot- 487814 Marie-Tooth disease type 2 due to 2 Cases 114 2 Families Auriculoosteodysplasia DGAT2 mutation Autism spectrum disorder due to 352490 60 Cases Autosomal dominant Charcot- AUTS2 deficiency 435819 Marie-Tooth disease type 2 due to 2 Cases Autism spectrum disorder-epilepsy- TFG mutation 370943 8 Cases arthrogryposis syndrome Autosomal dominant Charcot- Autism-epilepsy syndrome due to 401964 Marie-Tooth disease type 2 with 2 Families 308410 branched chain ketoacid 5 Families giant axons dehydrogenase kinase deficiency Autosomal dominant Charcot- 99946 1 Family Autism-facial port-wine stain Marie-Tooth disease type 2A1 137911 4 Cases syndrome Autosomal dominant Charcot- 99938 44 Cases Autoerythrocyte sensitization Marie-Tooth disease type 2D 324636 170 Cases syndrome Autosomal dominant Charcot- 521414 51 Cases Autoimmune encephalopathy with Marie-Tooth disease type 2DD 420789 parasomnia and obstructive sleep 10 Cases Autosomal dominant Charcot- 99940 5 Families apnea Marie-Tooth disease type 2F Autoimmune enteropathy and Autosomal dominant Charcot- 99941 1 Family 391487 endocrinopathy-susceptibility to 5 Cases Marie-Tooth disease type 2G chronic infections syndrome Autosomal dominant Charcot- 99944 30 Cases 98375 Autoimmune hemolytic anemia 2.02 I * Marie-Tooth disease type 2K Autosomal dominant Charcot- Autoimmune hemolytic anemia- 99945 1 Family autoimmune thrombocytopenia- Marie-Tooth disease type 2L 444463 6 Cases Autosomal dominant Charcot- primary immunodeficiency 228179 20 Cases syndrome Marie-Tooth disease type 2M Autosomal dominant Charcot- 2137 Autoimmune hepatitis 23.5 P 228174 28 Cases Marie-Tooth disease type 2N 2137 Autoimmune hepatitis 1.2 I Autosomal dominant Charcot- 329258 8 Cases Autoimmune interstitial lung Marie-Tooth disease type 2Q 444092 5 Families disease-arthritis syndrome Autosomal dominant Charcot- 397735 2 Cases Autoimmune lymphoproliferative Marie-Tooth disease type 2U 3261 500 Cases syndrome Autosomal dominant Charcot- 447964 21 Cases Autoimmune lymphoproliferative Marie-Tooth disease type 2V 436159 syndrome due to CTLA4 17 Cases Autosomal dominant Charcot- 488333 24 Cases haploinsuffiency Marie-Tooth disease type 2W Autoimmune lymphoproliferative Autosomal dominant Charcot- 435387 7 Cases 275517 syndrome with recurrent viral 1 Family Marie-Tooth disease type 2Y infections Autosomal dominant Charcot- 466768 21 Cases Marie-Tooth disease type 2Z

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families Autosomal dominant multiple 90348 Autosomal dominant cutis laxa 50 Cases 65743 4 Cases pterygium syndrome Autosomal dominant deafness- 79499 22 Cases Autosomal dominant onychodystrophy syndrome 99846 2 Families myoglobinuria Autosomal dominant distal axonal Autosomal dominant myopia- 476093 motor neuropathy-myofibrillar 8 Cases midfacial retrusion-sensorineural myopathy syndrome 440354 1 Family hearing loss-rhizomelic dysplasia Autosomal dominant focal 329466 28 Cases syndrome dystonia, DYT25 type Autosomal dominant neovascular Autosomal dominant focal non- 329211 99 Cases inflammatory vitreoretinopathy 402003 epidermolytic palmoplantar 21 Cases Autosomal dominant nocturnal keratoderma with plantar blistering 98784 100 Families frontal lobe epilepsy Autosomal dominant hyper-IgE 2314 0.1 I * syndrome 98672 Autosomal dominant optic atrophy 3.3 P Autosomal dominant hypohidrotic Autosomal dominant optic atrophy 1810 40 Cases 67036 3 Families ectodermal dysplasia and cataract Autosomal dominant Autosomal dominant optic atrophy 89937 100 Cases 1215 0.4 P * hypophosphatemic rickets plus syndrome Autosomal dominant intellectual Autosomal dominant optic atrophy, 98673 2.0 P 457193 disability-craniofacial anomalies- 16 Cases classic form cardiac defects syndrome Autosomal dominant osteopetrosis 2783 33 Cases Autosomal dominant intermediate type 1 100043 20 Cases Charcot-Marie-Tooth disease type A Autosomal dominant palmoplantar Autosomal dominant intermediate 1010 keratoderma and congenital 10 Cases 100044 37 Cases Charcot-Marie-Tooth disease type B alopecia Autosomal dominant intermediate Autosomal dominant polycystic 100045 35 Cases 730 3.96 P * Charcot-Marie-Tooth disease type C kidney disease Autosomal dominant intermediate Autosomal dominant polycystic 100046 12 Cases Charcot-Marie-Tooth disease type D 88924 kidney disease type 1 with tuberous 30 Cases Autosomal dominant intermediate sclerosis 93114 21 Cases Charcot-Marie-Tooth disease type E Autosomal dominant popliteal 1300 0.3 P Autosomal dominant intermediate pterygium syndrome 352670 8 Cases Charcot-Marie-Tooth disease type F Autosomal dominant preaxial Autosomal dominant intermediate 476119 polydactyly-upperback 1 Family 324585 Charcot-Marie-Tooth disease with 9 Cases hypertrichosis syndrome neuropathic pain Autosomal dominant primary Autosomal dominant limb-girdle 34528 hypomagnesemia with 28 Cases 266 4 Families muscular dystrophy type 1A hypocalciuria Autosomal dominant limb-girdle Autosomal dominant progressive 34516 6 Families 88659 14 Cases muscular dystrophy type 1D nephropathy with hypertension Autosomal dominant limb-girdle Autosomal dominant proximal 34517 20 Families 314889 1 Family muscular dystrophy type 1E renal tubular acidosis Autosomal dominant limb-girdle Autosomal dominant 55595 64 Cases muscular dystrophy type 1F 209867 rhegmatogenous retinal 38 Cases Autosomal dominant limb-girdle detachment 55596 2 Families muscular dystrophy type 1G Autosomal dominant Robinow 3107 100 Cases Autosomal dominant limb-girdle syndrome 238755 11 Cases muscular dystrophy type 1H Autosomal dominant slowed nerve 140481 1 Family Autosomal dominant conduction velocity 140957 100 Cases macrothrombocytopenia Autosomal dominant spastic ataxia 251282 53 Cases Autosomal dominant mendelian type 1 susceptibility to mycobacterial Autosomal dominant spastic 319581 68 Cases 100988 10 Families diseases due to partial IFNgammaR1 paraplegia type 6 deficiency Autosomal dominant spastic 100989 10 Families Autosomal dominant mendelian paraplegia type 8 susceptibility to mycobacterial Autosomal dominant spastic 319589 2 Cases 447753 2 Families diseases due to partial IFNgammaR2 paraplegia type 9A deficiency Autosomal dominant spastic 447757 3 Families Autosomal dominant mitochondrial paraplegia type 9B 457050 15 Cases myopathy with exercise intolerance

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families Autosomal dominant spastic Autosomal recessive cerebellar 100991 10 Families 352641 10 Cases paraplegia type 10 ataxia with late-onset spasticity Autosomal dominant spastic Autosomal recessive cerebellar 100993 27 Cases paraplegia type 12 ataxia-epilepsy-intellectual 404499 2 Cases Autosomal dominant spastic disability syndrome due to RUBCN 100994 10 Cases paraplegia type 13 deficiency Autosomal dominant spastic Autosomal recessive cerebellar 100998 20 Families paraplegia type 17 ataxia-epilepsy-intellectual 404493 3 Cases Autosomal dominant spastic disability syndrome due to TUD 100999 1 Family paraplegia type 19 deficiency Autosomal dominant spastic Autosomal recessive cerebellar 101009 1 Family paraplegia type 29 363429 ataxia-pyramidal signs-nystagmus- 17 Cases Autosomal dominant spastic oculomotor apraxia syndrome 320365 1 Family Autosomal recessive cerebellar paraplegia type 36 95434 1 Family Autosomal dominant spastic ataxia-saccadic intrusion syndrome 171612 13 Cases Autosomal recessive cerebral paraplegia type 37 363969 4 Cases Autosomal dominant spastic atrophy 171617 1 Family Autosomal recessive Charcot- paraplegia type 38 466775 29 Cases Autosomal dominant spastic Marie-Tooth disease type 2X 320355 7 Cases paraplegia type 41 Autosomal recessive complex Autosomal dominant spastic 506353 spastic paraplegia due to Kennedy 4 Cases 171863 1 Family paraplegia type 42 pathway dysfunction Autosomal dominant spastic Autosomal recessive congenital 444099 1 Family paraplegia type 73 363432 cerebellar ataxia due to GRID2 7 Cases deficiency Autosomal dominant striatal 228169 11 Cases neurodegeneration Autosomal recessive congenital 324262 cerebellar ataxia due to MGLUR1 10 Cases Autosomal dominant deficiency 466806 thrombocytopenia with platelet 4 Families Autosomal recessive congenital secretion defect 281097 0.5 P * ichthyosis Autosomal dominant 34149 0.11 P * Autosomal recessive cutis laxa type tubulointerstitial kidney disease 90349 60 Cases 1 Autosomal dominant 3086 3 Cases Autosomal recessive cutis laxa type vitreoretinochoroidopathy 90350 40 Cases 2 Autosomal erythropoietic 79278 0.92 P * Autosomal recessive dopa- protoporphyria 101150 50 Cases responsive dystonia Autosomal erythropoietic 79278 0.012 I * Autosomal recessive protoporphyria 1974 26 Cases faciodigitogenital syndrome 1027 Autosomal recessive amelia 3 Cases Autosomal recessive Autosomal recessive ataxia due to 329329 7 Cases 247815 6 Cases frontotemporal pachygyria PEX10 deficiency Autosomal recessive infantile Autosomal recessive ataxia due to 300547 12 Cases 139485 31 Cases hypercalcemia ubiquinone deficiency Autosomal recessive intermediate Autosomal recessive ataxia, Beauce 217055 8 Families 88644 57 Cases Charcot-Marie-Tooth disease type A type Autosomal recessive intermediate 254334 1 Case Autosomal recessive axonal Charcot-Marie-Tooth disease type B 521411 Charcot-Marie-Tooth disease due to 2 Cases Autosomal recessive intermediate 369867 3 Cases copper metabolism defect Charcot-Marie-Tooth disease type C Autosomal recessive axonal Autosomal recessive intermediate 324442 33 Families 435998 4 Cases neuropathy with neuromyotonia Charcot-Marie-Tooth disease type D Autosomal recessive Autosomal recessive isolated optic 139455 20 Cases 98676 5 Cases bestrophinopathy atrophy 448242 Autosomal recessive brachyolmia 20 Cases Autosomal recessive Autosomal recessive cerebellar leukoencephalopathy-ischemic 1172 3.3 P 314572 3 Cases ataxia stroke-retinitis pigmentosa Autosomal recessive cerebellar syndrome 453521 2 Cases Autosomal recessive limb-girdle ataxia due to CWF19L1 deficiency 267 1.0 P * Autosomal recessive cerebellar muscular dystrophy type 2A 412057 10 Families Autosomal recessive limb-girdle ataxia due to STUB1 deficiency 353 0.2 P * muscular dystrophy type 2C

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families Autosomal recessive limb-girdle Autosomal recessive optic atrophy, 119 0.1 P * 227976 17 Cases muscular dystrophy type 2E OPA7 type Autosomal recessive limb-girdle Autosomal recessive palmoplantar 219 0.3 P * muscular dystrophy type 2F 1366 keratoderma and congenital 8 Cases Autosomal recessive limb-girdle alopecia 34514 16 Cases muscular dystrophy type 2G Autosomal recessive polycystic 731 1.17 P * Autosomal recessive limb-girdle kidney disease 34515 1.0 P * muscular dystrophy type 2I Autosomal recessive primary Autosomal recessive limb-girdle immunodeficiency with defective 140922 1 Family 437552 3 Cases muscular dystrophy type 2J spontaneous natural killer cell Autosomal recessive limb-girdle cytotoxicity 206554 5 Families muscular dystrophy type 2M Autosomal recessive Robinow 1507 100 Cases Autosomal recessive limb-girdle syndrome 206559 1 Case muscular dystrophy type 2N Autosomal recessive severe Autosomal recessive limb-girdle 420702 congenital neutropenia due to 4 Cases 206564 2 Cases muscular dystrophy type 2O CSF3R deficiency Autosomal recessive limb-girdle Autosomal recessive severe 280333 1 Case muscular dystrophy type 2P 420699 congenital neutropenia due to 2 Cases Autosomal recessive limb-girdle CXCR2 deficiency 254361 6 Cases muscular dystrophy type 2Q Autosomal recessive severe Autosomal recessive limb-girdle 331176 congenital neutropenia due to 57 Cases 363543 2 Cases muscular dystrophy type 2R G6PC3 deficiency Autosomal recessive limb-girdle Autosomal recessive severe 369840 3 Cases muscular dystrophy type 2S 423384 congenital neutropenia due to 14 Cases JAGN1 deficiency Autosomal recessive limb-girdle 363623 2 Cases Autosomal recessive spastic ataxia muscular dystrophy type 2T 314603 54 Cases with leukoencephalopathy Autosomal recessive limb-girdle 352479 8 Cases Autosomal recessive spastic ataxia- muscular dystrophy type 2U 254343 6 Cases optic atrophy-dysarthria syndrome Autosomal recessive limb-girdle 466801 2 Cases Autosomal recessive spastic muscular dystrophy type 2W 447760 2 Families paraplegia type 9B Autosomal recessive limb-girdle 476084 3 Cases Autosomal recessive spastic muscular dystrophy type 2X 100995 1 Family paraplegia type 14 Autosomal recessive limb-girdle 424261 3 Cases Autosomal recessive spastic muscular dystrophy type 2Y 100996 10 Families paraplegia type 15 Autosomal recessive limb-girdle 480682 4 Cases Autosomal recessive spastic muscular dystrophy type 2Z 209951 9 Cases paraplegia type 18 Autosomal recessive lower motor Autosomal recessive spastic 206580 neuron disease with childhood 5 Cases 101000 36 Cases onset paraplegia type 20 Autosomal recessive Autosomal recessive spastic 238505 17 Cases 101001 35 Cases lymphoproliferative disease paraplegia type 21 Autosomal recessive malignant Autosomal recessive spastic 667 0.75 BP * 101003 5 Families osteopetrosis paraplegia type 23 Autosomal recessive spastic Autosomal recessive mendelian 101004 1 Family susceptibility to mycobacterial paraplegia type 24 477857 7 Cases Autosomal recessive spastic diseases due to complete 101005 1 Family RORgamma receptor deficiency paraplegia type 25 Autosomal recessive spastic Autosomal recessive mendelian 101006 10 Families susceptibility to mycobacterial paraplegia type 26 319569 18 Cases Autosomal recessive spastic diseases due to partial IFNgammaR1 101007 10 Cases deficiency paraplegia type 27 Autosomal recessive spastic Autosomal recessive mendelian 101008 7 Cases susceptibility to mycobacterial paraplegia type 28 319574 6 Cases diseases due to partial IFNgammaR2 Autosomal recessive spastic 171622 1 Family deficiency paraplegia type 32 Autosomal recessive myogenic Autosomal recessive spastic 319332 1 Family 171629 38 Cases arthrogryposis multiplex congenita paraplegia type 35 Autosomal recessive spastic 280654 Autosomal recessive nail dysplasia 4 Cases 139480 2 Families paraplegia type 39 93329 Autosomal recessive omodysplasia 23 Cases

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families Autosomal recessive spastic Autosomal recessive Stickler 320370 2 Cases 250984 15 Cases paraplegia type 43 syndrome Autosomal recessive spastic Autosomal semi-dominant severe 320401 3 Cases 280365 7 Cases paraplegia type 44 lipodystrophic laminopathy Autosomal recessive spastic Autosomal spastic paraplegia type 320396 7 Families 101010 3 Families paraplegia type 45 30 Autosomal recessive spastic Autosomal spastic paraplegia type 320391 5 Cases 397946 19 Cases paraplegia type 46 58 Autosomal recessive spastic Autosomal spastic paraplegia type 306511 2 Cases 401849 14 Cases paraplegia type 48 72 Autosomal recessive spastic Autosomal systemic lupus 319199 9 Cases 300345 7 Families paraplegia type 53 erythematosus Autosomal recessive spastic 320380 6 Families 454836 Avian influenza 826 Cases paraplegia type 54 Autosomal recessive spastic 782 Axenfeld-Rieger syndrome 0.5 P * 320375 14 Cases paraplegia type 55 Axial spondylometaphyseal 168549 13 Cases Autosomal recessive spastic dysplasia 320411 5 Families paraplegia type 56 AXIN2-related attenuated familial 401911 4 Families Autosomal recessive spastic adenomatous polyposis 431329 2 Cases paraplegia type 57 1272 Aymé-Gripp syndrome 18 Cases Autosomal recessive spastic 401795 3 Cases 79332 B4GALT1-CDG 1 Case paraplegia type 59 Autosomal recessive spastic 67038 B-cell chronic lymphocytic leukemia 48.0 P * 401800 1 Case paraplegia type 60 171915 B-cell non-Hodgkin lymphoma 17.45 I * Autosomal recessive spastic 401780 4 Cases paraplegia type 61 86852 B-cell prolymphocytic leukemia 0.05 I * Autosomal recessive spastic 401785 7 Cases 36234 Bacterial toxic-shock syndrome 3.0 P paraplegia type 62 Autosomal recessive spastic 93395 Ballard syndrome 12 Cases 401805 2 Cases paraplegia type 63 1225 Baller-Gerold syndrome 40 Cases Autosomal recessive spastic 401810 4 Cases paraplegia type 64 1226 Bamforth-Lazarus syndrome 8 Cases Autosomal recessive spastic 1227 2 Cases 401815 2 Cases Bangstad syndrome paraplegia type 66 1228 Banki syndrome 1 Family Autosomal recessive spastic 401820 2 Cases Baraitser-Winter paraplegia type 67 2995 60 Cases Autosomal recessive spastic cerebrofrontofacial syndrome 401830 2 Cases paraplegia type 69 1231 Barber-Say syndrome 16 Cases Autosomal recessive spastic 401835 4 Cases 110 Bardet-Biedl syndrome 0.7 P * paraplegia type 70 Autosomal recessive spastic 110 Bardet-Biedl syndrome 0.5 BP * 401840 1 Case paraplegia type 71 111 Barth syndrome 0.22 P * Autosomal recessive spastic 468661 11 Cases paraplegia type 74 1234 Bartsocas-Papas syndrome 24 Cases Autosomal recessive spastic 459056 5 Cases 112 Bartter syndrome 0.1 I * paraplegia type 75 100976 20 Cases Autosomal recessive spastic Bathing suit ichthyosis 488594 7 Families paraplegia type 76 166113 Bazex syndrome 145 Cases Autosomal recessive spastic 466722 8 Cases 113 Bazex-Dupré-Christol syndrome 143 Cases paraplegia type 77 Autosomal recessive spastic 98895 Becker muscular dystrophy 1.53 P 513436 7 Cases paraplegia type 78 98895 Becker muscular dystrophy 2.2 BP * Autosomal recessive 95433 spinocerebellar ataxia-blindness- 3 Families 116 Beckwith-Wiedemann syndrome 3.5 BP * deafness syndrome 1237 Beemer-Ertbruggen syndrome 2 Cases Autosomal recessive 401979 spondylometaphyseal dysplasia, 4 Cases 1241 Bencze syndrome 2 Families Mégarbané type Benign concentric annular macular 251287 27 Cases dystrophy

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families Blepharonasofacial malformation 1949 Benign familial neonatal epilepsy 100 Families 1252 3 Families syndrome Benign familial neonatal-infantile 140927 10 Families Blepharophimosis-epicanthus seizures 126 2.0 P inversus-ptosis syndrome Benign infantile focal epilepsy with Blepharophimosis-intellectual 166308 midline spikes and waves during 36 Cases 293642 58 Cases sleep disability syndrome Blepharophimosis-intellectual Benign infantile seizures associated 2728 30 Cases 166305 100 Cases disability syndrome, Ohdo type with mild gastroenteritis Blepharophimosis-intellectual Benign nocturnal alternating 3047 20 Cases 209973 12 Cases disability syndrome, SBBYS type hemiplegia of childhood Blepharophimosis-ptosis-esotropia- Benign paroxysmal tonic upgaze of 2057 6 Cases 1179 12 Cases syndactyly-short stature syndrome childhood with ataxia Blepharoptosis-myopia-ectopia Benign paroxysmal torticollis of 1259 3 Cases 71518 50 Cases lentis syndrome infancy Blindness-scoliosis-arachnodactyly Benign Samaritan congenital 171844 4 Cases 324581 4 Cases syndrome myopathy Blomstrand lethal 50945 13 Cases 252164 Benign schwannoma 6.0 P * chondrodysplasia 464336 BENTA disease 8 Cases 125 Bloom syndrome 400 Cases Berardinelli-Seip congenital 528 0.5 P * 16 Blue cone monochromatism 1.0 P lipodystrophy 16 Blue cone monochromatism 1.0 BP 274 Bernard-Soulier syndrome 100 Cases 1059 Blue rubber bleb nevus 200 Cases 118 Beta-mannosidosis 0.14 BP * Beta-mercaptolactate cysteine 217266 BNAR syndrome 9 Families 1035 1 Case disulfiduria 217008 Bockenheimer syndrome 40 Cases Beta-propeller protein-associated 329284 68 Cases Body skin hyperlaxity due to neurodegeneration 91135 vitamin K-dependent coagulation 11 Cases 848 Beta-thalassemia 1.0 I factor deficiency 65287 Beta-ureidopropionase deficiency 5 Cases 97297 Bohring-Opitz syndrome 30 Cases BICD2-related autosomal dominant Bone dysplasia, lethal Holmgren 1842 7 Cases 363454 childhood-onset proximal spinal 60 Cases type muscular atrophy 223727 Bone sarcoma 9.29 P * Bilateral acute depigmentation of 69736 62 Cases the iris 223727 Bone sarcoma 0.8 I * Bilateral microtia-deafness-cleft Bonnemann-Meinecke-Reich 140963 3 Families 1261 4 Cases palate syndrome syndrome Bilateral striopallidodentate 1980 200 Cases 1262 Böök syndrome 26 Cases calcinosis 1263 Boomerang dysplasia 10 Cases 79241 Biotinidase deficiency 1.6 P * Borjeson-Forssman-Lehmann 127 50 Cases 79241 Biotinidase deficiency 1.6 BP syndrome 364198 Bipartite talus 23 Cases 69737 Bosley-Salih-Alorainy syndrome 16 Cases 179 Birdshot chorioretinopathy 0.35 P 1267 Botulism 0.022 I * 122 Birt-Hogg-Dubé syndrome 0.5 P * 1270 Bowen-Conradi syndrome 60 Cases 123 Björnstad syndrome 33 Cases 93389 Brachydactyly type A5 2 Families 124 Blackfan-Diamond anemia 0.67 BP * 93382 Brachydactyly type A6 7 Cases 93930 Bladder exstrophy 3.05 BP 93397 Brachydactyly type A7 1 Family Bleeding diathesis due to a collagen Brachydactyly-arterial 73271 20 Cases 1276 10 Families receptor defect hypertension syndrome Bleeding disorder due to CalDAG- Brachydactyly-elbow wrist 420566 3 Cases 1275 4 Families GEFI deficiency dysplasia syndrome Bleeding disorder due to P2Y12 Brachydactyly-long thumb 36355 14 Cases 2946 4 Cases defect syndrome 1997 Blepharo-cheilo-odontic syndrome 50 Cases

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families Brachydactyly-mesomelia- 1308 C syndrome 0.11 P * 1277 intellectual disability-heart defects 2 Cases C11ORF73-related autosomal syndrome 495844 recessive hypomyelinating 6 Cases Brachydactyly-nystagmus- 1246 1 Family leukodystrophy cerebellar ataxia syndrome C12ORF65-related combined Brachydactyly-preaxial hallux varus 497623 30 Cases 1278 8 Cases oxidative phosphorylation defect syndrome Brachydactyly-short stature- 135 CACH syndrome 148 Cases 166035 12 Cases retinitis pigmentosa syndrome 448010 CAD-CDG 1 Case Brachydactyly-syndactyly, Zhao 93409 2 Families 136 CADASIL 3.0 P * type Brachymorphism-onychodysplasia- 369942 CADDS 4 Cases 1292 9 Cases dysphalangism syndrome 1310 Caffey disease 100 Cases 1293 Brachyolmia 100 Cases 280062 Calciphylaxis 5.0 P * 93302 Brachyolmia, Maroteaux type 4 Families Calvarial doughnut lesions-bone Brachytelephalangy-dysmorphism- 85192 20 Cases 1295 2 Cases fragility syndrome Kallmann syndrome 83472 CAMOS syndrome 5 Cases 52047 Braddock syndrome 2 Cases 1318 Campomelia, Cumming type 8 Cases 75374 Bradyopsia 5 Cases 140 Campomelic dysplasia 0.33 BP * 178506 Brain calcification, Rajab type 8 Cases 1319 Camptobrachydactyly 1 Family Brain demyelination due to Camptodactyly syndrome, 168598 methionine adenosyltransferase 2 Cases 1327 8 Cases deficiency Guadalajara type 1 Brain dopamine-serotonin vesicular Camptodactyly syndrome, 352649 8 Cases 1326 2 Cases transport disease Guadalajara type 2 Camptodactyly syndrome, Brain malformation-congenital 488434 5 Cases 75389 heart disease-postaxial polydactyly 2 Cases Guadalajara type 3 Camptodactyly-arthropathy-coxa- syndrome 2848 30 Families Brain malformations- vara-pericarditis syndrome musculoskeletal abnormalities- Camptodactyly-fibrous tissue 500150 29 Cases facial dysmorphism-intellectual 1321 hyperplasia-skeletal dysplasia 3 Cases disability syndrome syndrome Camptodactyly-joint contractures- 209905 Brain-lung-thyroid syndrome 100 Cases 1323 4 Cases facial skeletal defects syndrome 1297 Branchio-oculo-facial syndrome 150 Cases Camptodactyly-tall stature- 85164 30 Cases 50815 Branchiogenic deafness syndrome 5 Cases scoliosis-hearing loss syndrome Camptodactyly-taurinuria 1325 17 Cases 1299 Branchioskeletogenital syndrome 7 Cases syndrome 85284 BRESEK syndrome 5 Cases 1328 Camurati-Engelmann disease 300 Cases 90354 Brittle cornea syndrome 65 Cases 141 Canavan disease 1.0 BP 70589 Bronchopulmonary dysplasia 13.0 P * 325004 CANDLE syndrome 30 Cases 79493 Brooke-Spiegler syndrome 100 Cases 171881 Cap myopathy 21 Cases 1304 Brucellosis 0.1 I * 160148 Cap polyposis 67 Cases Capillary malformation- 2771 Bruck syndrome 60 Cases 137667 261 Cases arteriovenous malformation 130 Brugada syndrome 20.0 P * Carbamoyl-phosphate synthetase 1 147 0.31 P 131 Budd-Chiari syndrome 1.5 P * deficiency 36258 Buerger disease 16.0 P 70482 Carcinoma of esophagus 9.8 P Bullous diffuse cutaneous 70482 Carcinoma of esophagus 7.0 I 280785 40 Cases mastocytosis Carcinoma of esophagus, salivary 418945 0.01 I * 703 Bullous pemphigoid 26.0 P * gland type Carcinoma of gallbladder and 543 Burkitt lymphoma 0.17 I * 56044 12.0 I extrahepatic biliary tract 1306 Buschke-Ollendorff syndrome 5.0 I

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families Carcinoma of stomach, salivary Cataract-intellectual disability-anal 423781 0.01 I * 1381 3 Cases gland type atresia-urinary defects syndrome Cardiac anomalies-heterotaxy Cataract-intellectual disability- 137628 9 Cases 1387 20 Cases syndrome hypogonadism syndrome Cardiocranial syndrome, Pfeiffer 2872 7 Cases 1377 Cataract-microcornea syndrome 8 Families type Cataract-nephropathy- 1380 2 Cases 1340 Cardiofaciocutaneous syndrome 300 Cases encephalopathy syndrome Catecholaminergic polymorphic 97292 Cardiogenic shock 40.0 P * 3286 10.0 P * ventricular tachycardia Cardiomyopathy-cataract-hip spine 1345 9 Cases disease syndrome 1388 Catel-Manzke syndrome 33 Cases Cardiomyopathy-hypotonia-lactic Caudal appendage-deafness 91130 2 Cases 1123 2 Cases acidosis syndrome syndrome Cardiomyopathy-renal anomalies 90022 2 Cases 468684 CCDC115-CDG 8 Cases syndrome CD4+/CD56+ hematodermic Cardiospondylocarpofacial 86870 12.0 P * 3238 5 Cases neoplasm syndrome 66631 CEDNIK syndrome 13 Cases 1358 Carey-Fineman-Ziter syndrome 20 Cases Celiac disease-epilepsy-cerebral 1459 170 Cases 1359 Carney complex 160 Cases calcification syndrome Carney complex-trismus- 319340 3 Families 3258 Cenani-Lenz syndrome 30 Cases pseudocamptodactyly syndrome 2431 Central bilateral macrogyria 4 Cases 139411 Carney triad 150 Cases Central cloudy dystrophy of 98972 24 Cases 97286 Carney-Stratakis syndrome 20 Families François Carnitine palmitoyl transferase 1A 156 60 Cases 178029 Central diabetes insipidus 4.0 P * deficiency Central nervous system Carnitine palmitoyl transferase II 228302 300 Cases 3240 calcification-deafness-tubular 2 Cases deficiency, myopathic form acidosis-anemia syndrome Carnitine palmitoyl transferase II 228308 20 Families Central nervous system primitive deficiency, neonatal form 251870 0.07 I * neuroectodermal tumor Carnitine palmitoyl transferase II 228305 30 Families deficiency, severe infantile form 73256 Central neurocytoma 500 Cases Carnitine palmitoyltransferase II 411527 Central retinal vein occlusion 28.0 P * 157 1.0 P * deficiency Centripetalis recessive dystrophic Carnitine-acylcarnitine translocase 89841 10 Cases 159 60 Cases epidermolysis bullosa deficiency Cerebellar ataxia-areflexia-pes 1361 Carnosinase deficiency 0.2 BP 1171 cavus-optic atrophy-sensorineural 10 Cases hearing loss syndrome 53035 Caroli disease 0.1 I Cerebellar hypoplasia-tapetoretinal 2246 3 Cases 65759 Carpenter syndrome 70 Cases degeneration syndrome 93973 Carpenter-Waziri syndrome 6 Cases 444072 Cerebellar-facial-dental syndrome 3 Families Cerebral arteriovenous 65282 Carvajal syndrome 7 Cases 46724 6.0 P * malformation 195 Cat-eye syndrome 1.35 BP * Cerebral gigantism-jaw cysts 2081 9 Cases 50839 Cat-scratch disease 6.6 P * syndrome Cataract-aberrant oral frenula- 329217 Cerebral sinovenous thrombosis 0.35 I * 1373 3 Cases growth delay syndrome 1393 Cerebrocostomandibular syndrome 75 Cases 1368 Cataract-ataxia-deafness syndrome 2 Cases 314679 Cerebrofacioarticular syndrome 9 Cases Cataract-congenital heart disease- 314993 2 Cases neural tube defect syndrome 1394 Cerebrofaciothoracic dysplasia 20 Cases Cataract-deafness-hypogonadism 1383 3 Cases 66625 Cerebrooculonasal syndrome 21 Cases syndrome 169079 Cernunnos-XLF deficiency 5 Cases 162 Cataract-glaucoma syndrome 3 Families Cervical hypertrichosis-peripheral 2218 4 Cases Cataract-growth hormone neuropathy syndrome deficiency-sensory neuropathy- 436174 3 Cases Channelopathy-associated sensorineural hearing loss-skeletal 88642 20 Cases congenital insensitivity to pain dysplasia syndrome

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families 46627 Char syndrome 10 Cases Childhood-onset progressive 466921 contractures-limb-girdle weakness- 3 Families 65753 Charcot-Marie-Tooth disease type 1 17.5 P muscle dystrophy syndrome Charcot-Marie-Tooth disease type Childhood-onset spasticity with 101101 1 Family 401866 3 Cases 2B2 hyperglycinemia Charcot-Marie-Tooth disease type 228374 4 Cases 3474 CHIME syndrome 8 Cases 2B5 Charcot-Marie-Tooth disease type 137914 Choanal atresia 8.6 BP * 101102 13 Cases 2H Choanal atresia-hearing loss- Charcot-Marie-Tooth disease type 1200 cardiac defects-craniofacial 11 Families 300319 18 Cases 2P dysmorphism syndrome Charcot-Marie-Tooth disease type 397968 1 Case 70567 Cholangiocarcinoma 2.1 P 2R 70567 Cholangiocarcinoma 4.2 I Charcot-Marie-Tooth disease type 443073 35 Cases 2S 173 Cholera 0.01 I * Charcot-Marie-Tooth disease type 495274 10 Cases 1414 Cholestasis-lymphedema syndrome 47 Cases 2T Charcot-Marie-Tooth disease type Cholestasis-pigmentary 99955 11 Families 1415 5 Cases 4B1 retinopathy-cleft palate syndrome Charcot-Marie-Tooth disease type Chondrodysplasia punctata, 363981 3 Cases 79347 3 Cases 4B3 Toriello type Charcot-Marie-Tooth disease type Chondrodysplasia with joint 99954 15 Cases 280586 4 Cases 4H dislocations, gPAPP type Charcot-Marie-Tooth disease type Chondrodysplasia-disorder of sex 139515 18 Cases 1422 2 Cases 4J development syndrome Chondroectodermal dysplasia with Charcot-Marie-Tooth disease- 319195 4 Cases 90103 deafness-intellectual disability 7 Cases night blindness syndrome 404507 Chondromyxoid fibroma 50 Cases Charcot-Marie-Tooth 55880 Chondrosarcoma 0.24 I * 166 disease/Hereditary motor and 25.0 P * sensory neuropathy 251899 Choroid plexus carcinoma 0.01 I * Choroidal atrophy-alopecia 138 CHARGE syndrome 6.5 BP 1433 2 Cases syndrome 1406 Charlie M syndrome 4 Cases 180 Choroideremia 2.0 P * 167 Chédiak-Higashi syndrome 500 Cases Choroideremia-deafness-obesity 1435 4 Cases 1221 Cheilitis glandularis 100 Cases syndrome Choroideremia-hypopituitarism 184 Cherubism 300 Cases 1434 2 Cases syndrome 324625 Chikungunya 0.08 I * 85278 Christianson syndrome 30 Cases 90280 Chilblain lupus 70 Cases 319303 Chromophobe renal cell carcinoma 0.01 I * 139 CHILD syndrome 60 Cases Chronic atrial and intestinal 435988 17 Cases dysrhythmia syndrome 209908 Childhood apraxia of speech 22 Cases Chronic diarrhea due to guanylate 314373 32 Cases 168782 Childhood disintegrative disorder 2.0 P * cyclase 2C overactivity Childhood encephalopathy due to Chronic diarrhea with villous 1670 2 Cases 293955 thiamine pyrophosphokinase 5 Cases atrophy deficiency Chronic enteropathy associated 468641 18 Cases Childhood-onset autosomal with SLCO2A1 gene 363677 recessive myopathy with external 22 Cases 379 Chronic granulomatous disease 0.46 BP ophthalmoplegia Childhood-onset basal ganglia 396 Chronic hiccup 1.0 P * 497906 4 Cases degeneration syndrome Chronic inflammatory 2932 3.7 P * Childhood-onset benign chorea demyelinating polyneuropathy 494541 3 Cases with striatal involvement 521 Chronic myeloid leukemia 6.0 P * Childhood-onset motor and 500180 cognitive regression syndrome with 7 Cases 521 Chronic myeloid leukemia 1.25 I * extrapyramidal movement disorder 98823 Chronic myelomonocytic leukemia 0.29 I *

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families Chronic myeloproliferative disease, Classic Hodgkin lymphoma, nodular 86830 0.53 I * 98843 1.28 I * unclassifiable sclerosis type Chronic nonbacterial 394 Classic homocystinuria 1.65 P * 324964 osteomyelitis/Chronic recurrent 0.3 P multifocal osteomyelitis 394 Classic homocystinuria 0.3 BP Chronic nonbacterial 2584 Classic mycosis fungoides 0.5 I * 324964 osteomyelitis/Chronic recurrent 2.5 I Classic neuroendocrine tumor of multifocal osteomyelitis 329977 0.25 I appendix Chronic pain requiring intraspinal 95426 12.0 P * CLCN4-related X-linked intellectual analgesia 485350 38 Cases disability syndrome Chronic primary adrenal 101959 14.0 P * Clear cell adenocarcinoma of the insufficiency 398971 0.32 I * ovary Chronic primary adrenal 101959 0.4 I * insufficiency 319276 Clear cell renal carcinoma 1.99 I * Chronic thromboembolic Cleft lip and palate-craniofacial 70591 3.0 P * pulmonary hypertension 508476 dysmorphism-congenital heart 7 Cases defect-hearing loss syndrome 263463 CHST3-related skeletal dysplasia 2 Families 1995 Cleft lip-retinopathy syndrome 2 Cases 93971 Chudley-Lowry-Hoar syndrome 3 Cases 199306 Cleft lip/palate 80.0 BP 314597 Chudley-McCullough syndrome 25 Cases Cleft lip/palate-deafness-sacral 2003 2 Cases 71 Chylomicron retention disease 55 Cases lipoma syndrome CIDEC-related familial partial Cleft lip/palate-intestinal 435651 1 Case 2001 5 Cases lipodystrophy malrotation-cardiopathy syndrome 1451 CINCA syndrome 200 Cases 2014 Cleft palate 53.6 BP * Circumscribed palmoplantar Cleft palate-large ears-small head 69744 17 Cases 2013 8 Cases hypokeratosis syndrome Cirrhosis-dystonia-polycythemia- Cleft palate-lateral synechia 309854 20 Cases 2016 11 Cases hypermanganesemia syndrome syndrome Cleft palate-short stature-vertebral 247525 Citrullinemia type I 2.4 P * 2015 2 Cases anomalies syndrome 251383 CK syndrome 24 Cases Cleft palate-stapes fixation- 2010 2 Cases 168984 CLAPO syndrome 6 Cases oligodontia syndrome Classic congenital adrenal 1452 Cleidocranial dysplasia 0.1 P 90794 hyperplasia due to 21-hydroxylase 7.0 P * 1452 Cleidocranial dysplasia 0.4 BP * deficiency Classic congenital adrenal 1453 Cleidorhizomelic syndrome 2 Cases 90794 hyperplasia due to 21-hydroxylase 7.0 BP 284448 CLIPPERS 50 Cases deficiency Classic congenital adrenal 228357 CLN9 disease 2 Cases 315306 hyperplasia due to 21-hydroxylase 7.5 P * 314629 CLN11 disease 2 Cases deficiency, salt wasting form 352709 4 Cases Classic congenital adrenal CLN13 disease 315306 hyperplasia due to 21-hydroxylase 7.5 BP * 93929 Cloacal exstrophy 0.54 BP deficiency, salt wasting form Cloverleaf skull-multiple congenital 93267 3 Cases Classic congenital adrenal anomalies syndrome 315311 hyperplasia due to 21-hydroxylase 2.5 P * deficiency, simple virilizing form 140944 CLOVES syndrome 100 Cases COASY protein-associated 79239 Classic galactosemia 2.1 I * 397725 2 Cases neurodegeneration 58017 Classic hairy cell leukemia 0.29 I * 53721 Cobb syndrome 45 Cases 391 Classic Hodgkin lymphoma 2.38 I * 51577 Cobblestone lissencephaly 1.0 BP * Classic Hodgkin lymphoma, 98846 0.04 I * Cobblestone lissencephaly without lymphocyte-depleted type 352682 4 Cases muscular or ocular involvement Classic Hodgkin lymphoma, 98845 0.1 I * lymphocyte-rich type 90068 Cocaine intoxication 1.0 P * Classic Hodgkin lymphoma, mixed Cochleosaccular degeneration- 98844 0.42 I * 3233 2 Families cellularity type cataract syndrome

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families Combined immunodeficiency due 191 Cockayne syndrome 0.2 BP * 431149 1 Case to OX40 deficiency 191 Cockayne syndrome 0.5 I * Combined immunodeficiency due 231154 9 Cases 1458 CODAS syndrome 12 Cases to partial RAG1 deficiency Combined immunodeficiency due 192 Coffin-Lowry syndrome 1.5 P 314689 7 Cases to STK4 deficiency 1465 Coffin-Siris syndrome 190 Cases Combined immunodeficiency due 476113 2 Families to TFRC deficiency 1466 COFS syndrome 20 Cases Combined immunodeficiency with 221139 2 Cases 263508 COG1-CDG 3 Cases faciooculoskeletal anomalies Combined oxidative 435934 COG2-CDG 1 Case 254920 1 Case phosphorylation defect type 2 263501 COG4-CDG 2 Cases Combined oxidative 254925 2 Cases 263487 COG5-CDG 9 Cases phosphorylation defect type 4 Combined oxidative 254930 7 Cases 464443 COG6-CGD 10 Cases phosphorylation defect type 7 Combined oxidative 79333 COG7-CDG 8 Cases 319504 7 Cases phosphorylation defect type 8 95428 COG8-CDG 2 Cases Combined oxidative 319509 4 Cases 1467 Cogan syndrome 300 Cases phosphorylation defect type 9 Combined oxidative Cognitive impairment-coarse 324535 32 Cases facies-heart defects-obesity- phosphorylation defect type 11 444077 3 Cases Combined oxidative pulmonary involvement-short 319514 2 Cases stature-skeletal dysplasia syndrome phosphorylation defect type 13 Combined oxidative 193 Cohen syndrome 200 Cases 319519 5 Cases phosphorylation defect type 14 31824 Colchicine poisoning 0.1 P * Combined oxidative 319524 16 Cases 157820 Cold-induced sweating syndrome 6 Cases phosphorylation defect type 15 Combined oxidative 369913 20 Families 2050 Cole-Carpenter syndrome 3 Cases phosphorylation defect type 17 Coloboma of macula-brachydactyly Combined oxidative 1471 10 Cases 420728 2 Cases type B syndrome phosphorylation defect type 20 Colobomatous macrophthalmia- Combined oxidative 468672 21 Cases 420733 2 Cases microcornea syndrome phosphorylation defect type 21 Colobomatous microphthalmia- Combined oxidative 424099 5 Families 444013 11 Cases rhizomelic dysplasia syndrome phosphorylation defect type 23 Colobomatous optic disc-macular Combined oxidative 444458 3 Cases 435930 atrophy-chorioretinopathy 3 Cases phosphorylation defect type 24 syndrome Combined oxidative 447954 2 Cases Combined deficiency of factor V phosphorylation defect type 25 35909 0.5 P * and factor VIII Combined oxidative 477684 2 Cases Combined hamartoma of the retina phosphorylation defect type 26 440727 120 Cases and retinal pigment epithelium Combined oxidative 477774 3 Cases Combined immunodeficiency due phosphorylation defect type 27 169090 10 Cases to CRAC channel dysfunction Combined oxidative 478029 1 Case Combined immunodeficiency due phosphorylation defect type 29 217390 11 Cases to DOCK8 deficiency Combined oxidative 478042 2 Cases Combined immunodeficiency due phosphorylation defect type 30 505227 5 Cases to GINS1 deficiency Combined pancreatic lipase- 309111 3 Cases Combined immunodeficiency due colipase deficiency 357329 6 Cases to IL21R deficiency Complement component 3 280133 27 Cases Combined immunodeficiency due deficiency 445018 23 Cases to LRBA deficiency Complete androgen insensitivity 99429 0.83 P Combined immunodeficiency due syndrome 397964 3 Cases to MALT1 deficiency Complete androgen insensitivity Combined immunodeficiency due 99429 3.0 I * 504530 7 Cases syndrome to Moesin deficiency 1329 Complete atrioventricular canal 20.0 BP * Combined immunodeficiency due 317428 6 Cases to ORAI1 deficiency 98949 Complete cryptophthalmia 15 Cases

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families Complex lethal 457378 6 Cases 2040 Congenital bronchobiliary fistula 35 Cases osteochondrodysplasia Congenital cataract-hearing loss- Complication after organ 306644 9.0 P * 300313 severe developmental delay 5 Cases transplantation syndrome 268316 Complication in hemodialysis 13.0 I * Congenital cataract-hypertrophic 458758 Composite hemangioendothelioma 39 Cases 1369 cardiomyopathy-mitochondrial 40 Cases myopathy syndrome 168966 Composite lymphoma 0.01 I * Congenital cataract-microcephaly- Conductive deafness-malformed 464738 nevus flammeus simplex-severe 7 Cases 3216 8 Cases external ear syndrome intellectual disability syndrome Conductive deafness-ptosis-skeletal Congenital cataract-progressive 3236 3 Cases anomalies syndrome 330054 muscular hypotonia-hearing loss- 3 Cases Cone dystrophy with supernormal developmental delay syndrome 209932 45 Cases rod response Congenital cataract-severe 521432 neonatal hepatopathy-global 2 Cases 1872 Cone rod dystrophy 2.5 P * developmental delay syndrome 221142 Confetti-like macular atrophy 2 Cases Congenital cataracts-facial Congenital absence of upper arm 48431 dysmorphism-neuropathy 170 Cases 294975 0.62 BP and forearm with hand present syndrome Congenital absence/hypoplasia of Congenital cerebellar ataxia due to 973 2 Families 512260 6 Cases fingers excluding thumb, unilateral RNU12 mutation Congenital chronic diarrhea with 418 Congenital adrenal hyperplasia 6.0 P * 329242 2 Cases protein-losing enteropathy 418 Congenital adrenal hyperplasia 6.7 BP * Congenital deficiency in alpha- 168612 22 Cases 418 Congenital adrenal hyperplasia 13.35 I * fetoprotein Congenital adrenal hyperplasia due 2140 Congenital diaphragmatic hernia 30.0 BP 90791 to 3-beta-hydroxysteroid 68 Cases 137 Congenital disorder of glycosylation 1.5 BP * dehydrogenase deficiency Congenital dyserythropoietic Congenital adrenal hyperplasia due 85 0.16 BP * 90795 0.47 P * anemia to 11-beta-hydroxylase deficiency Congenital dyserythropoietic Congenital adrenal hyperplasia due 98870 60 Cases 90795 0.75 BP * anemia type III to 11-beta-hydroxylase deficiency Congenital dyserythropoietic Congenital adrenal hyperplasia due 293825 4 Cases 90793 0.1 P * anemia type IV to 17-alpha-hydroxylase deficiency Congenital enterocyte heparan Congenital adrenal hyperplasia due 103910 3 Cases sulfate deficiency 95699 to cytochrome P450 oxidoreductase 0.75 BP * Congenital erosive and vesicular deficiency 231573 31 Cases dermatosis 495879 6 Cases Congenital agenesis of the scrotum Congenital erythropoietic 79277 0.065 I * Congenital alpha2-antiplasmin 79 40 Cases porphyria deficiency 325 Congenital factor II deficiency 0.05 P * Congenital alveolar capillary 210122 40 Cases dysplasia 326 Congenital factor V deficiency 0.1 P * Congenital amegakaryocytic 3319 100 Cases 327 Congenital factor VII deficiency 0.33 P * thrombocytopenia 329 Congenital factor XI deficiency 0.1 P * 86816 Congenital analbuminemia 50 Cases 331 Congenital factor XIII deficiency 0.05 P * 1195 Congenital atransferrinemia 16 Cases Congenital bilateral absence of vas 331 Congenital factor XIII deficiency 0.04 I * 48 50.0 P * deferens 335 Congenital fibrinogen deficiency 0.15 P * Congenital bile acid synthesis 79302 2 Cases Congenital generalized defect type 3 476406 hypercontractile muscle stiffness 2 Cases Congenital bile acid synthesis 79095 5 Cases syndrome defect type 4 Congenital generalized 1023 40 Cases Congenital brachyesophagus- hypertrichosis, Ambras type 514352 intrathoracic stomach-vertebral 8 Cases 98976 Congenital glaucoma 3.6 BP * anomalies syndrome Congenital brain dysgenesis due to 60041 Congenital heart block 4.54 BP 71278 3 Cases glutamine synthetase deficiency

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families Congenital heart defect-round face- Congenital muscular dystrophy 1355 3 Cases 34520 0.03 P * developmental delay syndrome with integrin alpha-7 deficiency Congenital hereditary endothelial Congenital muscular dystrophy 98975 68 Cases dystrophy type I 329178 with intellectual disability and 3 Cases Congenital hereditary facial severe epilepsy 306530 paralysis-variable hearing loss 13 Cases Congenital muscular dystrophy- syndrome 1875 infantile cataract-hypogonadism 7 Cases 2185 Congenital hydrocephalus 46.5 BP * syndrome Congenital muscular dystrophy- 442 Congenital hypothyroidism 38.0 BP * respiratory failure-skin 486815 4 Cases Congenital hypothyroidism due to abnormalities-joint hyperlaxity 95711 21.3 P * developmental anomaly syndrome Congenital hypothyroidism due to 590 Congenital myasthenic syndrome 0.3 P * 95715 transplacental passage of TSH- 1.0 P * Congenital myopathy with internal binding inhibitory antibodies 319160 5 Cases nuclei and atypical cores Congenital ichthyosis-intellectual Congenital myopathy with 352333 disability-spastic quadriplegia 2 Cases 424107 2 Cases myasthenic-like onset syndrome Congenital ichthyosis- 199329 Congenital myopathy, Paradas type 2 Cases 2271 microcephalus-tetraplegia 2 Cases 206973 Congenital myotonia 1.0 P syndrome Congenital neuronal ceroid Congenital insensitivity to pain 168486 10 Cases 217399 2 Cases lipofuscinosis with hyperhidrosis Congenital neutropenia- Congenital insensitivity to pain 453510 3 Cases 369852 myelofibrosis-nephromegaly 16 Cases with severe intellectual disability syndrome Congenital intrauterine infection- 1229 30 Cases Congenital non-bullous 79394 0.3 P * like syndrome ichthyosiform erythroderma Congenital intrinsic factor 332 100 Cases Congenital osteogenesis deficiency 2772 imperfecta-microcephaly-cataracts 3 Cases 657 Congenital isolated hyperinsulinism 2.0 BP syndrome Congenital labioscrotal agenesis- 313906 Congenital pancreatic cyst 10 Cases cerebellar malformation-corneal 495875 3 Cases dystrophy-facial dysmorphism 139414 Congenital panfollicular nevus 3 Cases syndrome Congenital progressive bone marrow failure-B-cell 1954 Congenital lethal erythroderma 17 Cases 508542 5 Cases immunodeficiency-skeletal Congenital lethal myopathy, 210163 4 Cases dysplasia syndrome Compton-North type Congenital pseudoarthrosis of the 66630 200 Cases 1928 Congenital lobar emphysema 4.0 BP clavicle Congenital pulmonary airway 93109 Congenital megacalycosis 25 Cases 2444 8.2 BP * malformation Congenital membranous Congenital pulmonary nephropathy due to fetomaternal 2414 100 Cases 69063 15 Cases lymphangiectasia anti-neutral endopeptidase Congenital pulmonary valve alloimmunization 3189 39.3 BP * stenosis Congenital microcephaly-severe 391376 encephalopathy-progressive 20 Cases 3269 Congenital radioulnar synostosis 350 Cases cerebral atrophy syndrome Congenital reticular ichthyosiform 281190 40 Cases Congenital multiple café-au-lait erythroderma 508512 macules-increased sister chromatid 2 Cases 290 Congenital rubella syndrome 0.35 BP * exchange syndrome Congenital muscular dystrophy due 290 Congenital rubella syndrome 0.03 I * 157973 23 Cases to LMNA mutation 2301 Congenital short bowel syndrome 43 Cases Congenital muscular dystrophy 258 0.3 P * Congenital sideroblastic anemia-B- type 1A cell immunodeficiency-periodic Congenital muscular dystrophy 369861 16 Cases 98893 6 Cases fever-developmental delay type 1B syndrome Congenital muscular dystrophy 371007 14 Cases 103908 Congenital sodium diarrhea 15 Cases with hyperlaxity

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families Congenital stromal corneal 101068 6 Families 3071 Costello syndrome 300 Cases dystrophy Congenital sucrase-isomaltase 201 Cowden syndrome 0.5 P * 35122 20.0 P * deficiency 1508 Coxoauricular syndrome 4 Cases 499009 Congenital syphilis 1.4 BP * 1509 Coxopodopatellar syndrome 47 Cases Congenital total pulmonary venous 99125 9.0 BP 1512 Crane-Heise syndrome 9 Cases return anomaly 858 Congenital toxoplasmosis 33.0 BP * 1525 Cranio-osteoarthropathy 30 Cases 92050 Congenital tufting enteropathy 0.5 BP * 1513 Craniodiaphyseal dysplasia 20 Cases Craniodigital-intellectual disability 291 Congenital varicella syndrome 130 Cases 1514 5 Cases syndrome Congenital vertebral-cardiac-renal 521438 4 Cases 1515 Cranioectodermal dysplasia 60 Cases anomalies syndrome Congenitally corrected 85168 Craniofacial conodysplasia 1 Family 216694 3.0 BP transposition of the great arteries Craniofacial dysplasia-osteopenia Congenitally short costocoracoid 314555 5 Cases 2391 1 Family syndrome ligament Craniofacial dysplasia-short Congenitally uncorrected 860 24.25 BP * 459061 stature-ectodermal anomalies- 8 Cases transposition of the great arteries intellectual disability syndrome Connective tissue disorder due to 300284 2 Cases 1516 Craniofacial dyssynostosis 14 Cases lysyl hydroxylase-3 deficiency Craniofacial-deafness-hand 1529 3 Cases 420794 Cono-spondylar dysplasia 3 Cases syndrome Constitutional megaloblastic 363705 Craniofaciofrontodigital syndrome 4 Cases 319651 anemia with severe neurologic 6 Cases Craniofrontonasal dysplasia-Poland disease 1521 2 Cases Contractures-developmental delay- anomaly syndrome 436003 6 Cases Pierre Robin syndrome 50814 Craniolenticulosutural dysplasia 28 Cases Contractures-ectodermal dysplasia- Craniometadiaphyseal dysplasia, 1484 2 Cases 85184 4 Cases cleft lip/palate syndrome wormian bone type Contractures-webbed neck- 1522 Craniometaphyseal dysplasia 160 Cases 314002 micrognathia-hypoplastic nipples 2 Cases syndrome 54595 Craniopharyngioma 2.0 P * 1487 Cooks syndrome 12 Cases 54595 Craniopharyngioma 1.0 I 1488 Cooper-Jabs syndrome 2 Cases 157832 Craniorhiny 6 Cases Corneal dystrophy-perceptive 1490 24 Cases 1531 Craniosynostosis 24.3 BP * deafness syndrome Corneal intraepithelial 1541 Craniosynostosis, Boston type 3 Families dyskeratosis-palmoplantar Craniosynostosis, Herrmann-Opitz 352662 19 Cases 2145 2 Cases hyperkeratosis-laryngeal type dyskeratosis syndrome 1527 Craniosynostosis, Philadelphia type 1 Family 199 Cornelia de Lange syndrome 1.9 P * Craniosynostosis-anal anomalies- 85199 9 Cases 199 Cornelia de Lange syndrome 1.3 BP * porokeratosis syndrome Craniosynostosis-Dandy-Walker 3194 Corneodermatoosseous syndrome 7 Cases 1538 malformation-hydrocephalus 4 Cases Corpus callosum agenesis- syndrome 52055 intellectual disability-coloboma- 2 Cases Craniosynostosis-fibular aplasia 1533 2 Cases micrognathia syndrome syndrome Corpus callosum agenesis- Craniosynostosis-hydrocephalus- 459074 macrocephaly-hypertelorism 4 Cases 171839 Arnold-Chiari malformation type I- 2 Cases syndrome radioulnar synostosis syndrome Cortical blindness-intellectual Craniosynostosis-intracranial 1389 3 Cases 52054 3 Cases disability-polydactyly syndrome calcifications syndrome Cortical dysgenesis with 1528 Craniotelencephalic dysplasia 4 Cases 300570 pontocerebellar hypoplasia due to 12 Cases TUBB3 mutation 90290 CREST syndrome 8.0 P * Corticosteroid-sensitive aseptic 54251 49 Cases 205 Crigler-Najjar syndrome 1.0 P * abscess syndrome

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families Cystic fibrosis-gastritis- 205 Crigler-Najjar syndrome 0.1 BP * 2575 2 Cases megaloblastic anemia syndrome 1545 Crisponi syndrome 30 Cases Cystic hamartoma of lung and 2111 3 Cases 1461 Criss-cross heart 0.8 BP * kidney Cystic leukoencephalopathy 2930 Cronkhite-Canada syndrome 500 Cases 85136 50 Cases without megalencephaly 2935 Crossed polysyndactyly 12 Cases 213 Cystinosis 1.5 P * 207 Crouzon disease 0.9 BP * 213 Cystinosis 0.75 BP Crouzon syndrome-acanthosis 93262 0.1 BP 214 Cystinuria 14.0 P nigricans syndrome 75381 Cystoid macular dystrophy 97 Cases 1546 Cryptococcosis 11.0 I * Cryptogenic multifocal ulcerous Cytomegalic congenital adrenal 468635 60 Cases 95702 8.0 BP stenosing enteritis hypoplasia Cryptomicrotia-brachydactyly- Cytomegalovirus disease in 1547 2 Cases excess fingertip arch syndrome 137698 patients with impaired cell 25.5 P * mediated immunity deemed at risk Cryptorchidism-arachnodactyly- 1548 3 Cases intellectual disability syndrome 94087 Cytophagic histiocytic panniculitis 100 Cases 1549 Cryptosporidiosis 1.96 I * Cytosolic phospholipase-A2 alpha 477787 deficiency associated bleeding 2 Cases Curly hair-acral keratoderma-caries 307766 14 Cases disorder syndrome 137678 Czech dysplasia, metatarsal type 20 Cases 1552 Currarino syndrome 1.0 P * 2437 Czeizel-Losonci syndrome 3 Cases 1553 Curry-Jones syndrome 9 Cases 356978 D,L-2-hydroxyglutaric aciduria 13 Cases 96253 Cushing disease 4.0 P * 79315 D-2-hydroxyglutaric aciduria 80 Cases 96253 Cushing disease 0.2 I * Dacryocystitis-osteopoikilosis 1562 5 Cases 553 Cushing syndrome 5.9 P syndrome 553 Cushing syndrome 0.15 I * Dahlberg-Borer-Newcomer 1563 2 Cases Cushing syndrome due to syndrome 189427 0.08 P * Dandy-Walker malformation- macronodular adrenal hyperplasia 1566 5 Cases Cutaneous collagenous postaxial polydactyly syndrome 280779 20 Cases vasculopathy 218 Darier disease 3.4 P * Cutaneous neuroendocrine 79140 4.0 P * 300536 DDOST-CDG 1 Case carcinoma DDX41-related hematologic Cutaneous neuroendocrine 79140 0.27 I 488647 malignancy predisposition 3 Families carcinoma syndrome Cutaneous photosensitivity-lethal 2881 3 Cases colitis syndrome 2962 De Barsy syndrome 40 Cases Deaf blind hypopigmentation 451607 Cutaneous pseudolymphoma 60 Cases 3214 2 Cases syndrome, Yemenite type Cutis gyrata-acanthosis nigricans- 1555 12 Cases Deafness with labyrinthine aplasia, craniosynostosis syndrome 90024 56 Cases microtia, and microdontia 209 Cutis laxa 0.1 BP * 3241 Deafness-craniofacial syndrome 2 Cases Cutis laxa with severe pulmonary, Deafness-ear malformation-facial 221145 gastrointestinal and urinary 21 Cases 3232 4 Cases palsy syndrome anomalies Deafness-enamel hypoplasia-nail 3220 15 Families 171719 Cutis laxa-Marfanoid syndrome 18 Cases defects syndrome Cutis marmorata telangiectatica Deafness-encephaloneuropathy- 1556 300 Cases 254898 2 Cases congenita obesity-valvulopathy syndrome 2686 Cyclic neutropenia 0.1 P * Deafness-epiphyseal dysplasia- 3218 2 Cases Cyprus facial-neuromusculoskeletal short stature syndrome 2674 1 Family syndrome Deafness-genital anomalies- 3224 metacarpal and metatarsal 2 Cases 400 1.0 I * Cystic echinococcosis synostosis syndrome 586 Cystic fibrosis 7.4 P * 90646 Deafness-hypogonadism syndrome 5 Cases 94064 Deafness-infertility syndrome 3 Families

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families Deafness-intellectual disability 85321 3 Cases 873 Desmoid tumor 0.3 I * syndrome, Martin-Probst type Desmoplastic small round cell Deafness-lymphedema-leukemia 83469 300 Cases 3226 20 Cases tumor syndrome Desmoplastic/nodular 251863 0.01 I * 3230 Deafness-oligodontia syndrome 5 Cases medulloblastoma Deafness-onychodystrophy 3231 50 Cases 35107 Desmosterolosis 9 Cases syndrome Developmental and speech delay Deafness-small bowel 313892 12 Cases 3217 5 Cases due to SOX5 deficiency diverticulosis-neuropathy syndrome Developmental delay with autism Deafness-vitiligo-achalasia 3239 2 Cases 329195 spectrum disorder and gait 22 Cases syndrome instability 99970 Dedifferentiated liposarcoma 0.27 I * Developmental delay-deafness 163988 1 Family Deficiency in anterior pituitary syndrome, Hildebrand type 293978 function-variable immunodeficiency 7 Cases Developmental delay-facial syndrome 369891 dysmorphism syndrome due to 4 Cases Dehydrated hereditary MED13L deficiency 3202 20 Families stomatocytosis Developmental malformations- 79107 2 Cases Delayed membranous cranial deafness-dystonia syndrome 3034 2 Families ossification Dianzani autoimmune 275523 30 Cases Delayed speech-facial asymmetry- lymphoproliferative disease 3038 strabismus-ear lobe creases 6 Cases DIAPH1-related sensorineural syndrome 494444 hearing loss-thrombocytopenia 8 Cases 1627 Deletion 5q35 10 Cases syndrome 66637 Diaphanospondylodysostosis 18 Cases 79134 DEND syndrome 40 Cases Diaphragmatic defect-limb 2141 7 Cases 99828 Dengue fever 714.0 I deficiency-skull defect syndrome Diaphragmatic hernia-short bowel- 93571 Dense deposit disease 0.25 P 527468 2 Cases asplenia syndrome 1652 Dent disease 250 Families 628 Diastrophic dwarfism 1.2 P * 99789 Dentin dysplasia type I 1.0 P * 628 Diastrophic dwarfism 0.3 BP * 99791 Dentin dysplasia type II 19 Families 370046 Didymosis aplasticosebacea 18 Cases Dentin dysplasia-sclerotic bones 99792 1 Family syndrome 146 Differentiated thyroid carcinoma 5.25 I 49042 Dentinogenesis imperfecta 14.5 P * 90060 Diffuse alveolar hemorrhage 1.0 P * 166260 Dentinogenesis imperfecta type 2 14.6 P * Diffuse cerebral and cerebellar 404437 atrophy-intractable seizures- 4 Cases Dentinogenesis imperfecta-short progressive microcephaly syndrome 71267 stature-hearing loss-intellectual 2 Cases disability syndrome 79456 Diffuse cutaneous mastocytosis 30 Cases 220 Denys-Drash syndrome 200 Cases 544 Diffuse large B-cell lymphoma 16.0 P * 1656 Dermatitis herpetiformis 27.0 P * 544 Diffuse large B-cell lymphoma 2.79 I * 31112 Dermatofibrosarcoma protuberans 10.0 P * 2123 Diffuse neonatal hemangiomatosis 70 Cases Diffuse palmoplantar keratoderma- 1659 Dermatoleukodystrophy 2 Cases 86918 10 Cases acrocyanosis syndrome 221 Dermatomyositis 6.0 P * Digital anomalies-intellectual 352487 8 Cases 221 Dermatomyositis 0.55 I * disability-short stature syndrome Digital extensor muscle aplasia- 1657 Dermatoosteolysis, Kirghizian type 5 Cases 2926 3 Cases polyneuropathy Dermatopathia pigmentosa 86920 20 Cases 1146 Digitotalar dysmorphism 10.0 P reticularis Dihydropteridine reductase 79149 Dermochondrocorneal dystrophy 15 Cases 226 150 Cases deficiency 1660 Dermoodontodysplasia 11 Cases Dilated cardiomyopathy- 2229 hypergonadotropic hypogonadism 20 Families 1425 Desbuquois syndrome 50 Cases syndrome Desmin-related myopathy with Dimethylglycine dehydrogenase 84132 5 Cases 243343 1 Case Mallory body-like inclusions deficiency

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families DNA2-related mitochondrial DNA 227 Diphallia 0.02 BP 352470 4 Cases deletion syndrome 1681 Diprosopus 33 Cases DNAJB2-related Charcot-Marie- 443950 2 Cases Dislocation of the hip-dysmorphism Tooth disease type 2 2412 4 Cases syndrome DNM1L-related encephalopathy 79168 Disorder of bile acid synthesis 0.6 P * 330050 due to mitochondrial and 11 Cases peroxisomal fission defect Disorder of sex development- 2983 3 Cases intellectual disability syndrome 3262 Dobrow syndrome 2 Cases Disseminated peritoneal 71274 150 Cases 447737 DOCK2 deficiency 5 Cases leiomyomatosis Dominant dystrophic epidermolysis Distal 7q11.23 microdeletion 158676 10 Families 254351 41 Cases bullosa, nails only syndrome Dominant hypophosphatemia with Distal 7q11.23 microduplication 244305 12 Cases 261102 5 Cases nephrolithiasis or osteoporosis syndrome Distal 17p13.1 microdeletion 2143 Donnai-Barrow syndrome 50 Cases 319171 16 Cases syndrome 79500 DOORS syndrome 50 Cases Distal 17p13.3 microdeletion 261257 16 Cases syndrome 255 Dopa-responsive dystonia 0.5 P Dopa-responsive dystonia due to 399096 Distal anoctaminopathy 24 Cases 70594 43 Cases sepiapterin reductase deficiency 329457 Distal arthrogryposis type 5D 33 Cases Dopamine beta-hydroxylase 230 21 Cases 251515 Distal arthrogryposis type 10 53 Cases deficiency Distal hereditary motor neuropathy 3427 Double outlet left ventricle 0.5 BP 139525 4 Families type 2 Double uterus-hemivagina-renal 3411 60 Cases Distal hereditary motor agenesis syndrome 139552 30 Cases neuropathy, Jerash type 870 Down syndrome 95.0 BP Distal limb deficiencies- 1307 6 Cases micrognathia syndrome 86309 DPAGT1-CDG 18 Cases 1620 Distal monosomy 3p 34 Cases 79322 DPM1-CDG 9 Cases 96125 Distal monosomy 6p 35 Cases 263494 DPM3-CDG 1 Case 1642 Distal monosomy 9p 89 Cases 33069 Dravet syndrome 2.5 BP Duane anomaly-myopathy-scoliosis 96148 Distal monosomy 10q 40 Cases 50817 2 Cases syndrome 280325 Distal monosomy 12p 8 Cases 233 Duane retraction syndrome 10.0 P * 1590 Distal monosomy 13q 150 Cases 235 Dubowitz syndrome 0.2 BP * 1596 Distal monosomy 15q 30 Cases 98896 Duchenne muscular dystrophy 4.78 P Distal myopathy with anterior tibial 178400 4 Cases onset 98896 Duchenne muscular dystrophy 15.1 BP * Distal myopathy with posterior leg 1203 Duodenal atresia 9.0 P * 63273 16 Cases and anterior hand involvement 1203 Duodenal atresia 9.0 BP * 488650 Distal myopathy, Tateyama type 7 Cases 314621 Duplication of the pituitary gland 38 Cases 399103 Distal nebulin myopathy 13 Cases 237 Duplication of urethra 300 Cases Distal spinal muscular atrophy type 139547 28 Cases 3 239 Dyggve-Melchior-Clausen disease 60 Cases 3248 Distal symphalangism 8 Families DYRK1A-related intellectual 464306 54 Cases disability syndrome 314588 Distal tetrasomy 15q 23 Cases DYRK1A-related intellectual 1745 Distal trisomy 6p 40 Cases 268261 disability syndrome due to 19 Cases 21q22.13q22.2 microdeletion 96102 Distal trisomy 10q 40 Cases Dyschondrosteosis-nephritis Distal Xq28 microduplication 1765 1 Family 293939 9 Cases syndrome syndrome Dyschromatosis symmetrica 41 300 Cases 404546 DITRA 70 Cases hereditaria 91131 DK1-CDG 17 Cases 1766 Dysequilibrium syndrome 51 Cases 1775 Dyskeratosis congenita 0.1 P *

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families Dysmorphism-pectus carinatum- Early-onset spastic ataxia- 2104 2 Cases joint laxity syndrome 313772 myoclonic epilepsy-neuropathy 2 Cases Dysmorphism-short stature- syndrome 2282 deafness-disorder of sex 2 Cases 98890 Early-onset X-linked optic atrophy 4 Families development syndrome 199343 EAST syndrome 26 Cases 1822 Dysplasia epiphysealis hemimelica 0.1 I 391320 East Texas bleeding disorder 19 Cases 2204 Dysplastic cortical hyperostosis 2 Cases Dysraphism-cleft lip/palate-limb 319218 Ebola hemorrhagic fever 28220 Cases 2476 3 Cases reduction defects syndrome 1880 Ebstein malformation 1.25 P * 85198 Dysspondyloenchondromatosis 16 Cases 1880 Ebstein malformation 3.5 BP * 210571 Dystonia 16 12 Cases Ectodermal dysplasia, 1818 7 Cases trichoodontoonychial type 412217 Dystonia-aphonia syndrome 32 Cases Ectodermal dysplasia-blindness Dystonia-parkinsonism- 1806 2 Cases 521406 11 Cases syndrome hypermanganesemia syndrome Ectodermal dysplasia-cutaneous 247827 4 Cases 303 Dystrophic epidermolysis bullosa 0.7 P syndactyly syndrome Dystrophic epidermolysis bullosa Ectodermal dysplasia-sensorineural 89843 100 Families 1883 2 Cases pruriginosa deafness syndrome Ectodermal dysplasia-syndactyly 2554 Ear-patella-short stature syndrome 67 Cases 247820 22 Cases syndrome 1935 Early myoclonic encephalopathy 80 Cases 448270 Ectopia cordis 0.67 BP Early-onset epilepsy-intellectual Ectopia lentis-chorioretinal 488635 disability-brain anomalies 5 Cases 1884 4 Cases syndrome dystrophy-myopia syndrome Early-onset epileptic 1892 Ectrodactyly-polydactyly syndrome 1 Family encephalopathy-cortical blindness- Ectrodactyly-spina bifida- 411986 3 Cases 1894 1 Case intellectual disability-facial cardiopathy syndrome dysmorphism syndrome 293936 EDICT syndrome 4 Families Early-onset familial noncirrhotic 494348 3 Cases portal hypertension 1895 Edinburgh malformation syndrome 2 Families Early-onset generalized limb-onset 256 0.4 P * 1896 EEC syndrome 1.11 BP * dystonia 1897 EEM syndrome 7 Families 324290 Early-onset Lafora body disease 3 Cases Early-onset myopathy-areflexia- 98249 Ehlers-Danlos syndrome 0.9 BP * 439212 respiratory distress-dysphagia 13 Cases Ehlers-Danlos syndrome due to 230839 17 Cases syndrome tenascin-X deficiency Early-onset parkinsonism- 2379 2 Families 90309 Ehlers-Danlos syndrome type 1 5.0 P * intellectual disability syndrome Ehlers-Danlos syndrome, cardiac 230851 6 Cases Early-onset progressive diffuse valvular type 496641 brain atrophy-microcephaly-muscle 22 Cases Ehlers-Danlos syndrome, classic weakness-optic atrophy syndrome 287 5.0 P type Early-onset progressive Ehlers-Danlos syndrome, 1943 encephalopathy with migrant 3 Cases 1901 15 Cases dermatosparaxis type continuous myoclonus Ehlers-Danlos syndrome, Early-onset progressive 75501 1 Family fibronectinemic type 500144 encephalopathy-hearing loss-pons 3 Cases Ehlers-Danlos syndrome, hypoplasia-brain atrophy syndrome 285 12.5 P * hypermobility type Early-onset progressive encephalopathy-spastic ataxia- Ehlers-Danlos syndrome, 496756 6 Cases 300179 9 Cases distal spinal muscular atrophy kyphoscoliotic and deafness type Ehlers-Danlos syndrome, syndrome 1900 1.0 BP Early-onset progressive kyphoscoliotic type Ehlers-Danlos syndrome, 352654 neurodegeneration-blindness- 6 Cases 2953 34 Cases ataxia-spasticity syndrome musculocontractural type Ehlers-Danlos syndrome, Early-onset seizures-distal limb 75392 62 Cases anomalies-facial dysmorphism- periodontitis type 505237 12 Cases Ehlers-Danlos syndrome, global developmental delay 157965 6 Cases syndrome spondylocheirodysplastic type

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families Ehlers-Danlos syndrome, vascular 286 1.0 P * 301 Ependymal tumor 0.2 I * type Ehlers-Danlos syndrome, vascular- 251636 Ependymoma 0.16 I * 230845 3 Cases Epibulbar lipodermoid-preauricular like type 231742 1 Family appendage-polythelia syndrome 1902 Ehrlichiosis 50 Cases 35125 Epidermal nevus syndrome 400 Cases 79106 Eiken syndrome 6 Cases 302 Epidermodysplasia verruciformis 200 Cases 228240 Elastoderma 5 Cases 304 Epidermolysis bullosa simplex 1.8 P 289 Ellis Van Creveld syndrome 1.1 BP 304 Epidermolysis bullosa simplex 2.2 BP * 96170 Emanuel syndrome 350 Cases Epidermolysis bullosa simplex due 412181 2 Cases 180226 Embryonal carcinoma 0.01 I * to BP230 deficiency Embryonal tumor of Epidermolysis bullosa simplex due 251852 0.22 I * 412189 3 Cases neuroepithelial tissue to exophilin 5 deficiency Epidermolysis bullosa simplex with 261 Emery-Dreifuss muscular dystrophy 0.3 P * 257 40 Cases muscular dystrophy 1927 Emery-Nelson syndrome 2 Cases Epidermolysis bullosa simplex, 89838 19 Cases EMILIN-1-related connective tissue autosomal recessive K14 485418 3 Cases disease Epidermolysis bullosa simplex, 79401 6 Families 1031 Enamel-renal syndrome 11 Cases Ogna type Encephalocraniocutaneous 141077 Epignathus 1.68 BP 2396 77 Cases lipomatosis Epilepsy-microcephaly-skeletal 1948 2 Cases Encephalopathy due to dysplasia syndrome 527276 mitochondrial and peroxisomal 15 Cases 1951 Epilepsy-telangiectasia syndrome 6 Cases fission defect Encephalopathy due to prosaposin 1819 Epimetaphyseal skeletal dysplasia 4 Cases 139406 10 Cases deficiency Epiphyseal dysplasia-hearing loss- 1825 2 Cases Encephalopathy due to sulfite dysmorphism syndrome 833 100 Cases oxidase deficiency 79135 Episodic ataxia type 3 1 Family Encephalopathy-hypertrophic 319678 cardiomyopathy-renal tubular 1 Case 79136 Episodic ataxia type 4 2 Families disease syndrome 211067 Episodic ataxia type 5 7 Cases 296 Enchondromatosis 1.0 P * 209967 Episodic ataxia type 6 4 Cases Endocrine-cerebro-osteodysplasia 199332 7 Cases syndrome 209970 Episodic ataxia type 7 7 Cases 454723 Endometrioid carcinoma of ovary 0.81 I * 401953 Episodic ataxia with slurred speech 13 Cases Epithelial recurrent erosion 2790 Endosteal hyperostosis, Worth type 6 Families 293381 186 Cases dystrophy Endosteal sclerosis-cerebellar 85186 4 Cases Epstein-Barr virus-associated hypoplasia syndrome 313920 1.2 I gastric carcinoma 1937 Eng-Strom syndrome 2 Cases 35687 Erdheim-Chester disease 500 Cases 60015 Enlarged parietal foramina 3.7 P 999 Ermine phenotype 6 Cases 83620 Enteric anendocrinosis 7 Cases 317 Erythrokeratodermia variabilis 200 Cases Enthesitis-related juvenile 85438 5.7 P * Erythrokeratodermia- idiopathic arthritis 476096 3 Cases cardiomyopathy syndrome 449566 Eosinophilic angiocentric fibrosis 52 Cases 1199 Esophageal atresia 24.3 BP * 402035 Eosinophilic colitis 196 Cases 3318 Essential thrombocythemia 0.48 I * 73247 Eosinophilic esophagitis 40.08 P 1957 Esthesioneuroblastoma 0.02 I * 3165 Eosinophilic fasciitis 200 Cases 785 Estrogen resistance syndrome 2 Cases 2070 Eosinophilic gastroenteritis 280 Cases 51188 Ethylmalonic encephalopathy 80 Cases Eosinophilic granulomatosis with 183 1.5 P polyangiitis 1959 Evans syndrome 0.1 P * Eosinophilic granulomatosis with 496751 3 Cases 183 0.18 I * EVEN-plus syndrome polyangiitis 319 Ewing sarcoma 0.13 I *

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families Exostoses-anetodermia- 1962 1 Family 615 Familial atrial myxoma 17 Families brachydactyly type E syndrome Familial atrial tachyarrhythmia- Extensor tendons of finger 3294 2 Cases 436242 infra-Hisian cardiac conduction 7 Cases anomalies disease External auditory canal atresia- 1551 Familial benign copper deficiency 1 Family 3023 vertical talus-hypertelorism 10 Cases Familial calcium pyrophosphate syndrome 1416 100 Families deposition 363579 Extragonadal germ cell tumor 0.13 I * 1768 4 Cases Extraskeletal myxoid Familial caudal dysgenesis 209916 0.2 P * chondrosarcoma 464760 Familial cavitary optic disc anomaly 17 Cases Extrasystoles-short stature- Familial cerebral cavernous 221061 15.0 P 1964 hyperpigmentation-microcephaly 2 Cases malformation syndrome 481662 Familial Chilblain lupus 10 Families Eye defects-arachnodactyly- 2725 6 Cases cardiopathy syndrome 1428 Familial chondromalacia patellae 5 Families Eyebrow duplication-syndactyly Familial chylomicronemia 3172 3 Cases 444490 1.0 P * syndrome syndrome 324 Fabry disease 0.22 BP * Familial clubfoot due to 238578 4 Families Facial dysmorphism-anorexia- 17q23.1q23.2 microduplication 1969 cachexia-eye and skin anomalies 3 Cases Familial congenital mirror 238722 75 Cases syndrome movements Familial congenital nasolacrimal Facial dysmorphism-developmental 451612 4 Cases delay-behavioral abnormalities duct obstruction 284169 19 Cases syndrome due to 10p11.21p12.31 Familial congenital palsy of 91498 6 Cases microdeletion trochlear nerve Facial dysmorphism-developmental 319189 Familial cortical myoclonus 11 Cases delay-behavioral abnormalities 466950 10 Cases syndrome due to WAC point 53296 Familial cutaneous collagenoma 16 Cases mutation Familial cutaneous telangiectasia Facial dysmorphism- 313846 and oropharyngeal cancer 24 Cases 352712 immunodeficiency-livedo-short 11 Cases predisposition syndrome stature syndrome 1799 Familial developmental dysphasia 6 Families Facial dysmorphism-lens Familial dyskinesia and facial dislocation-anterior segment 324588 18 Cases 412022 4 Families myokymia abnormalities-spontaneous filtering Familial encephalopathy with blebs syndrome 85110 6 Families neuroserpin inclusion bodies Facial dysmorphism-macrocephaly- Familial episodic pain syndrome 1970 myopia-Dandy-Walker 3 Cases 391392 with predominantly lower limb 28 Cases malformation syndrome involvement Facial dysmorphism-shawl 1778 2 Cases Familial episodic pain syndrome scrotum-joint laxity syndrome 391389 with predominantly upper body 21 Cases Facial onset sensory and motor 85162 47 Cases involvement neuronopathy Familial gastric type 1 464756 5 Cases 1973 Faciocardiorenal syndrome 4 Cases neuroendocrine tumor Familial hyperaldosteronism type 269 Facioscapulohumeral dystrophy 4.5 P * 251274 7 Families III 306550 FADD-related immunodeficiency 4 Cases 238475 Familial hypercholanemia 23 Cases Fallot complex-intellectual 3304 5 Cases Familial hyperreninemic disability-growth delay syndrome 99764 5 Cases hypoaldosteronism type 2 Familial acute necrotizing 88619 11 Cases Familial hyperthyroidism due to encephalopathy 424 28 Families mutations in TSH receptor 733 Familial adenomatous polyposis 6.0 P * Familial hypocalciuric 93372 5.5 P Familial adrenal hypoplasia with hypercalcemia type 1 95700 absent pituitary luteinizing 3 Cases 300373 Familial infantile gigantism 3 Cases hormone Familial Alzheimer-like prion Familial infantile myoclonic 280397 2 Cases 352582 7 Cases disease epilepsy Familial isolated dilated 228277 Familial anetoderma 12 Families 154 17.5 P * cardiomyopathy

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families Familial isolated dilated Familial progressive retinal 154 2.91 I * cardiomyopathy 488197 dystrophy-iris coloboma-congenital 9 Cases Familial isolated cataract syndrome 99879 100 Families hyperparathyroidism Familial reactive perforating 79147 50 Cases Familial isolated collagenosis 2238 10 Families hypoparathyroidism 231108 Familial rhabdoid tumor 5 Families Familial isolated Familial scaphocephaly syndrome, 2239 hypoparathyroidism due to 2 Families 168624 11 Cases McGillivray type agenesis of parathyroid gland 166282 Familial sick sinus syndrome 11 Cases 314777 Familial isolated pituitary adenoma 150 Cases Familial steroid-resistant nephrotic Familial isolated restrictive 75249 2.5 P * 280406 syndrome with sensorineural 13 Cases cardiomyopathy deafness 411788 Familial isolated trichomegaly 2 Families Familial thoracic aortic aneurysm 91387 22 Cases 79293 Familial LCAT deficiency 70 Cases and aortic dissection 93953 Familial thyroglossal duct cyst 22 Cases 768 Familial long QT syndrome 40.0 BP * Familial thyroid Familial median cleft of the upper 95716 4.0 P * 401942 8 Cases dyshormonogenesis and lower lips Familial thyroid 95716 2.67 I 618 Familial melanoma 1.5 I * dyshormonogenesis Familial mesial temporal lobe 165805 4 Cases 84 Fanconi anemia 0.3 P epilepsy with febrile seizures 84 Fanconi anemia 0.62 BP * 495930 Familial monosomy 7 syndrome 14 Families 333 Farber disease 96 Cases 338 Familial multiple fibrofolliculoma 7 Cases FASTKD2-related infantile 166105 3 Cases 922 Familial nasal acilia 8 Cases mitochondrial encephalomyopathy Familial omphalocele syndrome Fatal congenital hypertrophic 280403 5 Cases with facial dysmorphism 439854 cardiomyopathy due to glycogen 10 Cases Familial or sporadic hemiplegic storage disease 569 10.0 P * migraine 466 Fatal familial insomnia 27 Cases Familial osteodysplasia, Anderson 2769 4 Cases Fatal infantile hypertonic type 280553 11 Cases myofibrillar myopathy Familial papillary thyroid carcinoma 97290 2 Cases Fatal mitochondrial disease due to with renal papillary neoplasia 168566 combined oxidative 7 Cases 98306 Familial partial lipodystrophy 1.0 P * phosphorylation defect type 3 Familial partial lipodystrophy, Fatal post-viral neurodegenerative 79084 20 Cases 391343 2 Cases Köbberling type disorder 34526 Familial primary hypomagnesemia 500 Cases 2492 FATCO syndrome 22 Cases Familial primary hypomagnesemia FBLN1-related developmental 306516 with hypercalciuria and 200 Cases 404451 delay-central nervous system 3 Cases nephrocalcinosis anomaly-syndactyly syndrome Familial primary hypomagnesemia Febrile infection-related epilepsy 163703 1.0 P * with hypercalciuria and syndrome 2196 72 Cases nephrocalcinosis with severe ocular 1305 Feingold syndrome 123 Cases involvement Familial primary hypomagnesemia 391641 Feingold syndrome type 1 120 Cases with hypercalciuria and 31043 110 Cases 391646 Feingold syndrome type 2 7 Cases nephrocalcinosis without severe Female infertility due to oocyte ocular involvement 488191 16 Cases meiotic arrest Familial primary hypomagnesemia Female infertility due to zona 34527 with normocalciuria and 5 Families 404466 4 Cases pellucida defect normocalcemia Female restricted epilepsy with Familial progressive cardiac 101039 5 Families 871 50 Cases intellectual disability conduction defect Familial progressive hyper- and 1988 Femoral-facial syndrome 62 Cases 280628 3 Families hypopigmentation 2019 Femur-fibula-ulna complex 1.5 BP * 397922 Ferro-cerebro-cutaneous syndrome 3 Cases

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families Fetal akinesia deformation Focal facial dermal dysplasia type 994 0.6 BP * 398189 21 Cases sequence IV Fetal akinesia-cerebral and retinal 363409 3 Cases 48918 Focal myositis 115 Cases hemorrhage syndrome Focal, segmental or multifocal 1866 11.7 P * 1915 Fetal alcohol syndrome 1.6 BP * dystonia Focal, segmental or multifocal 294 Fetal cytomegalovirus syndrome 40.0 P * 1866 2.0 I * dystonia 465824 Fetal encasement syndrome 2 Cases 2048 Foix-Chavany-Marie syndrome 150 Cases 85212 Fetal Gaucher disease 50 Cases Follicular cholangitis and 300552 5 Cases 1917 Fetal methylmercury syndrome 800 Cases pancreatitis 545 Follicular lymphoma 28.0 P * 1906 Fetal valproate syndrome 1.02 BP * Fever-associated acute infantile 545 Follicular lymphoma 2.12 I * 464724 11 Cases liver failure syndrome 228371 Foodborne botulism 0.1 I * 313855 FGFR2-related bent bone dysplasia 11 Cases 3219 Fountain syndrome 8 Cases 477650 Fibroblastic rheumatism 30 Cases Foveal hypoplasia-optic nerve 2021 Fibrochondrogenesis 20 Cases 397618 decussation defect-anterior 7 Families segment dysgenesis syndrome Fibrodysplasia ossificans 337 0.05 P Foveal hypoplasia-presenile progressiva 2253 11 Cases cataract syndrome 84090 Fibronectin glomerulopathy 16 Families 221126 Fowler syndrome 44 Cases 2030 Fibrosarcoma 0.01 I * 908 Fragile X syndrome 32.5 P Fibular aplasia-ectrodactyly 1118 50 Cases syndrome 908 Fragile X syndrome 2.4 BP * Fibular dimelia-diplopodia 1757 11 Cases 137834 Frank-Ter Haar syndrome 30 Cases syndrome 2052 Fraser syndrome 0.2 BP * 93323 Fibular hemimelia 2.0 P * Fibulo-ulnar hypoplasia-renal 347 Frasier syndrome 88 Cases 2256 2 Cases anomalies syndrome 834 Free sialic acid storage disease 130 Cases 3255 Filippi syndrome 29 Cases 2053 Freeman-Sheldon syndrome 100 Cases Finger hyperphalangy-toe 85335 Fried syndrome 1 Family 369979 anomalies-severe pectus excavatum 2 Cases syndrome 95 Friedreich ataxia 2.0 P * 97232 Fingerprint body myopathy 20 Cases 99672 Fried's tooth and nail syndrome 12 Cases Finnish upper limb-onset distal 399086 7 Cases 1791 Frontofacionasal dysplasia 14 Cases myopathy 79292 Fish-eye disease 30 Cases 1826 Frontometaphyseal dysplasia 100 Cases Flat face-microstomia-ear anomaly 250 Frontonasal dysplasia 0.7 BP * 1968 2 Cases syndrome Frontonasal dysplasia-alopecia- 228390 5 Cases 98970 Fleck corneal dystrophy 30 Cases genital anomalies syndrome Frontonasal dysplasia-bifid nose- 2044 Floating-Harbor syndrome 87 Cases 521308 11 Cases upper limb anomalies syndrome 2045 FLOTCH syndrome 6 Families Frontonasal dysplasia-severe 306542 microphthalmia-severe facial 3 Cases 2047 Flynn-Aird syndrome 10 Cases clefting syndrome 2092 Focal dermal hypoplasia 300 Cases 282 Frontotemporal dementia 3.0 P * Focal epilepsy-intellectual Frontotemporal dementia, right 352587 disability-cerebro-cerebellar 7 Cases 293848 200 Cases temporal atrophy variant malformation 2059 Fryns syndrome 7.0 BP * 398166 Focal facial dermal dysplasia 147 Cases 2058 Fryns-Smeets-Thiry syndrome 2 Cases 79133 Focal facial dermal dysplasia type I 81 Cases 247790 FTH1-related iron overload 4 Cases 398173 Focal facial dermal dysplasia type II 22 Cases Focal facial dermal dysplasia type 349 Fucosidosis 100 Cases 1807 20 Cases III 2854 Fuhrmann syndrome 11 Cases

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families Gingival fibromatosis-facial 24 Fumaric aciduria 40 Cases 2025 2 Cases dysmorphism syndrome 506358 Gabriele-de Vries syndrome 10 Cases Gingival fibromatosis-progressive 2027 2 Families 352 Galactosemia 2.0 BP * deafness syndrome 358 Gitelman syndrome 2.5 P * 352 Galactosemia 2.1 I * Glaucoma secondary to 351 Galactosialidosis 100 Cases 238763 spherophakia/ectopia lentis and 12 Cases 2065 Galloway-Mowat syndrome 97 Cases megalocornea Gamma-aminobutyric acid Glaucoma-ectopia lentis- 2066 3 Families transaminase deficiency 2084 microspherophakia-stiff joints-short 3 Cases Gamma-glutamyl transpeptidase stature syndrome 33573 7 Cases deficiency 2085 Glaucoma-sleep apnea syndrome 5 Cases 100026 Gamma-heavy chain disease 120 Cases 182067 Glial tumor 10.0 P * 2067 GAPO syndrome 38 Cases 182067 Glial tumor 5.35 I * 79665 Gardner syndrome 9.1 BP 360 Glioblastoma 1.0 P Gastric adenocarcinoma and 314022 28 Cases 360 Glioblastoma 3.0 I proximal polyposis of the stomach 251582 Gliomatosis cerebri 0.01 I * 2069 Gastrocutaneous syndrome 24 Cases 251576 Gliosarcoma 0.03 I * 44890 Gastrointestinal stromal tumor 13.0 P * Global developmental delay-lung 44890 Gastrointestinal stromal tumor 1.0 I 404476 cysts-overgrowth-Wilms tumor 2 Cases 2368 Gastroschisis 23.7 BP * syndrome Global developmental delay-neuro- 355 1.0 P * Gaucher disease ophthalmological abnormalities- 488613 26 Cases 355 Gaucher disease 1.3 BP seizures-intellectual disability syndrome 355 Gaucher disease 1.7 I * Global developmental delay- 77259 Gaucher disease type 1 1.0 P * 73223 osteopenia-ectodermal defect 3 Cases syndrome 77260 Gaucher disease type 2 0.01 P * Global developmental delay-visual 77261 Gaucher disease type 3 0.05 P * anomalies-progressive cerebellar 480898 6 Cases Gaucher disease-ophthalmoplegia- atrophy-truncal hypotonia 2072 cardiovascular calcification 10 Cases syndrome syndrome 141163 Glossopalatine ankylosis 30 Cases 438274 GCGR-related hyperglucagonemia 8 Cases 97280 Glucagonoma 0.005 I * 2623 Geleophysic dysplasia 27 Cases Glutamate-cysteine ligase 33574 10 Cases deficiency 2074 Gemignani syndrome 2 Cases Glutaryl-CoA dehydrogenase 25 1.0 BP Generalized basal epidermolysis deficiency 508529 bullosa simplex with skin atrophy, 14 Cases 32 Glutathione synthetase deficiency 70 Cases scarring and hair loss Generalized eruptive 407 Glycine encephalopathy 0.17 P * 411777 40 Cases keratoacanthoma Glycogen storage disease due to 365 0.8 BP * 98497 Genetic peripheral neuropathy 40.0 P acid maltase deficiency Glycogen storage disease due to 2075 Genitopalatocardiac syndrome 15 Cases 420429 1.75 BP acid maltase deficiency, late-onset 85201 Genitopatellar syndrome 22 Cases Glycogen storage disease due to 364 1.0 BP glucose-6-phosphatase deficiency 93398 Genochondromatosis type 2 10 Cases Glycogen storage disease due to 2077 German syndrome 5 Cases 79258 glucose-6-phosphatase deficiency 1.0 BP * 2078 Geroderma osteodysplastica 50 Cases type Ia Glycogen storage disease due to Gerstmann-Straussler-Scheinker 356 0.0055 I 79259 glucose-6-phosphatase deficiency 150 Cases syndrome type Ib 643 Giant axonal neuropathy 50 Families Glycogen storage disease due to 2088 200 Cases 251579 Giant cell glioblastoma 0.02 I * GLUT2 deficiency

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families Glycogen storage disease due to 2095 Gorlin-Chaudhry-Moss syndrome 7 Cases 367 glycogen branching enzyme 0.1 BP deficiency 39812 Graft versus host disease 3.0 P * Glycogen storage disease due to 79094 Grange syndrome 7 Cases 2089 hepatic glycogen synthase 16 Cases deficiency 2097 Grant syndrome 1 Family Glycogen storage disease due to 34587 84 Cases 900 Granulomatosis with polyangiitis 9.0 P * LAMP-2 deficiency 900 Granulomatosis with polyangiitis 0.85 I * Glycogen storage disease due to 264580 liver phosphorylase kinase 1.0 BP * 33111 Granulomatous slack skin 50 Cases deficiency 721 Gray platelet syndrome 60 Cases Glycogen storage disease due to Grayson-Wilbrandt corneal 137625 muscle and heart glycogen synthase 4 Cases 293375 1 Family deficiency dystrophy Glycogen storage disease due to 1426 Greenberg dysplasia 10 Cases 99849 1 Case muscle beta-enolase deficiency 381 Griscelli syndrome 150 Cases Glycogen storage disease due to 371 muscle phosphofructokinase 100 Cases 79476 Griscelli syndrome type 1 20 Cases deficiency 79477 Griscelli syndrome type 2 102 Cases Glycogen storage disease due to 715 muscle phosphorylase kinase 30 Cases 79478 Griscelli syndrome type 3 13 Cases deficiency Growth and developmental delay- Glycogen storage disease due to 391348 hypotonia-vision impairment-lactic 2 Cases 713 phosphoglycerate kinase 1 30 Families acidosis syndrome deficiency Growth delay due to insulin-like 73272 5 Cases Glycogen storage disease due to growth factor type 1 deficiency 97234 phosphoglycerate mutase 50 Cases Growth delay-hydrocephaly-lung 3035 4 Cases deficiency hypoplasia syndrome Glycogen storage disease due to 370 1.0 BP * Growth retardation-mild phosphorylase kinase deficiency 391366 developmental delay-chronic 2 Cases Glycogen storage disease with hepatitis syndrome 263297 severe cardiomyopathy due to 1 Case Grubben-de Cock-Borghgraef 2101 3 Cases glycogenin deficiency syndrome 354 GM1 gangliosidosis 0.75 BP * 2102 GTP cyclohydrolase I deficiency 16 Cases 79255 GM1 gangliosidosis type 1 200 Cases Guanidinoacetate 382 80 Cases methyltransferase deficiency 79256 GM1 gangliosidosis type 2 50 Cases 2103 Guillain-Barré syndrome 3.5 P * 79257 GM1 gangliosidosis type 3 70 Cases 2103 Guillain-Barré syndrome 1.45 I 309152 GM2 gangliosidosis 5.0 P * 2957 Guttmacher syndrome 3 Cases 309246 GM2 gangliosidosis, AB variant 10 Cases Gyrate atrophy of choroid and 414 200 Cases 2090 GMS syndrome 1 Family retina 602 GNE myopathy 1.0 P 168569 H syndrome 100 Cases 329984 Goblet cell carcinoma 0.025 I 99803 Haddad syndrome 60 Cases Goldberg-Shprintzen megacolon 2342 Haim-Munk syndrome 100 Cases 66629 8 Families syndrome Hair defect-photosensitivity- 1408 3 Cases 374 Goldenhar syndrome 2.9 BP * intellectual disability syndrome 53540 Goldmann-Favre syndrome 50 Cases 2107 Hall-Riggs syndrome 8 Cases 1986 Gollop-Wolfgang complex 200 Cases 2108 Hallermann-Streiff syndrome 150 Cases 1532 Gómez-López-Hernández syndrome 36 Cases 2109 Hallermann-Streiff-like syndrome 2 Cases Hallux varus-preaxial 169105 Good syndrome 241 Cases 2110 2 Cases polysyndactyly syndrome 65798 Goodman syndrome 3 Cases Hamel cerebro-palato-cardiac 93946 4 Cases 73 Gorham-Stout disease 300 Cases syndrome 73229 HANAC syndrome 6 Families 377 Gorlin syndrome 1.1 P

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families 457 Harlequin ichthyosis 200 Cases 98879 Hemophilia B 1.665 BP Hemorrhagic disease due to alpha- 199282 Harlequin syndrome 100 Cases 178396 4 Cases 1-antitrypsin Pittsburgh mutation 2115 Harrod syndrome 3 Cases 340 Hemorrhagic fever-renal syndrome 37.0 P * 2116 Hartnup disease 4.2 P 340 Hemorrhagic fever-renal syndrome 0.74 I * 2117 Hartsfield syndrome 17 Cases 324632 Hendra virus infection 7 Cases 99872 Hashimoto-Pritzker syndrome 50 Cases 2136 Hennekam syndrome 50 Cases 2118 Hawkinsinuria 5 Families 2135 Hennekam-Beemer syndrome 3 Cases Hearing loss-familial salivary gland Hepatic fibrosis-renal cysts- 3225 insensitivity to aldosterone 2 Cases 2031 4 Cases syndrome intellectual disability syndrome Heart defect-tongue hamartoma- 890 Hepatic veno-occlusive disease 11.0 P * 1338 4 Cases polysyndactyly syndrome Hepatic veno-occlusive disease- 79124 28 Cases Heart defects-limb shortening immunodeficiency syndrome 1354 2 Cases syndrome Hepatitis B reinfection following 90073 2.0 P * 1350 Heart-hand syndrome type 2 2 Families liver transplantation 402823 Hepatitis delta 40.0 P * 1342 Heart-hand syndrome type 3 3 Cases Heart-hand syndrome, Slovenian 449 Hepatoblastoma 0.02 I * 168796 14 Cases type 88673 Hepatocellular carcinoma 15.0 P * 2119 HEC syndrome 2 Cases 88673 Hepatocellular carcinoma 3.09 I * 178330 Heinz body anemia 10 Cases Hepatoencephalopathy due to Helicoid peripapillary chorioretinal 137681 combined oxidative 2 Cases 86813 100 Cases degeneration phosphorylation defect type 1 Hematopoietic stem cell 90053 0.65 P * 95159 Hepatoerythropoietic porphyria 40 Cases transplantation Hemidystonia-hemiatrophy 91378 Hereditary angioedema 1.5 P * 306741 100 Cases syndrome Hereditary arterial and articular 289601 16 Cases multiple calcification syndrome 141148 Hemifacial myohyperplasia 12 Cases Hereditary breast and ovarian Hemihyperplasia-multiple 145 25.0 P * 276280 10 Cases cancer syndrome lipomatosis syndrome Hereditary bullous dystrophy, 1867 2 Families 2130 Hemimelia 4.15 P * macular type Hemiparkinsonism-hemiatrophy Hereditary cerebral hemorrhage 306669 68 Cases 85458 350 Cases syndrome with amyloidosis 79230 Hemochromatosis type 2 74 Cases 676 Hereditary chronic pancreatitis 0.43 P * 225123 Hemochromatosis type 3 33 Cases Hereditary combined deficiency of 98434 vitamin K-dependent clotting 30 Families 139491 Hemochromatosis type 4 200 Cases factors Hereditary cryohydrocytosis with 280615 Hemoglobinopathy Toms River 10 Cases 398088 53 Cases normal stomatin Hemolytic anemia due to adenylate 86817 7 Families Hereditary cryohydrocytosis with kinase deficiency 168577 3 Cases reduced stomatin Hemolytic anemia due to 712 glucophosphate isomerase 50 Cases 26106 Hereditary diffuse gastric cancer 1.5 I * deficiency Hereditary diffuse Hemolytic anemia due to 313808 27 Cases 90030 3 Cases leukoencephalopathy with axonal glutathione reductase deficiency spheroids and pigmented glia Hemolytic anemia due to red cell 766 5.0 P * Hereditary fibrosing poikiloderma- pyruvate kinase deficiency 221043 tendon contractures-myopathy- 15 Cases 448 Hemophilia 7.7 P * pulmonary fibrosis syndrome 90045 Hereditary folate malabsorption 30 Cases 448 Hemophilia 6.25 I * 469 Hereditary fructose intolerance 5.0 P * 98878 Hemophilia A 4.85 P Hereditary hemorrhagic 774 16.0 P * 98878 Hemophilia A 11.25 BP telangiectasia 98879 Hemophilia B 1.7 P *

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families 3197 Hereditary hyperekplexia 150 Cases 685 Hereditary spastic paraplegia 5.2 P Hereditary hyperferritinemia- Hereditary thermosensitive 163 64 Cases 84093 1 Family cataract syndrome neuropathy Hereditary hypotrichosis with Hereditary thrombocytopenia with 217407 4 Cases 480851 9 Cases recurrent skin vesicles early-onset myelofibrosis Hereditary inclusion body 324381 17 Cases 3467 Hereditary xanthinuria 9.05 I * myopathy type 4 Heritable pulmonary arterial Hereditary inclusion body 275777 0.08 P * hypertension 79091 myopathy-joint contractures- 21 Cases ophthalmoplegia syndrome 79430 Hermansky-Pudlak syndrome 0.15 P Hereditary leiomyomatosis and Hermansky-Pudlak syndrome type 523 200 Cases 231531 2 Cases renal cell cancer 7 Hereditary motor and sensory Hermansky-Pudlak syndrome type 90117 120 Cases 231537 6 Cases neuropathy, Okinawa type 8 Hereditary myopathy with early Hermansky-Pudlak syndrome type 178464 10 Families 280663 2 Cases respiratory failure 9 Hereditary myopathy with lactic Hermansky-Pudlak syndrome with 43115 19 Cases 183678 40 Cases acidosis due to ISCU deficiency neutropenia Hereditary neurocutaneous 1062 9 Families 1930 Herpes simplex virus encephalitis 0.3 I malformation 189 Hidrotic ectodermal dysplasia 1.0 P * Hereditary neuropathy with 640 3.5 P * Hidrotic ectodermal dysplasia, liability to pressure palsies 1808 6 Cases Christianson-Fourie type 279943 Hereditary neutrophilia 16 Cases Hidrotic ectodermal dysplasia, Hereditary North American Indian 1809 4 Cases 168583 36 Cases Halal type childhood cirrhosis High bone mass osteogenesis 314029 2 Cases 30 Hereditary orotic aciduria 20 Cases imperfecta High myopia-sensorineural 79141 Hereditary painful callosities 2 Families 363396 7 Cases deafness syndrome Hereditary pediatric Behçet-like 476102 13 Cases High-grade dysplasia in patients disease 231080 36.0 P * with Barrett esophagus Hereditary persistence of alpha- 168615 19 Families fetoprotein 388 Hirschsprung disease 10.9 BP * Hereditary pheochromocytoma- Hirschsprung disease-deafness- 29072 0.3 I 2155 2 Cases paraganglioma polydactyly syndrome Hereditary progressive mucinous Hirschsprung disease-nail 158025 18 Cases 2153 3 Cases histiocytosis hypoplasia-dysmorphism syndrome Hereditary sclerosing poikiloderma, Hirschsprung disease-type D 221039 9 Cases 2150 4 Cases Weary type brachydactyly syndrome Hereditary sensorimotor Histidinuria-renal tubular defect 280598 4 Cases 2158 5 Cases neuropathy with hyperelastic skin syndrome Hereditary sensory and autonomic 98287 Histiocytic and dendritic cell tumor 0.05 I * 320385 neuropathy due to TECPR2 5 Cases mutation 98293 Hodgkin lymphoma 2.4 I * Hereditary sensory and autonomic 93970 Holmes-Gang syndrome 3 Cases 139564 2 Families neuropathy type 1B Holocarboxylase synthetase Hereditary sensory and autonomic 79242 0.5 BP * 970 35 Cases deficiency neuropathy type 2 2162 Holoprosencephaly 13.4 BP * Hereditary sensory and autonomic 314381 4 Cases Holoprosencephaly- neuropathy type 6 2163 11 Cases Hereditary sensory and autonomic craniosynostosis syndrome 391397 3 Cases Holoprosencephaly-radial heart neuropathy type 7 3186 4 Cases Hereditary sensory and autonomic renal anomalies syndrome 478664 11 Families neuropathy type 8 392 Holt-Oram syndrome 0.7 BP * Hereditary sensory and autonomic 2167 Holzgreve syndrome 3 Cases 139573 neuropathy with deafness and 4 Cases Homocystinuria without global delay 622 73 Cases Hereditary sensory neuropathy- methylmalonic aciduria 456318 6 Families Homozygous familial deafness-dementia syndrome 391665 0.1 P hypercholesterolemia

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families 3322 Hoyeraal-Hreidarsson syndrome 33 Cases Hyperammonemic encephalopathy 401948 due to carbonic anhydrase VA 4 Cases 391417 HSD10 disease 37 Cases deficiency Hyperandrogenism due to 85295 HSD10 disease, atypical type 5 Cases 168588 11 Cases cortisone reductase deficiency 391457 HSD10 disease, neonatal type 3 Cases 276405 Hyperbiliverdinemia 2 Cases HTRA1-related autosomal 482077 dominant cerebral small vessel 21 Cases Hypercholesterolemia due to disease 209902 cholesterol 7alpha-hydroxylase 24 Cases deficiency 228116 Hughes-Stovin syndrome 30 Cases Hypercoagulability syndrome due 56970 Human prion disease 0.3 P * 83639 to glycosylphosphatidylinositol 2 Families deficiency 56970 Human prion disease 0.15 I * 1032 Hyperdibasic aminoaciduria type 1 26 Cases 3265 Humero-radial synostosis 150 Cases 163985 Hyperekplexia-epilepsy syndrome 2 Cases 3266 Humero-radio-ulnar synostosis 30 Cases 168956 Hypereosinophilic syndrome 1.5 P * 94056 Humero-ulnar synostosis 5 Cases Hypergonadotropic hypogonadism- 2410 3 Cases 3383 Humerus trochlea aplasia 5 Cases cataract syndrome Hyperimmunoglobulinemia D with 97340 Hunter-McAlpine craniosynostosis 10 Cases 343 200 Cases periodic fever 399 Huntington disease 2.7 P Hyperinsulinism due to HNF1A 324575 2 Cases deficiency 399 Huntington disease 0.38 I Hyperinsulinism due to INSR 263458 10 Cases 98934 Huntington disease-like 2 50 Families deficiency Huntington disease-like syndrome Hyperinsulinism due to short chain 401901 10 Cases due to C9ORF72 expansions 71212 3-hydroxylacyl-CoA dehydrogenase 10 Cases 93473 Hurler syndrome 0.5 P * deficiency Hyperinsulinism due to UCP2 276556 2 Cases 93473 Hurler syndrome 0.7 BP * deficiency Hutchinson-Gilford progeria 740 0.005 P 682 Hyperkalemic periodic paralysis 0.5 P * syndrome Hyperkeratosis-hyperpigmentation Hutchinson-Gilford progeria 1336 10 Cases 740 0.025 BP syndrome syndrome 412 Hyperlipoproteinemia type 3 10.0 P 498474 Hyaline fibromatosis syndrome 150 Cases Hyperornithinemia- 2177 Hydranencephaly 10.0 BP 415 hyperammonemia- 12.0 P * Hydrocephalus with stenosis of the homocitrullinuria syndrome 2182 1.7 P aqueduct of Sylvius 3416 Hyperostosis corticalis generalisata 35 Cases Hydrocephalus with stenosis of the 2182 1.7 BP aqueduct of Sylvius 443098 Hyperostosis cranialis interna 13 Cases Hydrocephalus-blue sclerae- Hyperparathyroidism-jaw tumor 2186 1 Family 99880 100 Cases nephropathy syndrome syndrome Hyperphenylalaninemia due to Hydrocephalus-costovertebral 508523 6 Cases 2180 dysplasia-Sprengel anomaly 8 Cases DNAJC12 deficiency syndrome Hyperphenylalaninemia due to 238583 0.2 P Hydrocephalus-obesity- tetrahydrobiopterin deficiency 2183 2 Cases hypogonadism syndrome Hyperphosphatasia-intellectual 247262 24 Cases Hydrocephaly-low insertion disability syndrome 2184 2 Cases umbilicus syndrome 157798 Hyperplastic polyposis syndrome 1.0 I Hydrocephaly-tall stature-joint 2181 2 Cases laxity syndrome 1519 Hypertelorism, Teebi type 25 Cases Hypertelorism-hypospadias- Hydrops-lactic acidosis- 2211 3 Families 528091 sideroblastic anemia-multisystemic 1 Case polysyndactyly syndrome failure syndrome Hypertelorism-microtia-facial 2213 9 Cases clefting syndrome 79155 Hydroxykynureninuria 30 Cases Hypertelorism-preauricular sinus- 293958 13 Cases 309147 Hyper-beta-alaninemia 2 Cases punctual pits-deafness syndrome 2220 Hypertrichosis cubiti 28 Cases

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families Hypertrichosis lanuginosa Hypomyelination with atrophy of 2222 100 Cases 139441 19 Cases congenita basal ganglia and cerebellum Hypertrichosis-acromegaloid facial Hypomyelination with brain stem 966 27 Cases appearance syndrome 363412 and spinal cord involvement and leg 13 Cases Hypertrichotic spasticity 1517 50 Cases osteochondrodysplasia, Cantu type Hypomyelination-cerebellar Hypertrophic cardiomyopathy and 447893 atrophy-hypoplasia of the corpus 4 Cases 324525 renal tubular disease due to 3 Cases callosum syndrome mitochondrial DNA mutation Hypomyelination-congenital 85163 10 Cases 2224 Hypertryptophanemia 12 Cases cataract syndrome Hypomyelination- Hyperuricemia-pulmonary 88637 hypogonadotropic hypogonadism- 105 Cases 363694 hypertension-renal failure-alkalosis 4 Families hypodontia syndrome syndrome Hypoparathyroidism-sensorineural Hyperzincemia and 2237 180 Cases 251523 5 Cases deafness-renal disease syndrome hypercalprotectinemia Hypo- and hypermelanotic 436 Hypophosphatasia 0.21 BP * cutaneous macules-retarded Hypopigmentation-punctate 2435 14 Cases growth-intellectual disability 324561 palmoplantar keratoderma 6 Families syndrome syndrome 429 Hypochondroplasia 3.3 P * 722 Hypoplasminogenemia 0.2 P * Hypocomplementemic urticarial 36412 200 Cases 2248 Hypoplastic left heart syndrome 24.0 BP vasculitis Hypoplastic pancreas-intestinal 989 Hypoglossia-hypodactyly syndrome 47 Cases 293864 atresia-hypoplastic gallbladder 16 Cases Hypogonadism-mitral valve syndrome 2233 prolapse-intellectual disability 2 Cases 98723 Hypoplastic right heart syndrome 3.3 BP * syndrome Hyposmia-nasal and ocular Hypogonadotropic hypogonadism- 2230 6 Cases 2250 hypoplasia-hypogonadotropic 2 Cases frontoparietal alopecia syndrome hypogonadism syndrome Hypogonadotropic hypogonadism- 2235 2 Cases Hypospadias-intellectual disability, retinitis pigmentosa syndrome 2261 3 Cases Goldblatt type syndrome Hypogonadotropic hypogonadism- Hypotonia with lactic acidemia and severe microcephaly-sensorineural 137908 4 Cases 293967 4 Cases hyperammonemia hearing loss-dysmorphism syndrome 163690 Hypotonia-cystinuria syndrome 22 Cases Hypotonia-failure to thrive- Hypohidrosis-electrolyte 79507 2 Cases imbalance-lacrimal gland microcephaly syndrome 528105 22 Cases dysfunction-ichthyosis-xerostomia 55654 Hypotrichosis simplex 38 Cases syndrome Hypotrichosis with juvenile macular Hypohidrosis-enamel hypoplasia- 1573 50 Cases degeneration 363523 palmoplantar keratoderma- 12 Cases intellectual disability syndrome 330029 Hypotrichosis-deafness syndrome 1 Case Hypotrichosis-intellectual disability, 238468 Hypohidrotic ectodermal dysplasia 6.7 P * 2266 2 Cases Lopes type Hypohidrotic ectodermal dysplasia 98813 0.2 BP * Hypotrichosis-lymphedema- with immunodeficiency 69735 telangiectasia-renal defect 4 Cases Hypohidrotic ectodermal dysplasia- syndrome 1882 hypothyroidism-ciliary dyskinesia 3 Cases Hypotrichosis-osteolysis- syndrome 307936 periodontitis-palmoplantar 2 Cases Hypoinsulinemic hypoglycemia and 293964 5 Cases keratoderma syndrome body hemihypertrophy 254509 Iatrogenic botulism 180 Cases 681 Hypokalemic periodic paralysis 1.0 P * Hypomandibular faciocranial 2268 ICF syndrome 66 Cases 1790 3 Cases dysostosis Ichthyosis follicularis-alopecia- 2273 40 Cases Hypomyelinating leukodystrophy- photophobia syndrome 137639 ataxia-hypodontia-hypomyelination 8 Cases 79503 Ichthyosis hystrix of Curth-Macklin 10 Cases syndrome Ichthyosis-alopecia-eclabion- Hypomyelination neuropathy- 2680 9 Cases 2269 ectropion-intellectual disability 4 Cases arthrogryposis syndrome syndrome

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families Ichthyosis-hepatosplenomegaly- Immune-mediated necrotizing 2274 2 Cases 206569 300 Cases cerebellar degeneration syndrome myopathy Immunodeficiency by defective 91132 Ichthyosis-hypotrichosis syndrome 11 Cases 34592 30 Cases expression of HLA class 1 Ichthyosis-intellectual disability- Immunodeficiency by defective 2278 dwarfism-renal impairment 4 Cases 572 179 Cases syndrome expression of HLA class 2 Immunodeficiency due to CD25 Ichthyosis-oral and digital 169100 2 Cases 2272 2 Cases deficiency anomalies syndrome Immunodeficiency due to ficolin3 331190 1 Case 88621 Ichthyosis-prematurity syndrome 16 Families deficiency Ichthyosis-short stature- Immunodeficiency due to 363992 brachydactyly-microspherophakia 7 Cases 70592 interleukin-1 receptor-associated 49 Cases syndrome kinase-4 deficiency 930 Idiopathic achalasia 8.0 P Immunodeficiency due to MASP-2 331187 1 Case deficiency 930 Idiopathic achalasia 0.77 I Immunodeficiency due to selective Idiopathic acute eosinophilic 724 100 Cases 70593 anti-polysaccharide antibody 100 Cases pneumonia deficiency 139423 Idiopathic acute transverse myelitis 0.25 I * Immunodeficiency with factor I 200418 35 Families Idiopathic and/or familial anomaly 422 1.0 P * Imperforate oropharynx- pulmonary arterial hypertension 2759 2 Cases costovertebral anomalies syndrome 88 Idiopathic aplastic anemia 0.4 P * Incessant infant ventricular 45453 1.5 BP * 33208 Idiopathic hypersomnia 30.0 P * tachycardia Idiopathic intracranial Inclusion body myopathy with 238624 14.0 P * hypertension 52430 Paget disease of bone and 26 Families frontotemporal dementia 45452 Idiopathic neonatal atrial flutter 1.5 BP * 611 Inclusion body myositis 0.5 P * Idiopathic pleuroparenchymal 494428 37 Cases fibroelastosis 464 Incontinentia pigmenti 1.2 BP * Idiopathic pulmonary arterial 275766 1.1 P * 98848 Indolent systemic mastocytosis 3.8 P * hypertension Infant acute respiratory distress 2032 Idiopathic pulmonary fibrosis 11.5 P * 70587 20.0 P * syndrome 2032 Idiopathic pulmonary fibrosis 3.81 I * Infant acute respiratory distress 70587 3.5 I * Idiopathic pulmonary syndrome 99931 0.0425 I * hemosiderosis 178478 Infant botulism 0.2 BP * 90003 IgG4-related hepatopathy 140 Cases 178478 Infant botulism 0.3 I * IgG4-related retroperitoneal Infantile cerebellar-retinal 49041 0.35 I * 313850 11 Cases fibrosis degeneration IL21-related infantile inflammatory 477661 3 Cases Infantile cerebral and cerebellar bowel disease 402364 atrophy with postnatal progressive 5 Cases Ileal pouch anal anastomosis 238621 3.0 P * microcephaly related faecal incontinence Infantile choroidocerebral 1313 10 Cases 85173 IMAGe syndrome 28 Cases calcification syndrome 42062 Iminoglycinuria 6.68 P * 199267 Infantile digital fibromatosis 200 Cases 42062 Iminoglycinuria 6.67 BP * 238455 Infantile dystonia-parkinsonism 16 Cases Immune dysregulation- Infantile hypertrophic inflammatory bowel disease- 352563 cardiomyopathy due to MRPL44 2 Cases 238569 80 Cases arthritis-recurrent infections deficiency syndrome Infantile hypotonia-oculomotor anomalies-hyperkinetic Immune dysregulation- 522077 11 Cases 37042 polyendocrinopathy-enteropathy-X- 150 Cases movements-developmental delay linked syndrome syndrome Immune thrombocytopenic Infantile multisystem neurologic- 3002 25.0 P * 456312 2 Cases purpura endocrine-pancreatic disease Immune thrombocytopenic 2591 Infantile myofibromatosis 0.67 BP * 3002 6.75 I * purpura 35069 Infantile neuroaxonal dystrophy 150 Cases

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families Infantile onset panniculitis with Intellectual disability-cataracts- 251304 4 Cases 171860 3 Cases uveitis and systemic granulomatosis kyphosis syndrome Infantile onset spinocerebellar Intellectual disability-coarse face- 1186 29 Cases ataxia 397709 macrocephaly-cerebellar 30 Cases Infantile spasms-broad thumbs hypotrophy syndrome 3173 2 Cases syndrome Intellectual disability-craniofacial Infantile spasms-psychomotor 329224 dysmorphism-cryptorchidism 2 Cases retardation-progressive brain syndrome 263410 4 Cases atrophy-basal ganglia disease Intellectual disability- syndrome 3454 developmental delay-contractures 5 Families Infantile-onset ascending syndrome 293168 17 Families hereditary spastic paralysis Intellectual disability- Infantile-onset axonal motor and 3044 dysmorphism-hypogonadism- 4 Cases 457205 sensory neuropathy-optic atrophy- 2 Cases diabetes mellitus syndrome neurodegenerative syndrome Intellectual disability-epilepsy- 468620 3 Cases Infantile-onset generalized extrapyramidal syndrome 494526 dyskinesia with orofacial 8 Cases Intellectual disability-expressive involvement 436151 aphasia-facial dysmorphism 13 Cases Infantile-onset mesial temporal syndrome 391316 lobe epilepsy with severe cognitive 3 Cases Intellectual disability-facial regression 404440 dysmorphism syndrome due to 7 Cases Infantile-onset periodic fever- SETD5 haploinsufficiency 500062 5 Cases panniculitis-dermatosis syndrome Intellectual disability-facial Infantile-onset X-linked spinal 370010 dysmorphism-hand anomalies 3 Cases 1145 14 Families muscular atrophy syndrome Infundibulopelvic stenosis- Intellectual disability-feeding 1849 3 Cases multicystic kidney syndrome 363611 difficulties-developmental delay- 5 Cases microcephaly syndrome 247257 Inhalational anthrax 0.1 P * Intellectual disability-hyperkinetic 369847 5 Cases 254504 Inhalational botulism 10 Cases movement-truncal ataxia syndrome Inherited congenital spastic Intellectual disability-hypoplastic 210141 17 Cases tetraplegia 1495 corpus callosum-preauricular tag 3 Cases syndrome 79361 Inherited epidermolysis bullosa 0.8 P * Intellectual disability-hypotonia- 79361 Inherited epidermolysis bullosa 1.9 BP * 314575 brachycephaly-pyloric stenosis- 2 Cases 63259 Iniencephaly 50.0 P * cryptorchidism syndrome Intellectual disability- 411593 Insulin autoimmune syndrome 404 Cases 457279 macrocephaly-hypotonia-behavioral 16 Cases 97279 Insulinoma 0.25 I abnormalities syndrome Intellectual disability-muscle Intellectual disability syndrome due 464311 35 Cases 457365 weakness-short stature-facial 3 Cases to a DYRK1A point mutation dysmorphism syndrome Intellectual disability, Birk-Barel 166108 1 Family Intellectual disability-myopathy- type 3068 short stature-endocrine defect 2 Cases Intellectual disability, Buenos-Aires 3079 5 Cases syndrome type Intellectual disability-obesity-brain 3080 Intellectual disability, Wolff type 2 Cases 352530 malformations-facial dysmorphism 2 Cases Intellectual disability-balding- syndrome 3041 patella luxation-acromicria 3 Cases Intellectual disability-obesity- syndrome 397973 prognathism-eye and skin 2 Cases Intellectual disability- anomalies syndrome 364577 brachydactyly-Pierre Robin 4 Cases Intellectual disability-polydactyly- 3082 2 Cases syndrome uncombable hair syndrome Intellectual disability-cardiac Intellectual disability-seizures- 508498 anomalies-short stature-joint laxity 18 Cases 513456 abnormal gait-facial dysmorphism 15 Cases syndrome syndrome Intellectual disability-cataracts- Intellectual disability-seizures- 3042 calcified pinnae-myopathy 13 Cases 369837 hypophosphatasia-ophthalmic- 4 Cases syndrome skeletal anomalies syndrome

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families Intellectual disability-seizures- Isolated generalized anhidrosis 369950 7 Cases 468666 7 Cases macrocephaly-obesity syndrome with normal sweat glands Intellectual disability-severe speech Isolated hereditary congenital 391372 48 Cases 306527 8 Families delay-mild dysmorphism syndrome facial paralysis Intellectual disability-short stature- 3074 6 Cases 2345 Isolated Klippel-Feil syndrome 2.0 P * hypertelorism syndrome Intellectual disability-sparse hair- 2345 Isolated Klippel-Feil syndrome 0.6 BP * 3051 61 Cases brachydactyly syndrome Isolated microphthalmia- 2542 5.3 BP * Intellectual disability-spasticity- anophthalmia-coloboma 1891 3 Cases ectrodactyly syndrome Isolated neonatal sclerosing 480556 4 Cases Intellectual disability-strabismus cholangitis 363528 34 Cases syndrome 718 Isolated Pierre Robin syndrome 5.0 BP * 981 Internal carotid agenesis 100 Cases 35098 Isolated plagiocephaly 3.0 BP Interstitial granulomatous 79099 53 Cases 2924 Isolated polycystic liver disease 1.0 P * dermatitis with arthritis Isolated sedoheptulokinase 182095 Interstitial lung disease 5.4 I * 440713 2 Cases deficiency Intestinal obstruction in the 823 Isolated spina bifida 18.6 BP * 314376 newborn due to guanylate cyclase 16 Cases 2C deficiency 457083 Isolated splenogonadal fusion 145 Cases Intractable diarrhea-choanal Isolated split hand-split foot 137622 3 Cases 2440 5.4 BP * atresia-eye anomalies syndrome malformation Intrauterine growth restriction- Isolated succinate-CoQ reductase 3208 37 Cases 436144 short stature-early adult-onset 15 Cases deficiency diabetes syndrome 99731 Isolated sulfite oxidase deficiency 50 Cases Inverse Klippel-Trénaunay 329324 15 Cases syndrome 454750 Isolated tracheoesophageal fistula 2.2 BP 209981 IRIDA syndrome 75 Cases 3366 Isolated trigonocephaly 6.7 BP * 209943 IRVAN syndrome 30 Cases 2306 Isotretinoin-like syndrome 6 Cases 84142 Isaac syndrome 150 Cases 33 Isovaleric acidemia 1.0 P * 229717 Isolated agammaglobulinemia 0.3 P 439254 ITM2B amyloidosis 2 Families 1048 Isolated anencephaly/exencephaly 35.0 BP * 435 Ito hypomelanosis 10.85 I * 250923 Isolated aniridia 1.31 I * 457375 ITPA-related encephalopathy 7 Cases 557 Isolated anorectal malformation 20.0 BP 2307 IVIC syndrome 4 Families Isolated anterior cervical 3387 20 Cases 1540 Jackson-Weiss syndrome 200 Cases hypertrichosis 2308 Jacobsen syndrome 1.0 BP * 1134 Isolated arrhinia 20 Cases Isolated autosomal dominant 1873 Jalili syndrome 49 Cases 199326 hypomagnesemia, Glaudemans 21 Cases 79139 Japanese encephalitis 0.65 I * type 313795 Jawad syndrome 4 Cases 30391 Isolated biliary atresia 18.5 BP 90647 Jervell and Lange-Nielsen syndrome 0.3 P 2343 Isolated cloverleaf skull syndrome 120 Cases 474 Jeune syndrome 1.4 BP * 79143 Isolated congenital anonychia 50 Cases 324999 JMP syndrome 3 Cases 88620 Isolated congenital anosmia 15 Cases 2315 Johanson-Blizzard syndrome 0.4 BP * 91396 Isolated cryptophthalmia 30 Cases Isolated Dandy-Walker 475 Joubert syndrome 1.125 BP 217 2.1 P * malformation Joubert syndrome and related 140874 1.1 BP Isolated Dandy-Walker disorders 217 1.0 BP * malformation Joubert syndrome with hepatic 1454 8 Cases 1885 Isolated ectopia lentis 90 Cases defect Joubert syndrome with Jeune 397715 8 Cases 93928 Isolated epispadias 2.4 BP * asphyxiating thoracic dystrophy Isolated focal non-epidermolytic Joubert syndrome with oculorenal 448264 2 Cases 2318 17 Cases palmoplantar keratoderma defect

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families 2319 Juberg-Hayward syndrome 13 Cases 480 Kearns-Sayre syndrome 2.0 P * 93972 Juberg-Marsidi syndrome 16 Cases 2662 Keipert syndrome 12 Cases Junctional epidermolysis bullosa 79405 9 Cases 2333 Kenny-Caffey syndrome 65 Cases inversa 435628 3 Cases Junctional epidermolysis bullosa Keppen-Lubinsky syndrome 306504 3 Cases Keratoderma hereditarium with respiratory and renal 494 50 Cases involvement mutilans Junctional epidermolysis bullosa, Keratoderma hereditarium 79404 0.17 BP 79395 50 Cases generalized severe mutilans with ichthyosis Junctional epidermolysis bullosa- Keratosis follicularis-dwarfism- 79403 100 Cases 2339 6 Cases pyloric atresia syndrome cerebral atrophy syndrome Keratosis palmaris et plantaris- 2321 Jung-Wolff-Back-Stahl syndrome 2 Cases 86919 20 Cases clinodactyly syndrome 1941 Juvenile absence epilepsy 7.5 I * 293807 Ketamine-induced biliary dilatation 2 Cases Juvenile cataract-microcornea- 247794 12 Cases Ketoacidosis due to renal glucosuria syndrome 438075 monocarboxylate transporter-1 9 Cases 93672 Juvenile dermatomyositis 0.295 I deficiency 248111 Juvenile Huntington disease 0.6 P * 85202 Keutel syndrome 30 Cases 248111 Juvenile Huntington disease 0.04 I * 477 KID syndrome 100 Cases 2028 Juvenile hyaline fibromatosis 70 Cases 50918 Kikuchi-Fujimoto disease 1052 Cases 92 Juvenile idiopathic arthritis 1.5 I * 482 Kimura disease 300 Cases 86834 Juvenile myelomonocytic leukemia 0.1 P * 2908 Kindler syndrome 250 Cases 2801 Juvenile Paget disease 50 Cases 99741 King-Denborough syndrome 18 Cases 79076 Juvenile polyposis of infancy 11 Cases 261494 Kleefstra syndrome 114 Cases Kleefstra syndrome due to 9q34 2929 Juvenile polyposis syndrome 3.85 I * 96147 86 Cases microdeletion 247604 Juvenile primary lateral sclerosis 4 Cases Kleefstra syndrome due to a point 261652 23 Cases 26137 Juvenile temporal arteritis 20 Cases mutation KLHL9-related early-onset distal Juvenile-onset diabetes mellitus- 399081 10 Cases 445062 central and peripheral 5 Cases myopathy Klippel-Feil anomaly-myopathy- neurodegeneration syndrome 447974 2 Cases facial dysmorphism syndrome 2322 Kabuki syndrome 3.1 P * 90308 Klippel-Trénaunay syndrome 0.007 P * 254519 Kagami-Ogata syndrome 84 Cases 96169 Koolen-De Vries syndrome 4.0 P * Kagami-Ogata syndrome due to 254534 7 Cases Koolen-De Vries syndrome due to a maternal 14q32.2 hypermethylation 363965 4 Cases Kagami-Ogata syndrome due to point mutation 254528 8 Cases maternal 14q32.2 microdeletion 99749 Kostmann syndrome 45 Cases Kagami-Ogata syndrome due to 2351 Kousseff syndrome 8 Cases 96334 paternal uniparental disomy of 37 Cases chromosome 14 487 Krabbe disease 1.0 P * 478 Kallmann syndrome 3.75 P * 487 Krabbe disease 0.7 BP Kallmann syndrome-heart disease 2326 8 Cases 306674 Kufor-Rakeb syndrome 16 Cases syndrome 454745 Kuru 2700 Cases 33276 Kaposi sarcoma 0.34 I * 1149 Kuskokwim syndrome 8 Families 2328 Kapur-Toriello syndrome 6 Cases Kyphoscoliosis-lateral tongue 2329 Karsch-Neugebauer syndrome 11 Cases 496689 atrophy-hereditary spastic 12 Cases 401996 Karyomegalic interstitial nephritis 12 Families paraplegia syndrome Kyphosis-lateral tongue atrophy- 496686 3 Cases 2330 Kasabach-Merritt syndrome 300 Cases myofibrillar myopathy syndrome 2332 KBG syndrome 100 Cases 79314 L-2-hydroxyglutaric aciduria 140 Cases KCNQ2-related epileptic L-Arginine:glycine 439218 11 Families 35704 9 Cases encephalopathy amidinotransferase deficiency

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families 440731 L-ferritin deficiency 2 Cases 506 Leigh syndrome 2.0 P * Lacrimoauriculodentodigital 2363 100 Cases 506 Leigh syndrome 2.8 BP * syndrome 507 Leishmaniasis 0.1 P * 501 Lafora disease 300 Cases 507 25.0 I LAMA5-related multisystemic Leishmaniasis 521450 11 Cases syndrome 140936 Lelis syndrome 9 Cases LAMB2-related infantile-onset 306507 14 Cases 137839 Lemierre syndrome 10.0 I * nephrotic syndrome 1296 Lambert syndrome 4 Cases 2382 Lennox-Gastaut syndrome 15.0 P * Lambert-Eaton myasthenic 2382 Lennox-Gastaut syndrome 0.1 I * 43393 0.35 P syndrome Lenz-Majewski hyperostotic 2658 10 Cases 313 Lamellar ichthyosis 0.55 P * dwarfism 2632 Langer mesomelic dysplasia 50 Cases 548 Leprosy 3.7 I 389 Langerhans cell histiocytosis 1.5 P * 509 Leptospirosis 0.12 I * 626 Large congenital melanocytic nevus 2.75 P * 510 Lesch-Nyhan syndrome 0.34 BP * Lethal acantholytic epidermolysis 633 Laron syndrome 0.3 P * 158687 4 Cases bullosa Laron syndrome with Lethal arteriopathy syndrome due 220465 10 Cases 314718 22 Cases immunodeficiency to fibulin-4 deficiency 503 Larsen syndrome 0.4 BP * Lethal arthrogryposis-anterior horn 53696 15 Cases Larsen-like osseous dysplasia-short cell disease syndrome 2370 3 Cases Lethal ataxia with deafness and stature syndrome 1187 4 Families optic atrophy 284139 Larsen-like syndrome, B3GAT3 type 14 Cases Lethal congenital contracture 137776 1 Family 2808 Laryngeal abductor paralysis 9 Cases syndrome type 2 Laryngeal abductor paralysis- Lethal congenital contracture 2375 20 Cases 137783 14 Cases intellectual disability syndrome syndrome type 3 2004 Laryngotracheoesophageal cleft 7.5 BP * 1972 Lethal faciocardiomelic dysplasia 3 Cases Laryngotracheoesophageal cleft Lethal fetal brain malformation- 93940 30 Cases type 3 444069 duodenal atresia-bilateral renal 4 Cases Laryngotracheoesophageal cleft hypoplasia syndrome 93941 20 Cases type 4 Lethal fetal Late-onset distal myopathy, 439897 cerebrorenogenitourinary 2 Cases 98912 11 Cases Markesbery-Griggs type agenesis/hypoplasia syndrome Lethal hemolytic anemia-genital 228227 Late-onset focal dermal elastosis 5 Cases 1046 2 Cases anomalies syndrome Late-onset junctional epidermolysis 79406 37 Cases Lethal hydranencephaly- bullosa 480528 2 Cases diaphragmatic hernia syndrome Late-onset localized junctional Lethal intrauterine growth 231556 epidermolysis bullosa-intellectual 2 Cases 2570 restriction-cortical malformation- 4 Cases disability syndrome congenital contractures syndrome 2789 Lateral meningocele syndrome 14 Cases 2347 Lethal Kniest-like dysplasia 2 Cases 46059 Lathosterolosis 4 Cases 2371 Lethal Larsen-like syndrome 8 Cases 2378 Laurin-Sandrow syndrome 14 Cases Lethal left ventricular non- compaction-seizures-hypotonia- 650 LCAT deficiency 125 Cases 478049 4 Cases cataract-developmental delay 330015 Lead poisoning 2.3 P * syndrome Lethal multiple pterygium 65 Leber congenital amaurosis 2.5 P 33108 28 Families syndrome 65 2.5 BP Leber congenital amaurosis Lethal neonatal spasticity-epileptic 435845 8 Cases 104 Leber hereditary optic neuropathy 4.3 P encephalopathy syndrome Lethal occipital encephalocele- 99718 Leber plus disease 0.04 P * 293925 5 Cases skeletal dysplasia syndrome 549 Legionellosis 1.3 I * Lethal omphalocele-cleft palate 2736 3 Cases syndrome 137605 Legius syndrome 2.2 BP

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families Lethal osteosclerotic bone Limbic encephalitis with DPP6 1832 40 Cases 329341 4 Cases dysplasia antibodies Lethal polymalformative syndrome, Limbic encephalitis with neurexin-3 210144 10 Cases 498700 5 Cases Boissel type antibodies 1423 Lethal recessive chondrodysplasia 4 Cases 220407 Limited systemic sclerosis 200 Cases 99870 Letterer-Siwe disease 0.2 P * 140933 Linear atrophoderma of Moulin 30 Cases 2968 Leukocyte adhesion deficiency 350 Cases 228236 Linear focal elastosis 30 Cases Leukocyte adhesion deficiency type 99842 0.1 P * 2612 Linear nevus sebaceus syndrome 10.0 BP * I LIPE-related familial partial Leukocyte adhesion deficiency type 435660 4 Cases 99843 7 Cases lipodystrophy II Lipoatrophy with diabetes, Leukocyte adhesion deficiency type 99844 40 Cases leukomelanodermic papules, liver 156156 1 Case III steatosis, and hypertrophic Leukoencephalopathy with cardiomyopathy 139444 29 Cases bilateral anterior temporal lobe Lipodystrophy due to peptidic cysts 1979 1 Family growth factors deficiency Leukoencephalopathy with brain Lipodystrophy-intellectual 137898 stem and spinal cord involvement- 127 Cases 50811 3 Cases disability-deafness syndrome high lactate syndrome Leukoencephalopathy with mild 401859 Lipoic acid synthetase deficiency 3 Cases 363540 cerebellar ataxia and white matter 6 Cases 530 Lipoid proteinosis 500 Cases edema 69078 Liposarcoma 1.0 I * Leukoencephalopathy-dystonia- 163684 2 Cases motor neuropathy syndrome 401862 Lipoyl transferase 1 deficiency 4 Cases Leukoencephalopathy-metaphyseal 83629 4 Cases 98955 Lisch epithelial corneal dystrophy 36 Cases chondrodysplasia syndrome Lissencephaly due to TUBA1A Leukoencephalopathy- 171680 15 Cases 2386 palmoplantar keratoderma 4 Cases mutation Lissencephaly type 3-familial fetal syndrome 86821 5 Cases Leukoencephalopathy-thalamus akinesia sequence syndrome Lissencephaly type 3-metacarpal 314051 and brainstem anomalies-high 14 Cases 86822 2 Cases lactate syndrome bone dysplasia syndrome Lissencephaly with cerebellar Leukomelanoderma-infantilism- 100012 50 Cases 1816 intellectual disability-hypodontia- 4 Cases hypoplasia type B hypotrichosis syndrome Lissencephaly with cerebellar 100013 2 Cases Leukonychia totalis-acanthosis- hypoplasia type C 210133 nigricans-like lesions-abnormal hair 11 Cases 533 Listeriosis 0.337 I syndrome LMNA-related cardiocutaneous 363618 5 Cases 48162 Lewis-Sumner syndrome 0.9 P * progeria syndrome 65285 Lhermitte-Duclos disease 220 Cases 2407 LOC syndrome 50 Cases 524 Li-Fraumeni syndrome 6.0 P 93685 Localized Castleman disease 1.0 P Localized junctional epidermolysis 525 Lichen planopilaris 300 Cases 251393 20 Cases bullosa, non-Herlitz type 254478 Lichen planus pemphigoides 100 Cases Localized lichen myxedematosus 2390 Lichtenstein syndrome 2 Cases 90398 with mixed features of different 10 Cases subtypes 526 Liddle syndrome 80 Cases Localized lichen myxedematosus 99812 LIG4 syndrome 28 Cases 90399 with monoclonal gammopathy or 5 Cases systemic symptoms 97231 Ligneous conjunctivitis 200 Cases 2406 Locked-in syndrome 33 Cases 263 Limb-girdle muscular dystrophy 2.32 P 60030 Loeys-Dietz syndrome 52 Families Limb-girdle muscular dystrophy 445110 2 Cases Long chain 3-hydroxyacyl-CoA due to POMK deficiency 5 8.0 P * dehydrogenase deficiency 69085 Limb-mammary syndrome 38 Cases Long chain 3-hydroxyacyl-CoA 5 1.0 BP * 171673 Limbal stem cell deficiency 3.0 P * dehydrogenase deficiency 2408 Lowe-Kohn-Cohen syndrome 1 Family

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families Lower limb malformation- 2487 2 Cases 420179 Malan overgrowth syndrome 20 Cases hypospadias syndrome Lower motor neuron syndrome 673 Malaria 3.0 P * 276435 17 Families with late-adult onset 673 Malaria 73.0 I 844 Lown-Ganong-Levine syndrome 12 Cases Male hypergonadotropic hypogonadism-intellectual 2409 Lowry-MacLean syndrome 3 Cases 2234 2 Cases disability-skeletal anomalies 1824 Lowry-Wood syndrome 8 Cases syndrome Maligant granulosa cell tumor of 83628 LUMBAR syndrome 54 Cases 99915 0.12 I * the ovary Lung agenesis-heart defect-thumb 1120 9 Cases anomalies syndrome 679 Malignant atrophic papulosis 200 Cases Lung fibrosis-immunodeficiency- Malignant dysgerminomatous germ 137631 2 Cases 99912 0.04 I * 46,XX gonadal dysgenesis syndrome cell tumor of the ovary 90283 Lupus erythematosus tumidus 250 Cases 398934 Malignant epithelial tumor of ovary 9.39 I * Malignant epithelial tumor of 91546 Lyme disease 21.9 I 276145 0.73 I * salivary glands 538 Lymphangioleiomyomatosis 0.15 P 35807 Malignant germ cell tumor of ovary 0.08 I * 538 Lymphangioleiomyomatosis 0.0135 I Malignant melanoma of the 168999 0.26 I * Lymphedema-atrial septal defects- mucosa 86915 5 Cases facial changes syndrome Malignant migrating partial 293181 114 Cases Lymphedema-cerebral seizures of infancy 86914 5 Cases arteriovenous anomaly syndrome Malignant mixed Müllerian tumor 213512 0.12 I * Lymphedema-posterior choanal of the ovary 99141 6 Cases atresia syndrome Malignant non-epithelial tumor of 398940 0.43 I * 275761 Lysosomal acid lipase deficiency 2.0 P * ovary Malignant peripheral nerve sheath Macrocephaly-developmental 3148 1.0 I 397612 9 Cases tumor delay syndrome Malignant peritoneal Macrocephaly-intellectual 168811 1.5 P * 210548 40 Cases mesothelioma disability-autism syndrome Malignant sex cord stromal tumor Macrocephaly-intellectual 35808 1.85 P * of ovary 466791 disability-left ventricular non 6 Cases Malignant sex cord stromal tumor compaction syndrome 35808 0.13 I * of ovary Macrocephaly-intellectual 457485 disability-neurodevelopmental 8 Cases 398987 Malignant teratoma of ovary 0.07 I * disorder-small thorax syndrome 252212 Malignant triton tumor 170 Cases Macrocephaly-short stature- 2427 2 Cases paraplegia syndrome 180242 Malignant tumor of fallopian tubes 1.0 P * Macrosomia-microphthalmia-cleft 2432 5 Cases 398043 Malignant tumor of penis 1.075 I * palate syndrome 943 34 Cases Macrostomia-preauricular tags- Malonic aciduria 83619 external ophthalmoplegia 9 Cases 52417 MALT lymphoma 4.0 P * syndrome 52417 MALT lymphoma 0.3 I * Macrothrombocytopenia with 220448 2 Cases mitral valve insufficiency 238744 Mammary-digital-nail syndrome 11 Cases Macrothrombocytopenia- 397941 MAN1B1-CDG 25 Cases lymphedema-developmental delay- 487796 2 Cases facial dysmorphism-camptodactyly Mandibular hypoplasia-deafness- syndrome 363649 progeroid features-lipodystrophy 21 Cases Macular coloboma-cleft palate- syndrome 91494 2 Cases hallux valgus syndrome 2457 Mandibuloacral dysplasia 40 Cases 137867 Madras motor neuron disease 200 Cases Mandibulofacial dysostosis with 443995 4 Cases alopecia 163634 Maffucci syndrome 250 Cases Mandibulofacial dysostosis- 324972 MAGIC syndrome 21 Cases 357158 macroblepharon-macrostomia 2 Cases syndrome 77297 Majeed syndrome 4 Families Mandibulofacial dysostosis- 79113 107 Cases 87503 Mal de Meleda 1.0 P microcephaly syndrome

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families Medial condensing osteitis of the 52416 Mantle cell lymphoma 3.5 P * 57196 58 Cases clavicle 511 Maple syrup urine disease 0.67 BP 2006 Median cleft lip/mandibule 70 Cases 99826 Marburg hemorrhagic fever 500 Cases 2699 Median nodule of the upper lip 4 Families 221074 Marchiafava-Bignami disease 250 Cases 370127 Medich giant platelet syndrome 3 Cases 2461 Marden-Walker syndrome 50 Cases Medium chain acyl-CoA 42 6.85 P 558 Marfan syndrome 15.0 P dehydrogenase deficiency Medium chain acyl-CoA 558 Marfan syndrome 25.0 I * 42 12.0 BP * dehydrogenase deficiency Marfanoid habitus-autosomal 171851 MEDNIK syndrome 5 Families 2463 recessive intellectual disability 4 Cases syndrome 1332 Medullary thyroid carcinoma 7.0 P * Marfanoid habitus-inguinal hernia- 314041 2 Cases 1332 Medullary thyroid carcinoma 0.22 I * advanced bone age syndrome 616 Medulloblastoma 1.0 P * 2464 Marfanoid syndrome, De Silva type 6 Cases 616 Medulloblastoma 0.11 I * 300912 Marginal zone lymphoma 7.0 P * 98954 Meesmann corneal dystrophy 250 Cases 300912 Marginal zone lymphoma 0.3 I * Megaconial congenital muscular 280671 19 Cases 559 Marinesco-Sjögren syndrome 200 Cases dystrophy 560 Marshall syndrome 17 Cases Megacystis-microcolon-intestinal 2241 230 Cases hypoperistalsis syndrome 561 Marshall-Smith syndrome 33 Cases Megalencephalic Martinique crinkled retinal pigment 466718 14 Cases 2478 leukoencephalopathy with 100 Cases epitheliopathy subcortical cysts 98292 Mastocytosis 9.0 P * Megalencephaly-capillary 60040 malformation-polymicrogyria 170 Cases 2209 Maternal phenylketonuria 10.0 I * syndrome 411712 Maternal riboflavin deficiency 2 Cases Megalencephaly-polymicrogyria- Maternal uniparental disomy of 83473 postaxial polydactyly- 62 Cases 96181 15 Cases chromosome 6 hydrocephalus syndrome Maternal uniparental disomy of Megalencephaly-severe 97678 3 Cases chromosome 13 457359 kyphoscoliosis-overgrowth 2 Cases Maternal uniparental disomy of syndrome 96186 12 Cases chromosome 20 352328 MEGDEL syndrome 67 Cases Maternal uniparental disomy of 96187 2 Cases 85282 MEHMO syndrome 8 Cases chromosome 21 Maternal uniparental disomy of 550 MELAS 0.6 P * 96188 4 Cases chromosome 22 2482 Melhem-Fahl syndrome 2 Cases Maternally-inherited diabetes and 225 0.1 P * deafness 2484 Melnick-Needles syndrome 70 Cases 2470 Matthew-Wood syndrome 43 Cases 2485 Melorheostosis 0.09 P * Mayer-Rokitansky-Küster-Hauser Melorheostosis with 3109 11.0 BP 1879 5 Families syndrome osteopoikilosis Mayer-Rokitansky-Küster-Hauser 2578 1.0 BP * 401973 MEND syndrome 19 Cases syndrome type 2 Mendelian susceptibility to 57782 Mazabraud syndrome 54 Cases 99898 mycobacterial diseases due to 31 Cases complete IFNgammaR1 deficiency 562 McCune-Albright syndrome 0.55 P * Mendelian susceptibility to 2471 McDonough syndrome 2 Families 319547 mycobacterial diseases due to 13 Cases 2473 McKusick-Kaufman syndrome 90 Cases complete IFNgammaR2 deficiency Mendelian susceptibility to McLeod neuroacanthocytosis 59306 100 Cases 319558 mycobacterial diseases due to 49 Cases syndrome complete IL12B deficiency 3097 Meacham syndrome 13 Cases Mendelian susceptibility to 564 Meckel syndrome 4.0 BP 319552 mycobacterial diseases due to 180 Cases complete IL12RB1 deficiency 70588 Meconium aspiration syndrome 2.44 P *

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families Mendelian susceptibility to Methylmalonic acidemia with 79282 500 Cases 319563 mycobacterial diseases due to 6 Cases homocystinuria, type cblC complete ISG15 deficiency Methylmalonic acidemia with 79283 17 Cases Mendelian susceptibility to homocystinuria, type cblD 319600 mycobacterial diseases due to 2 Cases Methylmalonic acidemia with 369955 2 Cases partial IRF8 deficiency homocystinuria, type cblJ Mendelian susceptibility to Methylmalonic acidemia with 369962 18 Cases 319595 mycobacterial diseases due to 17 Cases homocystinuria, type cblX partial STAT1 deficiency Methylmalonic aciduria due to 280183 5 Cases 2495 Meningioma 0.15 I * transcobalamin receptor defect Metopic ridging-ptosis-facial 565 Menkes disease 0.33 BP * 502430 8 Cases dysmorphism syndrome Menstrual cycle-dependent 498251 5 Cases 309025 Mevalonate kinase deficiency 300 Cases periodic fever 508093 MEPAN syndrome 7 Cases 29 Mevalonic aciduria 30 Cases Mesoaxial synostotic syndactyly MFF-related encephalopathy due 157801 6 Families with phalangeal reduction 485421 to mitochondrial and peroxisomal 4 Cases fission defect 2496 Mesomelia-synostoses syndrome 5 Cases 79329 MGAT2-CDG 13 Cases Mesomelic dwarfism-cleft palate- 2631 2 Cases camptodactyly syndrome 2510 Micro syndrome 203 Cases Mesomelic dysplasia, Kantaputra Microbrachycephaly-ptosis-cleft lip 1836 5 Families 2511 2 Cases type syndrome Microcephalic osteodysplastic 2499 Metachondromatosis 25 Cases 85172 4 Cases dysplasia, Saul-Wilson type 512 Metachromatic leukodystrophy 0.1 P * Microcephalic osteodysplastic 2637 150 Cases 512 Metachromatic leukodystrophy 1.47 BP * primordial dwarfism type II Microcephalic osteodysplastic 1240 Metaphyseal acroscyphodysplasia 4 Cases 2636 30 Cases primordial dwarfism types I and III 1040 Metaphyseal anadysplasia 27 Cases Microcephalic primordial dwarfism 468631 12 Cases Metaphyseal chondrodysplasia, due to RTTN deficiency 33067 16 Cases Jansen type Microcephalic primordial dwarfism 329228 10 Cases Metaphyseal chondrodysplasia, due to ZNF335 deficiency 166038 2 Cases Kaitila type Microcephalic primordial dwarfism, 319671 10 Cases Metaphyseal chondrodysplasia, Alazami type 2501 18 Cases Spahr type Microcephalic primordial dwarfism, 319675 2 Cases Metaphyseal dysostosis-intellectual Dauber type 2502 disability-conductive deafness 3 Cases Microcephalic primordial dwarfism, 2617 3 Cases syndrome Montreal type Metaphyseal dysplasia-maxillary Microcephalic primordial dwarfism, 2504 2 Families 2643 2 Cases hypoplasia-brachydacty syndrome Toriello type Metaplastic carcinoma of the Microcephalic primordial dwarfism- 213531 0.06 I * 436182 2 Cases breast insulin resistance syndrome Microcephaly-albinism-digital 2635 Metatropic dysplasia 0.2 BP * 2513 2 Cases anomalies syndrome 1923 Methimazole embryofetopathy 40 Cases Microcephaly-brachydactyly- 3433 3 Cases Methotrexate toxicity or dose kyphoscoliosis syndrome 413690 3.0 P * selection Microcephaly-brain defect- 2523 3 Cases Methylcobalamin deficiency type spasticity-hypernatremia syndrome 2169 27 Cases cblE Microcephaly-capillary 294016 10 Cases Methylcobalamin deficiency type malformation syndrome 2170 33 Cases cblG Microcephaly-cardiac defect-lung 2516 3 Cases Methylmalonic acidemia due to malsegmentation syndrome 308425 methylmalonyl-CoA epimerase 7 Cases Microcephaly-cardiomyopathy 2515 3 Cases deficiency syndrome Methylmalonic acidemia with 26 500 Cases Microcephaly-cerebellar homocystinuria 329332 hypoplasia-cardiac conduction 4 Cases Methylmalonic acidemia with defect syndrome 79284 15 Cases homocystinuria type cblF Microcephaly-cervical spine fusion 2522 2 Cases anomalies syndrome

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families Microcephaly-cleft palate- Microlissencephaly-micromelia 50810 2 Cases 2521 abnormal retinal pigmentation 3 Cases syndrome syndrome Microphthalmia with brain and 139471 2 Families Microcephaly-complex motor and digit anomalies 423894 sensory axonal neuropathy 3 Cases Microphthalmia with limb 1106 35 Families syndrome anomalies Microcephaly-congenital cataract- Microphthalmia with linear skin 488168 5 Cases 2556 55 Cases psoriasiform dermatitis syndrome defects syndrome Microcephaly-corpus callosum and Microphthalmia-anophthalmia- 98555 8.3 BP * cerebellar vermis hypoplasia-facial coloboma 500159 4 Cases dysmorphism-intellectual disability Microphthalmia-brain atrophy 77299 3 Cases syndrom syndrome Microcephaly-corpus callosum Microphthalmia-microtia-fetal 2547 2 Cases 457284 hypoplasia-intellectual disability- 5 Cases akinesia syndrome facial dysmorphism syndrome Microphthalmia-retinitis Microcephaly-deafness-intellectual 2533 2 Cases 251279 pigmentosa-foveoschisis-optic disc 9 Cases disability syndrome drusen syndrome Microcephaly-facial dysmorphism- 727 Microscopic polyangiitis 1.0 I * 521445 ocular anomalies-multiple 10 Cases congenital anomalies syndrome 83463 Microtia 15.5 BP Microcephaly-facio-cardio-skeletal 217026 5 Cases Microtia-eye coloboma- syndrome, Hadziselimovic type 139450 imperforation of the nasolacrimal 1 Family Microcephaly-glomerulonephritis- duct syndrome 2172 2 Cases marfanoid habitus syndrome 289522 Microtriplication 11q24.1 2 Cases Microcephaly-intellectual disability-sensorineural hearing 2290 Microvillus inclusion disease 137 Cases 457351 14 Cases loss-epilepsy-abnormal muscle tone 2557 Mietens syndrome 9 Cases syndrome Microcephaly-lymphedema- 2558 Mikati-Najjar-Sahli syndrome 5 Cases 2526 50 Families chorioretinopathy syndrome 169799 Mild hemophilia B 0.6 P * Microcephaly-microcornea 2528 2 Cases Mild spondyloepiphyseal dysplasia syndrome, Seemanova type 93279 due to COL2A1 mutation with early- 4 Families Microcephaly-polymicrogyria- 171703 4 Cases onset osteoarthritis corpus callosum agenesis syndrome 531 Miller-Dieker syndrome 1.0 BP * Microcephaly-seizures-intellectual 2519 2 Cases disability-heart disease syndrome 98919 Miller-Fisher syndrome 0.1 I * Microcephaly-short stature- Minimal pigment oculocutaneous 352734 10 Cases 423306 intellectual disability-facial 2 Cases albinism type 1 dysmorphism syndrome 494433 MIRAGE syndrome 19 Cases Microcephaly-thin corpus callosum- 397951 4 Cases intellectual disability syndrome Mirror polydactyly-vertebral Microcornea-corectopia-macular 3004 segmentation-limbs defects 0.3 P * 2535 3 Cases hypoplasia syndrome syndrome Microcornea-glaucoma-absent MITF-related melanoma and renal 2536 4 Cases frontal sinuses syndrome 293822 cell carcinoma predisposition 30 Families syndrome Microcornea-myopic chorioretinal 369970 14 Cases atrophy-telecanthus syndrome Mitochondrial DNA depletion 1933 syndrome, encephalomyopathic 2 Cases Microcornea-posterior form with methylmalonic aciduria 231736 megalolenticonus-persistent fetal 8 Cases vasculature-coloboma syndrome Mitochondrial DNA depletion 255235 syndrome, encephalomyopathic 5 Cases Microcytic anemia with liver iron 83642 3 Cases form with renal tubulopathy overload Mitochondrial DNA depletion Microduplication Xp11.22p11.23 217377 12 Cases syndrome, encephalomyopathic syndrome 369897 20 Cases form with variable craniofacial Microgastria-limb reduction defect 2538 16 Cases anomalies syndrome Mitochondrial DNA depletion Micrognathia-recurrent infections- 363534 syndrome, hepatocerebrorenal 3 Cases 476126 behavioral abnormalities-mild 4 Cases form intellectual disability syndrome

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families Mitochondrial DNA depletion 254875 45 Cases 1723 Mosaic trisomy 2 22 Cases syndrome, myopathic form Mitochondrial DNA-related 100071 Mosaic trisomy 3 6 Cases 1349 2 Families cardiomyopathy and hearing loss 1747 Mosaic trisomy 7 31 Cases Mitochondrial hypertrophic 96061 Mosaic trisomy 8 3.0 I * 314637 cardiomyopathy with lactic acidosis 8 Cases due to MTO1 deficiency 99776 Mosaic trisomy 9 50 Cases Mitochondrial membrane protein- 289560 0.1 P 1708 Mosaic trisomy 16 226 Cases associated neurodegeneration Mitochondrial myopathy and 1711 Mosaic trisomy 17 31 Cases 2598 7 Cases sideroblastic anemia Mosaic variegated aneuploidy 1052 41 Cases Mitochondrial myopathy-cerebellar syndrome 502423 ataxia-pigmentary retinopathy 9 Cases 3347 Mounier-Kühn syndrome 300 Cases syndrome Mitochondrial myopathy-lactic 2152 Mowat-Wilson syndrome 1.7 BP * 2597 2 Cases acidosis-deafness syndrome Moyamoya angiopathy-short Mitochondrial stature-facial dysmorphism- 280679 9 Cases 298 neurogastrointestinal 0.1 P * hypergonadotropic hypogonadism encephalomyopathy syndrome Mitochondrial oxidative 2573 Moyamoya disease 0.035 I * 2443 phosphorylation disorder due to 9.0 P * Moyamoya disease with early- nuclear DNA anomalies 401945 9 Cases onset achalasia Mitochondrial pyruvate carrier 447784 4 Cases deficiency 2574 Moynahan syndrome 26 Cases Mitochondrial trifunctional protein 746 1.0 P * 79323 MPDU1-CDG 8 Cases deficiency 79319 MPI-CDG 25 Cases 180234 Mixed germ cell tumor 0.01 I * 263347 7 Cases Mixed sclerosing bone dystrophy MRCS syndrome 324364 2 Cases with extra-skeletal manifestations MSH3-related attenuated familial 480536 4 Cases MME-related autosomal dominant adenomatous polyposis 497757 19 Cases Charcot Marie Tooth disease type 2 MT-ATP6-related mitochondrial 320360 5 Cases Moderate and severe traumatic spastic paraplegia 90056 37.8 P * brain injury 100024 Mu-heavy chain disease 35 Cases 169796 Moderately severe hemophilia B 0.6 P * 398961 Mucinous adenocarcinoma of ovary 0.85 I * 570 Moebius syndrome 300 Cases Mucinous cystadenocarcinoma of 424053 0.01 I * Moebius syndrome-axonal the pancreas 2560 neuropathy-hypogonadotropic 7 Cases 575 Muckle-Wells syndrome 200 Cases hypogonadism syndrome 576 Mucolipidosis type II 0.84 BP * 79330 MOGS-CDG 3 Cases 577 Mucolipidosis type III 1.0 BP * 52368 Mohr-Tranebjaerg syndrome 91 Cases 423461 Mucolipidosis type III alpha/beta 13.0 P 2563 MOMO syndrome 8 Cases 579 Mucopolysaccharidosis type 1 0.25 P * Monocytopenia with susceptibility 228423 22 Cases to infections 579 Mucopolysaccharidosis type 1 0.82 BP 2565 Mononen-Karnes-Senac syndrome 1 Family 580 Mucopolysaccharidosis type 2 10.0 P * 77301 Monosomy 9q22.3 42 Cases 580 Mucopolysaccharidosis type 2 0.68 BP 1598 Monosomy 18p 2.0 BP * Mucopolysaccharidosis type 2, 217085 0.4 BP * severe form 1600 Monosomy 18q 2.5 BP 581 Mucopolysaccharidosis type 3 0.3 P * 574 Monosomy 21 50 Cases 581 Mucopolysaccharidosis type 3 0.87 BP * 48652 Monosomy 22q13 200 Cases 309297 Mucopolysaccharidosis type 4A 15.0 P * 83467 Morvan syndrome 60 Cases 583 Mucopolysaccharidosis type 6 0.16 P * Mosaic genome-wide paternal 329813 13 Cases uniparental disomy 583 Mucopolysaccharidosis type 6 0.16 BP * 1692 Mosaic trisomy 1 18 Cases 584 Mucopolysaccharidosis type 7 0.01 P *

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families Mucopolysaccharidosis-like 29073 Multiple myeloma 6.0 I syndrome with congenital heart 505248 19 Cases defects and hematopoietic 321 Multiple osteochondromas 1.0 P * disorders Multiple paragangliomas 324299 2 Cases 53271 Muenke syndrome 3.33 BP associated with polycythemia Multiple pterygium-malignant 2215 4 Cases 587 Muir-Torre syndrome 205 Cases hyperthermia syndrome 2576 MULIBREY nanism 150 Cases Multiple sclerosis-ichthyosis-factor 3151 2 Cases Müllerian derivatives- VIII deficiency syndrome Multiple self-healing squamous 1655 lymphangiectasia-polydactyly 8 Cases 65748 100 Cases syndrome epithelioma Müllerian duct anomalies-limb 585 Multiple sulfatase deficiency 50 Cases 2491 5 Cases anomalies syndrome 3237 Multiple synostoses syndrome 30 Families 93686 Multicentric Castleman disease 100 Cases 102 Multiple system atrophy 3.5 P Multicentric osteolysis-nodulosis- 371428 50 Cases arthropathy spectrum 102 Multiple system atrophy 1.8 I Multiple system atrophy, 139436 Multicentric reticulohistiocytosis 200 Cases 98933 2.4 P * parkinsonian type 1851 Multicystic dysplastic kidney 23.26 BP Multisystemic smooth muscle 404463 7 Cases 3282 Multifocal atrial tachycardia 0.67 BP dysfunction syndrome Muscle-eye-brain disease with 641 Multifocal motor neuropathy 1.5 P 370997 2 Cases bilateral multicystic leucodystrophy Multinodular goiter-cystic kidney- 2091 3 Cases Muscular atrophy-ataxia-retinitis polydactyly syndrome 2579 pigmentosa-diabetes mellitus 10 Cases Multinucleated neurons- syndrome anhydramnios-renal dysplasia- 500135 3 Cases 199340 Muscular dystrophy, Selcen type 12 Cases cerebellar hypoplasia- Muscular dystrophy-white matter hydranencephaly syndrome 1877 2 Cases Multiple congenital anomalies- spongiosis syndrome 280633 15 Cases hypotonia-seizures syndrome Muscular hypertrophy- Multiple congenital anomalies- 324416 hepatomegaly-polyhydramnios 2 Cases 300496 15 Cases hypotonia-seizures syndrome type 2 syndrome Multiple endocrine neoplasia type Mutilating hereditary sensory 652 3.3 P * 139578 14 Cases 1 neuropathy with spastic paraplegia Multiple endocrine neoplasia type Mutilating palmoplantar 653 2.9 P * 2 659 keratoderma with periorificial 73 Cases keratotic plaques 251 Multiple epiphyseal dysplasia 5.0 P * 589 Myasthenia gravis 7.77 P Multiple epiphyseal dysplasia type 93311 18 Families 5 589 Myasthenia gravis 0.53 I Multiple epiphyseal dysplasia, Al- 166024 4 Cases MYBPC1-related autosomal Gazali type 498693 recessive non-lethal arthrogryposis 4 Cases Multiple epiphyseal dysplasia, multiplex congenita syndrome 166011 1 Family Beighton type Mycophenolate mofetil 268249 25 Cases Multiple epiphyseal dysplasia, embryopathy 166016 2 Cases Lowry type 178566 Mycosis fungoides and variants 0.59 I * Multiple epiphyseal dysplasia, with 166032 2 Cases miniepiphyses 52688 Myelodysplastic syndrome 1.5 I * Multiple epiphyseal dysplasia, with Myelodysplastic/myeloproliferative 166029 3 Cases 98275 0.29 I * severe proximal femoral dysplasia disease Multiple mitochondrial 401869 21 Cases 86850 Myeloid sarcoma 0.02 I * dysfunctions syndrome type 1 98274 Myeloproliferative neoplasm 3.07 I * Multiple mitochondrial 401874 6 Cases dysfunctions syndrome type 2 MYH7-related late-onset Multiple mitochondrial 437572 scapuloperoneal muscular 12 Cases 363424 2 Cases dysfunctions syndrome type 3 dystrophy Multiple mitochondrial 182050 MYH9-related disease 0.3 P * 457406 8 Cases dysfunctions syndrome type 4 2588 Myhre syndrome 55 Cases 29073 Multiple myeloma 11.9 P *

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families MYO5B-related progressive familial Neonatal ichthyosis-sclerosing 480491 5 Cases 59303 12 Cases intrahepatic cholestasis cholangitis syndrome Neonatal inflammatory skin and 86909 Myoclonic epilepsy of infancy 106 Cases 294023 3 Cases bowel disease Myoclonus-cerebellar ataxia- 2589 4 Cases deafness syndrome 398127 Neonatal scleroderma 6 Cases Myopathy-growth delay- Neonatal severe cardiopulmonary 2601 intellectual disability-hypospadias 1 Case 466784 failure due to mitochondrial 3 Cases syndrome methylation defect 206647 Myotonic dystrophy 6.7 P 94058 Neovascular glaucoma 24.4 P * 99967 Myxoid/round cell liposarcoma 0.1 I * 654 Nephroblastoma 10.0 BP * 2608 N syndrome 3 Cases 654 Nephroblastoma 0.14 I * Naegeli-Franceschetti-Jadassohn 69087 0.035 P * 223 Nephrogenic diabetes insipidus 0.15 P * syndrome Nephrogenic diabetes insipidus- 3145 2 Cases 245 Nager syndrome 100 Cases intracranial calcification syndrome Nail and teeth abnormalities- Nephrogenic syndrome of 93606 21 Cases marginal palmoplantar inappropriate antidiuresis 423454 6 Cases keratoderma-oral Nephropathy-deafness- 2668 5 Cases hyperpigmentation syndrome hyperparathyroidism syndrome Nephrosis-deafness-urinary tract- 2614 Nail-patella syndrome 0.2 BP * 2669 5 Cases digital malformations syndrome 2613 Nail-patella-like renal disease 3 Cases Nephrotic syndrome-deafness- 2615 Nakajo-Nishimura syndrome 30 Cases 300333 pretibial epidermolysis bullosa 3 Cases syndrome 627 Nance-Horan syndrome 196 Cases Nestor-Guillermo progeria 280576 2 Cases 2073 Narcolepsy type 1 25.0 P * syndrome Nasopalpebral lipoma-coloboma 634 Netherton syndrome 0.5 P * 2399 30 Cases syndrome 634 Netherton syndrome 0.5 BP * 150 Nasopharyngeal carcinoma 2.0 P * 2671 Neu-Laxova syndrome 91 Cases 150 Nasopharyngeal carcinoma 0.36 I * 2672 Neuhauser-Eichner-Opitz syndrome 5 Cases 2663 Nathalie syndrome 1 Family 3388 Neural tube defect 91.05 BP * 255229 Navajo neurohepatopathy 49 Cases 635 Neuroblastoma 11.0 P * NDE1-related 443162 1 Family microhydranencephaly 635 Neuroblastoma 5.8 BP * 391673 Necrotizing enterocolitis 45.0 P 635 Neuroblastoma 1.26 I NEK9-related lethal skeletal 464366 5 Cases 2481 Neurocutaneous melanocytosis 1.25 P * dysplasia Neurodegeneration due to 3- 607 Nemaline myopathy 2.0 BP * 88639 hydroxyisobutyryl-CoA hydrolase 20 Cases Neonatal acute respiratory distress deficiency 217563 0.067 BP due to SP-B deficiency Neurodegeneration with brain iron 385 0.2 P * Neonatal antiphospholipid accumulation 398097 34 Cases syndrome Neurodegenerative syndrome due Neonatal autoimmune hemolytic 217382 to cerebral folate transport 3 Cases 398109 2 Cases anemia deficiency 398117 Neonatal dermatomyositis 3 Cases Neurodevelopmental disorder- 453499 craniofacial dysmorphism-cardiac 15 Cases 224 Neonatal diabetes mellitus 1.1 BP * defect-hip dysplasia syndrome Neonatal diabetes-congenital Neurodevelopmental disorder- hypothyroidism-congenital craniofacial dysmorphism-cardiac 79118 3 Cases 352665 13 Cases glaucoma-hepatic fibrosis-polycystic defect-hip dysplasia syndrome due kidneys syndrome to 9q21 microdeletion Neonatal encephalomyopathy- Neurodevelopmental disorder- 457185 cardiomyopathy-respiratory distress 11 Cases craniofacial dysmorphism-cardiac 453504 2 Cases syndrome defect-hip dysplasia syndrome due 446 Neonatal hemochromatosis 35 Cases to a point mutation

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families Neuroectodermal melanolysosomal Non-acquired combined pituitary 33445 20 Cases 467 29.0 BP * disease hormone deficiency Neuroectodermal-endocrine Non-acquired combined pituitary 2676 4 Cases syndrome hormone deficiency-sensorineural 231720 13 Cases 877 Neuroendocrine neoplasm 2.53 I * hearing loss-spine abnormalities syndrome 97253 Neuroendocrine tumor of pancreas 0.21 I * Non-acquired isolated growth 631 0.39 P 100075 Neuroendocrine tumor of stomach 3.2 P * hormone deficiency Non-epidermolytic palmoplantar 2337 2.5 P * 2673 Neurofaciodigitorenal syndrome 3 Cases keratoderma 157846 90 Cases Non-eruption of teeth-maxillary Neuroferritinopathy 2972 4 Cases hypoplasia-genu valgum syndrome 636 Neurofibromatosis type 1 21.3 P * 91349 Non-functioning pituitary adenoma 1.05 I 636 Neurofibromatosis type 1 33.3 BP 357034 Non-hereditary retinoblastoma 0.038 I * 637 Neurofibromatosis type 2 1.7 P * 547 Non-Hodgkin lymphoma 11.6 I * Neurogenic arthrogryposis 1143 4.3 BP * Non-hypoproteinemic hypertrophic multiplex congenita 329883 1 Family Neurological conditions associated gastropathy 137754 15 Cases with aminoacylase 1 deficiency 363999 Non-immune hydrops fetalis 42.0 BP Neurometabolic disorder due to 35705 30 Cases Non-immunoglobulin-mediated serine deficiency 329918 membranoproliferative 14.0 P * 71211 Neuromyelitis optica 1.5 P * glomerulonephritis Neuropathy with hearing Non-immunoglobulin-mediated 139512 1 Family 329918 0.15 I * impairment membranoproliferative glomerulonephritis 137596 Neurotrophic keratopathy 4.2 P * 90061 Non-infectious posterior uveitis 18.0 P * 165 50 Cases Neutral lipid storage disease Non-papillary transitional cell 209989 37.0 P * 98908 Neutral lipid storage myopathy 36 Cases carcinoma of the bladder Neutropenia-monocytopenia- Non-progressive cerebellar ataxia 2690 3 Cases 314647 15 Cases deafness syndrome with intellectual disability Neutrophil immunodeficiency Non-seminomatous germ cell 183707 2 Cases 363494 1.21 I * syndrome tumor of testis Non-spherocytic hemolytic anemia 263432 Nevus of Ito 1.17 P * 90031 17 Families due to hexokinase deficiency 77292 Niemann-Pick disease type A 0.25 BP * Noonan syndrome with multiple 500 296 Cases lentigines 77293 Niemann-Pick disease type B 0.4 P * Noonan syndrome-like disorder 2701 27 Cases 646 Niemann-Pick disease type C 1.0 P * with loose anagen hair Night blindness-skeletal anomalies- 1390 2 Cases 649 Norrie disease 400 Cases dysmorphism syndrome 75327 North Carolina macular dystrophy 2 Families 647 Nijmegen breakage syndrome 1.0 BP NPHP3-related Meckel-like Nijmegen breakage syndrome-like 3032 10 Cases 240760 1 Case syndrome disorder 397615 Obesity due to CEP19 deficiency 15 Cases 447731 NIK deficiency 2 Cases Obesity due to congenital leptin 66628 30 Cases 99825 Nipah virus disease 556 Cases deficiency Obesity due to pro- 263665 NK-cell enteropathy 8 Cases 71526 7 Cases opiomelanocortin deficiency NKX6-2-related autosomal Obesity due to prohormone 527497 recessive hypomyelinating 25 Cases 71528 16 Cases convertase I deficiency leukodystrophy Obesity-colitis-hypothyroidism- NLRP12-associated hereditary 247868 19 Cases 88643 cardiac hypertrophy-developmental 2 Cases periodic fever syndrome delay syndrome Nodal marginal zone B-cell 86867 1.0 P * lymphoma 198 Occipital horn syndrome 20 Cases Nodular lymphocyte predominant Occipital pachygyria and 86893 0.12 I 280640 3 Cases Hodgkin lymphoma polymicrogyria 2704 Ochoa syndrome 100 Cases

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families Ocular albinism with congenital 352740 3 Families 1811 Odontomicronychial dysplasia 5 Cases sensorineural deafness Ocular albinism with late-onset 2723 Odontotrichomelic syndrome 4 Cases 1000 9 Cases Off-periods in Parkinson disease sensorineural deafness 391655 4.15 P * not responding to oral treatment 1125 Ocular motor apraxia, Cogan type 50 Cases 276432 Ogden syndrome 8 Cases 2714 Oculo-palato-cerebral syndrome 5 Cases Oculoauricular syndrome, 75382 Oguchi disease 50 Cases 157962 5 Cases Schorderet type 2729 Okamoto syndrome 5 Cases Oculoauriculofrontonasal Oligoarticular juvenile idiopathic 398156 41 Cases 85410 20.5 P * syndrome arthritis 2705 Oculocerebral dysplasia 2 Cases 251651 Oligoastrocytic tumor 0.11 I * Oculocerebral hypopigmentation 2719 14 Cases 75378 Oligocone trichromacy 14 Cases syndrome, Cross type Oculocerebral hypopigmentation 46484 Oligodendroglial tumor 0.35 I * 2720 2 Cases syndrome, Preus type 251627 Oligodendroglioma 0.25 I * 1647 Oculocerebrocutaneous syndrome 38 Cases Oligodontia-cancer predisposition Oculocerebrofacial syndrome, 300576 2 Families 2707 14 Cases syndrome Kaufman type 2920 Oliver syndrome 7 Cases Oculocerebrorenal syndrome of 534 0.2 P Lowe 39041 Omenn syndrome 25 Cases 55 Oculocutaneous albinism 5.9 P 2733 Omodysplasia 30 Cases 352731 Oculocutaneous albinism type 1 2.5 P 660 Omphalocele 11.7 BP * 79431 1.3 P Omphalocele syndrome, Oculocutaneous albinism type 1A 3164 5 Cases Shprintzen-Goldberg type 79434 Oculocutaneous albinism type 1B 1.3 P Omphalocele-diaphragmatic 79432 Oculocutaneous albinism type 2 2.55 P 496693 hernia-cardiovascular anomalies- 7 Cases radial ray defect syndrome 79435 Oculocutaneous albinism type 4 1.0 P 352540 Oncogenic osteomalacia 400 Cases 370091 Oculocutaneous albinism type 5 1 Family 300504 Onychocytic matricoma 5 Cases 370097 Oculocutaneous albinism type 6 1 Case 300512 Onychomatricoma 50 Cases 352745 Oculocutaneous albinism type 7 9 Cases Ophthalmomandibulomelic Oculodental syndrome, Rutherfurd 2741 3 Cases 2709 1 Family dysplasia type Ophthalmoplegia-intellectual 2743 6 Cases 2710 Oculodentodigital dysplasia 243 Cases disability-lingua scrotalis syndrome Oculogastrointestinal muscular 2745 Opitz G/BBB syndrome 3.0 P * 1876 1 Family dystrophy 2746 Opsismodysplasia 30 Cases 1794 Oculomaxillofacial dysostosis 4 Cases 1183 Opsoclonus-myoclonus syndrome 0.02 I * 2713 Oculoosteocutaneous syndrome 3 Cases Optic atrophy-intellectual disability 401777 6 Cases 99806 Oculootodental syndrome 1 Family syndrome 2715 Oculorenocerebellar syndrome 5 Cases Optic atrophy-peripheral 496790 neuropathy-developmental delay 8 Cases 2717 Oculotrichoanal syndrome 20 Cases syndrome Optic nerve edema-splenomegaly 2718 Oculotrichodysplasia 2 Cases 313800 3 Cases syndrome Odonto-onycho dysplasia-alopecia 2722 2 Cases syndrome 2086 Optic pathway glioma 0.12 I 2721 Odonto-onycho-dermal dysplasia 30 Cases Oral-facial-digital syndrome with 508501 short stature and 3 Cases Odonto-tricho-ungual-digito- 69082 21 Cases brachymesophalangy palmar syndrome 52994 Orbital leiomyoma 26 Cases 166272 Odontochondrodysplasia 11 Cases Ornithine transcarbamylase 664 1.4 P * 77295 Odontoleukodystrophy 4 Cases deficiency Odontomatosis-aortae esophagus Ornithine transcarbamylase 2724 3 Cases 664 1.77 BP stenosis syndrome deficiency

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families Osteosclerosis-ichthyosis- 2750 Orofaciodigital syndrome type 1 1.2 BP * 75325 3 Cases premature ovarian failure syndrome 2751 Orofaciodigital syndrome type 2 20 Cases Osteosclerotic metaphyseal 500548 7 Cases 2752 Orofaciodigital syndrome type 3 5 Cases dysplasia 2791 Otodental syndrome 10 Families 2753 Orofaciodigital syndrome type 4 29 Cases 2793 Otoonychoperoneal syndrome 6 Cases 2919 Orofaciodigital syndrome type 5 12 Cases 90652 Otopalatodigital syndrome type 2 40 Cases 2754 Orofaciodigital syndrome type 6 2 Families Otospondylomegaepiphyseal 2755 Orofaciodigital syndrome type 8 20 Cases 1427 30 Cases dysplasia 141007 Orofaciodigital syndrome type 9 10 Cases 213500 Ovarian cancer 30.0 P * 141327 Orofaciodigital syndrome type 12 1 Case 99853 Ovarioleukodystrophy 17 Cases 141330 Orofaciodigital syndrome type 13 1 Case Overgrowth syndrome with 2q37 498488 4 Cases translocation 434179 Orofaciodigital syndrome type 14 2 Families Overgrowth-macrocephaly-facial 137634 6 Families 2760 OSLAM syndrome 3 Cases dysmorphism syndrome Ossification anomalies- Overgrowth-metaphyseal 73230 psychomotor developmental delay 2 Cases 498485 undermodeling-spondylar dysplasia 4 Cases syndrome syndrome Overhydrated hereditary 2764 Osteochondritis dissecans 35.0 P * 3203 20 Families stomatocytosis Osteochondrodysplatic nanism- 2653 deafness-retinitis pigmentosa 2 Cases 2796 Pachydermoperiostosis 204 Cases syndrome Pachygyria-intellectual disability- 2798 5 Cases 2763 Osteocraniostenosis 30 Cases epilepsy syndrome 2309 Pachyonychia congenita 1000 Cases 666 Osteogenesis imperfecta 10.0 P * 1952 Pacman dysplasia 4 Cases 216804 Osteogenesis imperfecta type 2 0.4 BP * 180275 Paget disease of the nipple 0.51 I * 216828 Osteogenesis imperfecta type 5 47 Cases Osteogenesis imperfecta- 991 PAGOD syndrome 6 Cases 2773 retinopathy-seizures-intellectual 2 Cases 1993 Pai syndrome 37 Cases disability syndrome Painful orbital and systemic 2645 Osteoglosphonic dysplasia 7 Cases 300501 neurofibromas-marfanoid habitus 4 Cases 2777 Osteomesopyknosis 35 Cases syndrome Palatal anomalies-widely spaced Osteopathia striata-cranial sclerosis 2780 100 Cases 477993 teeth-facial dysmorphism- 3 Cases syndrome developmental delay syndrome Osteopathia striata-pigmentary 2779 dermopathy-white forelock 3 Cases 672 Pallister-Hall syndrome 100 Cases syndrome Palmoplantar keratoderma, 140966 40 Cases Osteopenia-intellectual disability- Nagashima type 2324 2 Cases sparse hair syndrome Palmoplantar keratoderma- 2202 10 Families Osteopenia-myopia-hearing loss- deafness syndrome 91133 intellectual disability-facial 2 Cases Palmoplantar keratoderma- 2198 10 Families dysmorphism syndrome esophageal carcinoma syndrome Palmoplantar keratoderma-spastic 2781 Osteopetrosis and related disorders 1.0 I * 2201 25 Cases paralysis syndrome Osteopetrosis with renal tubular 2785 100 Cases Palmoplantar keratoderma-XX sex acidosis 85112 reversal-predisposition to 5 Cases Osteopetrosis- 178389 8 Cases squamous cell carcinoma syndrome hypogammaglobulinemia syndrome Osteoporosis-oculocutaneous 309108 Pancreatic colipase deficiency 2 Cases 2786 1 Case hypopigmentation syndrome Pancreatic hypoplasia-diabetes- 2255 10 Cases Osteoporosis-pseudoglioma congenital heart disease syndrome 2788 0.05 P * syndrome Pancreatic insufficiency-anemia- 199337 5 Cases 668 Osteosarcoma 0.23 I * hyperostosis syndrome Osteosclerosis-developmental 677 Pancreatoblastoma 60 Cases 178377 13 Cases delay-craniosynostosis syndrome

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families Pancytopenia due to IKZF1 PCNA-related progressive 317473 39 Cases mutations 438134 neurodegenerative photosensitivity 4 Cases Pancytopenia-developmental delay syndrome 401764 3 Cases syndrome PDE4D haploinsufficiency 439822 7 Cases Pantothenate kinase-associated syndrome 157850 0.15 P * neurodegeneration 699 Pearson syndrome 95 Cases 319298 Papillary renal cell carcinoma 0.14 I * Pectus excavatum-macrocephaly- 2835 1 Family 678 Papillon-Lefèvre syndrome 0.25 P dysplastic nails syndrome 93682 Pediatric Castleman disease 150 Cases 2812 Parana hard skin syndrome 8 Cases 487809 Pediatric collagenous gastritis 24 Cases 63455 Paraneoplastic pemphigus 60 Cases Paraplegia-intellectual disability- 33402 Pediatric hepatocellular carcinoma 0.15 I * 2824 6 Cases hyperkeratosis syndrome 263548 Peeling skin syndrome type A 40 Families 143 Parathyroid carcinoma 0.02 I * 263553 Peeling skin syndrome type B 30 Families 2825 PARC syndrome 2 Cases Peeling skin-leukonychia-acral Parietal foramina with clavicular 444138 punctate keratoses-cheilitis-knuckle 4 Cases 251290 8 Cases hypoplasia pads syndrome 851 Paris-Trousseau thrombocytopenia 50 Cases 99807 PEHO-like syndrome 10 Cases Paroxysmal dystonic 702 Pelizaeus-Merzbacher disease 0.25 P * 53583 choreathetosis with episodic ataxia 20 Cases Pelizaeus-Merzbacher disease, 280219 0.17 P * and spasticity classic form Paroxysmal exertion-induced Pelizaeus-Merzbacher disease, 98811 50 Cases 280210 0.03 P * dyskinesia connatal form 46348 Paroxysmal extreme pain disorder 4 Families Pelizaeus-Merzbacher disease, 280224 0.03 P * 157835 Paroxysmal hemicrania 2.0 P * transitional form Pelvic dysplasia-arthrogryposis of 2840 5 Cases 98809 Paroxysmal kinesigenic dyskinesia 0.6 P lower limbs syndrome Paroxysmal nocturnal 447 2.0 P * 2839 Pelvis-shoulder dysplasia 10 Cases hemoglobinuria Paroxysmal non-kinesigenic 93333 Pelviscapular dysplasia 4 Cases 98810 0.1 P dyskinesia 704 Pemphigus vulgaris 18.0 P * 1330 Partial atrioventricular canal 30.0 P * 705 Pendred syndrome 7.0 P * 1330 Partial atrioventricular canal 20.0 BP * 49 Penile agenesis 80 Cases 1646 Partial chromosome Y deletion 20.8 P 313936 PENS syndrome 13 Cases Partial corpus callosum agenesis- 1335 Pentalogy of Cantrell 0.67 BP 401959 cerebellar vermis hypoplasia with 2 Cases posterior fossa cysts syndrome Pericardial and diaphragmatic 2847 20 Cases Partial deep dermal and full defect 90076 10.0 P * thickness burns 65250 Perineural cyst 50.0 I * Partial duplication of the long arm 262941 50 Cases Periodic fever-infantile of chromosome 14 436166 enterocolitis-autoinflammatory 4 Cases 2805 Partial pancreatic agenesis 50 Cases syndrome Periodic paralysis with later-onset 94083 Partington syndrome 2 Families 397750 9 Cases distal motor neuropathy 86789 Patella aplasia/hypoplasia 5 Families Periodic paralysis with transient 397755 4 Cases Patent ductus arteriosus-bicuspid compartment-like syndrome 228190 aortic valve-hand anomalies 7 Cases 139426 Perioral myoclonia with absences 10 Cases syndrome Paternal 20q13.2q13.3 563 Peripartum cardiomyopathy 30.0 BP 261304 2 Cases microdeletion syndrome Peripheral demyelinating Paternal uniparental disomy of neuropathy-central dysmyelinating 96192 4 Cases 163746 40 Cases chromosome 7 leukodystrophy-Waardenburg Patterson-Stevenson-Fontaine syndrome-Hirschsprung disease 2439 7 Cases syndrome 1795 Peripheral dysostosis 6 Cases

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families Peripheral motor neuropathy- Pigmentation defects-palmoplantar 2400 2 Cases dysautonomia syndrome 447961 keratoderma-skin carcinoma 2 Cases Peripheral neuropathy-myopathy- syndrome 397744 15 Cases hoarseness-hearing loss syndrome Pigmented paravenous 251295 100 Cases Peripheral resistance to thyroid retinochoroidal atrophy 97927 2.5 P * hormones 66627 Pigmented villonodular synovitis 20.0 P * 168816 Peritoneal cystic mesothelioma 150 Cases Pili torti-developmental delay- 2849 Perlman syndrome 30 Cases 2891 neurological abnormalities 2 Cases syndrome Permanent congenital 226292 33.3 BP * hypothyroidism 2890 Pili torti-onychodysplasia syndrome 1 Family Permanent neonatal diabetes Pilodental dysplasia-refractive 99885 0.38 BP * 2892 2 Cases mellitus errors syndrome Permanent neonatal diabetes 251909 Pineoblastoma 0.02 I * 65288 mellitus-pancreatic and cerebellar 4 Cases agenesis syndrome 2896 Pitt-Hopkins syndrome 500 Cases Peroxisomal acyl-CoA oxidase 221150 Pitt-Hopkins-like syndrome 105 Cases 2971 40 Cases deficiency 300385 Pituitary carcinoma 0.04 I * 2855 Perrault syndrome 61 Cases 2897 Pityriasis rubra pilaris 48 Cases 178509 Perry syndrome 53 Cases PLAA-associated 521426 15 Cases 97341 Persistent placoid maculopathy 5 Cases neurodevelopmental disorder Persistent polyclonal B-cell 439167 Placental insufficiency 33.0 P 300324 154 Cases lymphocytosis 99928 Placental site trophoblastic tumor 0.02 I * 708 Peters anomaly 60 Cases 707 Plague 2.2 I * 709 Peters plus syndrome 100 Cases 454714 Plasma cell leukemia 0.04 I * 2869 Peutz-Jeghers syndrome 0.4 P * PLCG2-associated antibody 2869 Peutz-Jeghers syndrome 2.2 BP 300359 deficiency and immune 3 Families dysregulation 42642 PFAPA syndrome 500 Cases 99969 Pleomorphic liposarcoma 0.05 I * 710 Pfeiffer syndrome 1.0 I * Pleomorphic salivary gland 454821 2.725 I 2871 Pfeiffer-Palm-Teller syndrome 2 Cases adenoma 319646 PGM1-CDG 46 Cases 251607 Pleomorphic xanthoastrocytoma 0.01 I * 443811 PGM3-CDG 20 Cases 449266 Pleural empyema 13.0 P * 42775 PHACE syndrome 300 Cases 50251 Pleural mesothelioma 3.1 P * 2874 Phakomatosis pigmentokeratotica 34 Cases 50251 Pleural mesothelioma 1.9 I * 352636 Phalangeal microgeodic syndrome 50 Cases 64742 Pleuropulmonary blastoma 0.5 BP * Pleuropulmonary blastoma familial 2876 PHAVER syndrome 2 Cases 284343 0.007 I tumor susceptibility syndrome 716 Phenylketonuria 10.0 BP * PLIN1-related familial partial 280356 3 Cases Phocomelia-ectrodactyly-deafness- lipodystrophy 2878 4 Cases sinus arrhythmia syndrome 54028 Plummer-Vinson syndrome 25 Cases Phosphoenolpyruvate 2880 10 Cases PMP2-related Charcot-Marie-Tooth carboxykinase deficiency 476394 13 Cases disease type 1 Phosphoribosylpyrophosphate 3222 30 Families PMP22-RAI1 contiguous gene synthetase superactivity 477817 23 Cases duplication syndrome 498228 Phyllodes tumor of the prostate 90 Cases Pneumonia caused by 90066 50.0 P * Piebald trait-neurologic defects Pseudomonas aeruginosa infection 2885 8 Cases syndrome 221046 Poikiloderma with neutropenia 50 Cases 487825 Pierpont syndrome 7 Cases 2911 Poland syndrome 1.5 BP * Pierre Robin syndrome-faciodigital 2888 2 Cases Poliomyelitis in patients with anomaly syndrome 330009 8.0E-4 P * immunodeficiencies deemed at risk 2670 Pierson syndrome 40 Families 767 Polyarteritis nodosa 3.0 P *

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families Polycystic ovaries-urethral Porencephaly-microcephaly- 2795 33 Cases sphincter dysfunction syndrome 306547 bilateral congenital cataract 8 Cases 729 Polycythemia vera 30.0 P * syndrome Porokeratotic eccrine ostial and 166286 45 Cases 729 Polycythemia vera 1.9 I * dermal duct nevus 2917 Polydactyly-myopia syndrome 1 Family 738 Porphyria 5.25 P Polyendocrine-polyneuropathy 453533 3 Cases 101330 Porphyria cutanea tarda 4.0 P * syndrome Polyglucosan body myopathy type 101330 Porphyria cutanea tarda 0.6 I * 397937 11 Cases 1 79473 Porphyria variegata 0.32 P * Polyglucosan body myopathy type 456369 15 Cases 2 79473 Porphyria variegata 0.008 I * Polyhydramnios-megalencephaly- Port-wine nevi-mega cisterna 500533 17 Cases 2703 5 Cases symptomatic epilepsy syndrome magna-hydrocephalus syndrome Post-transplant Polymalformative genetic 70568 26.2 P * 183422 syndrome with increased risk of 10.0 P * lymphoproliferative disease developing cancer 246 Postaxial acrofacial dysostosis 30 Cases Polymicrogyria due to TUBB2B 300573 36 Cases Postaxial polydactyly-anterior mutation 420584 pituitary anomalies-facial 112 Cases Polymicrogyria with optic nerve 250972 4 Cases dysmorphism syndrome hypoplasia Postaxial polydactyly-dental and 2916 3 Cases 732 Polymyositis 7.1 P * vertebral anomalies syndrome 732 Polymyositis 0.585 I * 2730 Postaxial tetramelic oligodactyly 4 Cases Posterior amorphous corneal Polyneuropathy-hearing loss- 98971 11 Families 171848 ataxia-retinitis pigmentosa-cataract 19 Cases dystrophy syndrome Posterior column ataxia-retinitis 88628 20 Cases Polyneuropathy-intellectual pigmentosa syndrome 2928 disability-acromicria-premature 3 Cases Posterior fusion of lumbosacral 2064 3 Cases menopause syndrome vertebrae-blepharoptosis syndrome Polysyndactyly-cardiac 2934 8 Cases 93110 Posterior urethral valve 2.0 P * malformation syndrome 93110 Posterior urethral valve 4.125 BP * Polyvalvular heart disease 228410 19 Cases syndrome Postnatal microcephaly-infantile hypotonia-spastic diplegia- Pontine autosomal dominant 477673 17 Cases 477749 microangiopathy with 11 Cases dysarthria-intellectual disability leukoencephalopathy syndrome 269229 Pontine tegmental cap dysplasia 22 Cases 279947 Postorgasmic illness syndrome 45 Cases Postural orthostatic tachycardia 2254 Pontocerebellar hypoplasia type 1 40 Families 443236 2 Cases syndrome due to NET deficiency 2524 Pontocerebellar hypoplasia type 2 81 Families 52022 Potocki-Shaffer syndrome 40 Cases 97249 Pontocerebellar hypoplasia type 3 3 Families 217067 Pouchitis 22.0 P * 166063 Pontocerebellar hypoplasia type 4 10 Families PPARG-related familial partial 79083 10 Cases lipodystrophy 166068 Pontocerebellar hypoplasia type 5 3 Cases 739 Prader-Willi syndrome 3.1 BP * 166073 Pontocerebellar hypoplasia type 6 10 Cases Prader-Willi syndrome due to a 398069 28 Cases 284339 Pontocerebellar hypoplasia type 7 4 Cases point mutation 324569 Pontocerebellar hypoplasia type 8 6 Cases 398073 Prader-Willi-like syndrome 117 Cases Prader-Willi-like syndrome due to a 369920 Pontocerebellar hypoplasia type 9 14 Cases 398079 4 Cases point mutation 411493 Pontocerebellar hypoplasia type 10 23 Cases 293462 Pre-Descemet corneal dystrophy 5 Cases 294963 Popliteal pterygium syndrome 0.3 P * Preaxial polydactyly-colobomata- 2921 2 Cases Porencephaly-cerebellar intellectual disability syndrome 2941 hypoplasia-internal malformations 2 Cases 275555 Preeclampsia 45.0 P * syndrome

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families Prenatal-onset spinal muscular Primary mediastinal large B-cell 98838 3.0 P * 486811 atrophy with congenital bone 7 Cases lymphoma fractures Primary membranoproliferative 54370 16.0 P * Pretibial dystrophic epidermolysis glomerulonephritis 79410 40 Families bullosa Primary microcephaly-epilepsy- 186 Primary biliary cholangitis 21.05 P 306558 permanent neonatal diabetes 8 Cases syndrome 186 Primary biliary cholangitis 3.0 I Primary microcephaly-mild 169464 Primary CD59 deficiency 6 Cases 391408 intellectual disability-young-onset 8 Cases diabetes syndrome 244 Primary ciliary dyskinesia 5.0 BP * 824 Primary myelofibrosis 3.0 P * Primary ciliary dyskinesia-retinitis 247522 20 Cases pigmentosa syndrome 824 Primary myelofibrosis 1.0 I * 226295 Primary congenital hypothyroidism 37.5 P * 238606 Primary orthostatic tremor 390 Cases Primary cutaneous CD30+ T-cell Primary pigmented nodular 541 0.18 I * 189439 0.04 P * lymphoproliferative disease adrenocortical disease 542 Primary cutaneous lymphoma 0.75 I * 95432 Primary progressive aphasia 7.0 P Primary cutaneous T-cell Primary progressive apraxia of 171901 24.0 P * 314566 16 Cases lymphoma speech Primary cutaneous T-cell 171901 5.2 I * 171 Primary sclerosing cholangitis 8.1 P lymphoma 171 Primary sclerosing cholangitis 0.65 I 98805 Primary dystonia, DYT4 type 22 Cases 289390 Primary Sjögren syndrome 48.99 P * 98806 Primary dystonia, DYT6 type 53 Cases 289390 Primary Sjögren syndrome 6.92 I 98807 Primary dystonia, DYT13 type 8 Cases 314701 Primary systemic amyloidosis 30.0 P * 370103 Primary dystonia, DYT17 type 3 Cases PRKAR1B-related 306734 Primary dystonia, DYT21 type 16 Cases 412066 neurodegenerative dementia with 12 Cases 464440 Primary dystonia, DYT27 type 5 Cases intermediate filaments Progeria-short stature-pigmented 2959 11 Cases 48686 Primary effusion lymphoma 200 Cases nevi syndrome 90026 Primary erythromelalgia 30 Families Progeroid and marfanoid aspect- 300382 7 Cases Primary hepatic neuroendocrine lipodystrophy syndrome 100085 0.2 I Progeroid features-hepatocellular carcinoma 435953 3 Cases Primary hyperaldosteronism- carcinoma predisposition syndrome 369929 seizures-neurological abnormalities 2 Cases 2963 Progeroid syndrome, Petty type 1 Case syndrome Progressive autosomal recessive 448251 13 Cases Primary hypergonadotropic ataxia-deafness syndrome 2232 hypogonadism-partial alopecia 7 Cases Progressive bifocal chorioretinal 75373 2 Families syndrome atrophy 93599 Primary hyperoxaluria type 2 10 Cases Progressive cavitating 139447 19 Cases leukoencephalopathy 93600 Primary hyperoxaluria type 3 50 Cases Progressive cerebello-cerebral Primary hypomagnesemia with 247198 7 Cases 30924 100 Cases atrophy secondary hypocalcemia Progressive encephalopathy with Primary immunodeficiency 90023 4 Cases 431361 leukodystrophy due to DECR 2 Cases syndrome due to p14 deficiency deficiency Primary immunodeficiency with Progressive essential tremor- 75391 natural-killer cell deficiency and 4 Cases speech impairment-facial 457212 5 Cases adrenal insufficiency dysmorphism-intellectual disability- Primary immunodeficiency with abnormal behavior syndrome 431166 post-measles-mumps-rubella 1 Case Progressive external vaccine viral infection 352447 ophthalmoplegia-myopathy- 6 Cases Primary intralymphatic 458768 30 Cases emaciation syndrome angioendothelioma Progressive familial intrahepatic 480483 14 Cases 35689 Primary lateral sclerosis 1.5 P * cholestasis type 4 Progressive familial intrahepatic 77240 Primary lymphedema 16.7 P * 480476 4 Cases cholestasis type 5

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families Progressive microcephaly-seizures- 606 Proximal myotonic myopathy 1.0 P * 477814 cortical blindness-developmental 9 Cases delay syndrome 70 Proximal spinal muscular atrophy 20.0 BP * Progressive myoclonic epilepsy 263516 9 Families 70 Proximal spinal muscular atrophy 2.6 I * type 3 Proximal spinal muscular atrophy Progressive myoclonic epilepsy 83330 0.26 I * 402082 3 Cases type 1 type 5 Proximal spinal muscular atrophy Progressive myoclonic epilepsy 83418 1.23 I * 280620 12 Cases type 2 type 6 Proximal spinal muscular atrophy Progressive myoclonic epilepsy 83419 1.1 I * 435438 13 Cases type 3 type 7 Proximal spinal muscular atrophy Progressive myoclonic epilepsy 83420 0.32 I * 424027 4 Cases type 4 type 8 Proximal tubulopathy-diabetes Progressive myoclonic epilepsy 3390 2 Cases 457265 2 Cases mellitus-cerebellar ataxia syndrome type 9 397606 PrP systemic amyloidosis 16 Cases Progressive myoclonic epilepsy 352596 5 Cases with dystonia 52530 Pseudo-von Willebrand disease 60 Cases 100070 Progressive non-fluent aphasia 2.5 P * 750 Pseudoachondroplasia 3.3 P 100070 Progressive non-fluent aphasia 0.7 I * 221120 Pseudoaminopterin syndrome 11 Cases Progressive non-infectious anterior 2062 67 Cases 85174 Pseudodiastrophic dysplasia 13 Cases vertebral fusion Progressive polyneuropathy with 756 Pseudohypoaldosteronism type 1 107 Cases 217396 4 Cases bilateral striatal necrosis 757 Pseudohypoaldosteronism type 2 80 Families Progressive retinal dystrophy due 352718 5 Cases to retinol transport defect 300525 Pseudohypoaldosteronism type 2D 24 Cases Progressive 300530 Pseudohypoaldosteronism type 2E 17 Cases 447977 scapulohumeroperoneal distal 33 Cases Pseudoleprechaunism syndrome, myopathy 2976 2 Cases Patterson type Progressive sensorineural hearing 228012 loss-hypertrophic cardiomyopathy 4 Families 26790 Pseudomyxoma peritonei 0.1 I syndrome 2985 Pseudoprogeria syndrome 2 Cases Progressive spondyloepimetaphyseal dysplasia- 758 Pseudoxanthoma elasticum 2.5 P * 457395 short stature-short fourth 4 Cases Pseudoxanthoma elasticum-like metatarsals-intellectual disability 436274 skin manifestations with retinitis 13 Cases syndrome pigmentosa Pseudoxanthomatous diffuse 683 Progressive supranuclear palsy 6.0 P 280794 10 Cases cutaneous mastocytosis 683 Progressive supranuclear palsy 0.65 I Psoriasis-related juvenile idiopathic 85436 4.2 P * Progressive supranuclear palsy- arthritis 240103 0.6 P * corticobasal syndrome Psychomotor regression- Progressive supranuclear palsy- 505242 oculomotor apraxia-movement 6 Cases 240112 progressive non-fluent aphasia 10 Cases disorder-nephropathy syndrome syndrome Psychomotor retardation due to S- 742 Prolidase deficiency 90 Cases 88618 adenosylhomocysteine hydrolase 4 Cases deficiency Prominent glabella-microcephaly- 2083 2 Cases Pterin-4 alpha-carbinolamine hypogenitalism syndrome 1578 21 Cases dehydratase deficiency 35 Propionic acidemia 0.2 P * Pterygium colli-intellectual 35 Propionic acidemia 1.5 I 2988 disability-digital anomalies 2 Cases syndrome 324977 Proteasome disability syndrome 40 Cases Ptosis-strabismus-ectopic pupils 2999 1 Family 251598 Protoplasmic astrocytoma 0.01 I * syndrome Proximal 16p11.2 microdeletion Ptosis-upper ocular movement 261197 20.0 P * syndrome 228396 limitation-absence of lacrimal 3 Cases Proximal myopathy with punctum syndrome 401768 15 Cases Ptosis-vocal cord paralysis extrapyramidal signs 2997 2 Cases Proximal myopathy with focal syndrome 521305 4 Cases depletion of mitochondria

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families 182090 Pulmonary arterial hypertension 3.3 P * 781 Q fever 0.16 I * Pulmonary arterial hypertension 3010 Qazi-Markouizos syndrome 3 Cases 275803 associated with congenital heart 0.57 P * Radial hypoplasia-triphalangeal disease 2252 thumbs-hypospadias-maxillary 8 Cases Pulmonary arterial hypertension diastema syndrome 275798 associated with connective tissue 0.25 P * Radial ray hypoplasia-choanal disease 3026 3 Cases atresia syndrome Pulmonary arteriovenous 2038 2.5 I malformation 70475 Radiation proctitis 35.0 P * Pulmonary artery coming from the 99050 200 Cases 3015 Radio-renal syndrome 4 Cases aorta Radio-ulnar synostosis- 64741 Pulmonary blastoma 350 Cases 71289 amegakaryocytic thrombocytopenia 20 Cases Pulmonary capillary syndrome 199241 100 Cases hemangiomatosis Radioulnar synostosis- Pulmonary fibrosis-hepatic 3270 developmental delay-hypotonia 4 Cases 210136 hyperplasia-bone marrow 4 Cases syndrome hypoplasia syndrome Radioulnar synostosis- 3268 13 Cases Pulmonary fungal infections in microcephaly-scoliosis syndrome 217080 22.0 P * patients deemed at risk 3019 Ramon syndrome 8 Cases Pulmonary non-tuberculous 411703 6.0 P * 1051 Ramos-Arroyo syndrome 6 Cases mycobacterial infection 31837 Pulmonary venoocclusive disease 0.015 I * 3021 RAPADILINO syndrome 20 Cases Punctate palmoplantar Rapid-onset childhood obesity- 79501 35 Families hypothalamic dysfunction- keratoderma type 1 293987 48 Cases Punctate palmoplantar hypoventilation-autonomic 79502 13 Cases keratoderma type 2 dysregulation syndrome PURA-related severe neonatal 71517 Rapid-onset dystonia-parkinsonism 100 Cases 438213 hypotonia-seizures-encephalopathy 24 Cases 213528 Rare adenocarcinoma of the breast 3.55 I * syndrome PURA-related severe neonatal 217074 Rare carcinoma of pancreas 3.5 P 438216 hypotonia-seizures-encephalopathy 24 Cases 217074 Rare carcinoma of pancreas 3.9 I syndrome due to a point mutation Rare congenital non-syndromic Pure hair and nail ectodermal 88991 7.8 BP * 69084 20 Cases heart malformation dysplasia Rare cutaneous lupus Purine nucleoside phosphorylase 535 50.0 P * 760 70 Cases erythematosus deficiency 63443 Rare epithelial tumor of stomach 18.6 I * 763 Pycnodysostosis 0.13 P PYCR2-related microcephaly- 2415 Rare lymphatic malformation 12.5 P * 481152 18 Cases progressive leukoencephalopathy 182114 Rare urogenital tumor 0.13 I * 3003 Pyknoachondrogenesis 5 Cases RARS-related autosomal recessive 438114 4 Cases 3005 Pyle disease 30 Cases hypomyelinating leukodystrophy RAS-associated autoimmune 268114 20 Cases 48104 Pyoderma gangrenosum 0.74 I leukoproliferative disease Pyogenic arthritis-pyoderma 69126 34 Cases 1929 Rasmussen subacute encephalitis 100 Cases gangrenosum-acne syndrome Pyogenic bacterial infections due to 99852 Ravine syndrome 38 Cases 183713 24 Cases MyD88 deficiency Recessive aplasia cutis congenita of 1115 6 Cases Pyramidal molars-abnormal upper limbs 2561 8 Cases lip syndrome Recessive dystrophic epidermolysis 79409 100 Cases Pyridoxal phosphate-responsive bullosa inversa 79096 0.2 P * seizures Recessive intellectual disability- 3006 Pyridoxine-dependent epilepsy 0.2 BP * 280384 motor dysfunction-multiple joint 12 Cases contractures syndrome 3008 Pyruvate carboxylase deficiency 0.4 BP * 461 Recessive X-linked ichthyosis 16.6 P * Pyruvate carboxylase deficiency, 353320 5 Cases benign type 461 Recessive X-linked ichthyosis 15.0 I * Pyruvate dehydrogenase E3 2394 20 Cases 64740 Recurrent acute pancreatitis 10.0 P * deficiency

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families Recurrent hepatitis C virus induced 791 Retinitis pigmentosa 26.7 P 90052 liver disease in liver transplant 7.0 P * Retinitis pigmentosa-hearing loss- recipients 494439 premature aging-short stature-facial 3 Cases Recurrent metabolic dysmorphism syndrome encephalomyopathic crises- 480864 24 Cases Retinitis pigmentosa-intellectual rhabdomyolysis-cardiac arrhythmia- 3085 disability-deafness-hypogonadism 2 Families intellectual disability syndrome syndrome 97239 Reducing body myopathy 4 Families Retinitis pigmentosa-juvenile Refractory anemia with excess 436245 cataract-short stature-intellectual 3 Cases 86839 0.15 I * blasts disability syndrome Refractory anemia with excess 168960 0.04 I * 52427 Retinitis punctata albescens 0.125 P blasts in transformation 790 Retinoblastoma 6.0 BP 773 Refsum disease 0.1 P * 790 Retinoblastoma 0.05 I * 83450 Regional odontodysplasia 140 Cases Retinohepatoendocrinologic Regressive spondylometaphyseal 3087 7 Cases 448267 2 Cases syndrome dysplasia 778 Rett syndrome 10.0 P * 98961 Reis-Bücklers corneal dystrophy 81 Cases 778 Rett syndrome 5.0 BP * 728 Relapsing polychondritis 0.35 I Reunion Island Larsen-like REN-related autosomal dominant 294049 30 Cases 217330 21 Cases syndrome tubulointerstitial kidney disease 3088 Revesz syndrome 4 Cases 1848 Renal agenesis, bilateral 1.7 BP * 244310 RFT1-CDG 8 Cases 93100 Renal agenesis, unilateral 50.0 BP Renal caliceal diverticuli-deafness 69077 Rhabdoid tumor 500 Cases 2838 4 Cases syndrome 780 Rhabdomyosarcoma 0.59 I * 217071 Renal cell carcinoma 42.0 P * 3099 Rheumatic fever 5.0 I * 217071 Renal cell carcinoma 8.35 I * Rheumatoid factor-negative 85408 8.0 P * juvenile idiopathic arthritis 1475 Renal coloboma syndrome 180 Cases Rheumatoid factor-positive 93108 Renal dysplasia 43.5 BP * 85435 polyarticular juvenile idiopathic 4.2 P * 93975 Renier-Gabreels-Jasper syndrome 5 Cases arthritis Rhizomelic chondrodysplasia 177 1.0 P * 3242 Renpenning syndrome 64 Cases punctata RERE-related neurodevelopmental Rhizomelic chondrodysplasia 494344 10 Cases 468717 4 Cases syndrome punctata type 5 Resistance to thyrotropin-releasing Rhizomelic dysplasia, Patterson- 99832 2 Cases 2831 5 Cases hormone syndrome Lowry type 1662 Restrictive dermopathy 30 Cases 3098 Rhizomelic syndrome, Urbach type 3 Cases 33355 Reticular dysgenesis 0.03 I * 59315 Rhombencephalosynapsis 100 Cases Reticulate acropigmentation of 178307 130 Cases 140976 RHYNS syndrome 4 Cases Kitamura 97229 Riboflavin transporter deficiency 80 Cases 458763 Retiform hemangioendothelioma 32 Cases 440706 Ribose-5-P isomerase deficiency 1 Case 75326 Retinal arterial tortuosity 100 Cases Retinal degeneration- 3101 Richieri Costa-da Silva syndrome 4 Cases 1574 nanophthalmos-glaucoma 7 Cases 3102 Richieri Costa-Pereira syndrome 33 Cases syndrome Retinal dystrophy with inner retinal 83312 Rickettsialpox 800 Cases 397758 dysfunction and ganglion cell 14 Cases 420741 RIDDLE syndrome 2 Cases anomalies 217335 RIN2 syndrome 10 Cases Retinal ischemic syndrome- digestive tract small vessel 363203 2.0 BP 3018 3 Cases Ring chromosome hyalinosis-diffuse cerebral 1437 35 Cases calcifications syndrome Ring chromosome 1 syndrome 319640 Retinal macular dystrophy type 2 5 Families 96171 Ring chromosome 2 syndrome 18 Cases

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families Salivary gland type cancer of the 96172 Ring chromosome 3 syndrome 11 Cases 213557 0.05 I * breast 1447 Ring chromosome 4 syndrome 20 Cases 370938 Salt-and-pepper syndrome 3 Cases 1448 Ring chromosome 6 syndrome 25 Cases 796 Sandhoff disease 0.67 BP * 1449 Ring chromosome 7 syndrome 18 Cases 79269 Sanfilippo syndrome type A 0.32 P * 1450 Ring chromosome 8 syndrome 8 Cases 79269 Sanfilippo syndrome type A 1.4 BP 96173 Ring chromosome 9 syndrome 31 Cases 79270 Sanfilippo syndrome type B 0.2 P * 1438 Ring chromosome 10 syndrome 16 Cases 79271 Sanfilippo syndrome type C 5.0 P * 96175 Ring chromosome 11 syndrome 20 Cases 797 Sarcoidosis 12.5 P 1439 Ring chromosome 12 syndrome 10 Cases 3129 Sarcosinemia 2.0 BP 1440 Ring chromosome 14 syndrome 80 Cases 3130 Satoyoshi syndrome 50 Cases 96177 Ring chromosome 15 syndrome 50 Cases 3132 Say-Barber-Miller syndrome 2 Cases 96178 Ring chromosome 16 syndrome 10 Cases 3133 Say-Field-Coldwell syndrome 4 Cases 1441 Ring chromosome 17 syndrome 18 Cases Scalp defects-postaxial polydactyly 1003 2 Cases 1442 Ring chromosome 18 syndrome 70 Cases syndrome 370052 SCALP syndrome 4 Cases 1443 Ring chromosome 19 syndrome 10 Cases 2036 Scalp-ear-nipple syndrome 30 Cases 1444 Ring chromosome 20 syndrome 50 Cases Scapuloperoneal spinal muscular 1446 Ring chromosome 22 syndrome 100 Cases 431255 31 Cases atrophy 91481 Ring dermoid of cornea 30 Cases 3134 SCARF syndrome 2 Cases 3103 Roberts syndrome 150 Cases Scarring in glaucoma filtration 90080 22.0 P * Robin sequence-oligodactyly surgical procedures 3104 3 Cases syndrome 2353 Schilbach-Rott syndrome 18 Cases 97360 Robinow syndrome 200 Cases 1830 Schimke immuno-osseous dysplasia 71 Cases 3105 Robinow-like syndrome 2 Cases 798 Schinzel-Giedion syndrome 46 Cases 353298 Roifman syndrome 7 Cases 37748 Schnitzler syndrome 150 Cases Rolandic epilepsy-paroxysmal 98967 Schnyder corneal dystrophy 115 Cases 163727 exercise-induced dystonia-writer's 1 Family cramp syndrome 50944 Schöpf-Schulz-Passarge syndrome 25 Cases 101016 Romano-Ward syndrome 40.0 P * 800 Schwartz-Jampel syndrome 129 Cases 158014 Rosaï-Dorfman disease 1000 Cases 185 Scimitar syndrome 2.0 BP * 2909 Rothmund-Thomson syndrome 400 Cases 801 Scleroderma 42.0 P Rothmund-Thomson syndrome 221008 100 Cases 801 Scleroderma 1.41 I type 1 Rothmund-Thomson syndrome 167635 Scleromyxedema 250 Cases 221016 200 Cases type 2 Scleromyxedema without 90400 15 Cases 3111 Rotor syndrome 50 Cases monoclonal gammopathy 3152 Sclerosteosis 80 Cases 83616 Rubella panencephalitis 20 Cases 806 Scott syndrome 4 Cases 783 Rubinstein-Taybi syndrome 0.7 BP * Rubinstein-Taybi syndrome due to 158029 Sea-blue histiocytosis 60 Cases 353284 34 Cases EP300 haploinsufficiency Seborrhea-like dermatitis with 168606 44 Cases Sacral agenesis-abnormal psoriasiform elements ossification of the vertebral bodies- 397927 4 Cases 808 Seckel syndrome 0.2 BP * persistent notochordal canal Segmental odontomaxillary syndrome 67039 32 Cases dysplasia 794 Saethre-Chotzen syndrome 3.0 BP * Segmental progressive overgrowth 300493 Sagliker syndrome 60 Cases 314662 syndrome with fibroadipose 10 Cases hyperplasia 140969 Saldino-Mainzer syndrome 10 Cases

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families Seizures-intellectual disability due Severe early-onset obesity-insulin 79156 6 Cases to hydroxylysinuria syndrome 329249 resistance syndrome due to SH2B1 13 Cases Seizures-scoliosis-macrocephaly deficiency 466926 4 Cases syndrome Severe feeding difficulties-failure to 281122 Self-improving collodion baby 25 Cases 352577 thrive-microcephaly due to ASXL3 28 Cases deficiency syndrome 3156 Senior-Loken syndrome 150 Cases Severe growth deficiency- Sensorineural deafness with dilated strabismus-extensive dermal 217622 2 Families 488627 3 Cases cardiomyopathy melanocytosis-intellectual disability Sensorineural hearing loss-early syndrome 66633 3 Cases graying-essential tremor syndrome 169802 Severe hemophilia A 2.8 P * 90051 Sepsis in premature infants 32.0 P * 169793 Severe hemophilia B 0.8 P * 3157 Septo-optic dysplasia spectrum 10.0 BP * Severe hereditary thrombophilia 745 due to congenital protein C 0.16 BP 139466 SERKAL syndrome 3 Cases deficiency Severe achondroplasia- Severe hypotonia-psychomotor 85165 developmental delay-acanthosis 5 Cases 467176 developmental delay-strabismus- 6 Cases nigricans syndrome cardiac septal defect syndrome Severe autosomal recessive 438207 2 Cases Severe intellectual disability and macrothrombocytopenia 280763 15 Cases progressive spastic paraplegia Severe combined 183660 1.65 BP * Severe intellectual disability-corpus immunodeficiency callosum agenesis-facial 466688 6 Cases Severe combined dysmorphism-cerebellar ataxia 277 immunodeficiency due to adenosine 0.2 P * syndrome deaminase deficiency Severe intellectual disability- Severe combined 94066 epilepsy-anal anomalies-distal 2 Cases 277 immunodeficiency due to adenosine 0.3 BP * phalangeal hypoplasia deaminase deficiency Severe intellectual disability- Severe combined epilepsy-cataract syndrome due to 438178 3 Cases 357237 immunodeficiency due to CARD11 3 Cases fatty acyl-CoA reductase 1 deficiency deficiency Severe combined Severe intellectual disability- 331206 immunodeficiency due to complete 1.0 P * 436141 hypotonia-strabismus-coarse face- 6 Cases RAG1/2 deficiency planovalgus syndrome Severe combined Severe intellectual disability-poor 228003 immunodeficiency due to CORO1A 6 Cases 363686 language-strabismus-grimacing 4 Cases deficiency face-long fingers syndrome Severe combined Severe intellectual disability- 420573 immunodeficiency due to CTPS1 8 Cases progressive postnatal microcephaly- 397933 3 Cases deficiency midline stereotypic hand Severe combined movements syndrome 317425 immunodeficiency due to DNA-PKcs 2 Cases Severe intellectual disability- deficiency 404473 progressive spastic diplegia 4 Cases Severe combined syndrome 397787 immunodeficiency due to IKK2 9 Cases Severe intellectual disability-short deficiency 391307 stature-behavioral abnormalities- 3 Cases Severe combined facial dysmorphism syndrome 504523 immunodeficiency due to LAT 3 Cases Severe lateral tibial bowing with 324307 2 Cases deficiency short stature Severe combined Severe microbrachycephaly- 280142 immunodeficiency due to LCK 4 Cases 1236 intellectual disability-athetoid 2 Cases deficiency cerebral palsy syndrome Severe congenital hypochromic 300298 3 Cases Severe motor and intellectual anemia with ringed sideroblasts 369939 disabilities-sensorineural deafness- 7 Cases 42738 Severe congenital neutropenia 0.07 P dystonia syndrome Severe myopia-generalized joint 42738 Severe congenital neutropenia 0.4 BP * 527450 5 Cases laxity-short stature syndrome Severe dermatitis-multiple 369992 allergies-metabolic wasting 3 Cases syndrome

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families Severe neonatal hypotonia- Short stature-webbed neck-heart 2865 4 Cases 314655 seizures-encephalopathy syndrome 7 Cases disease syndrome due to 5q31.3 microdeletion Short stature-wormian bones- 2863 3 Cases Severe neonatal lactic acidosis due dextrocardia syndrome 397593 5 Cases to NFS1-ISD11 complex deficiency 3163 SHORT syndrome 32 Cases Severe neonatal-onset 209370 30 Cases Short tarsus-absence of lower encephalopathy with microcephaly 2832 11 Cases eyelashes syndrome Severe neurodegenerative 363400 10 Cases Short ulna-dysmorphism- syndrome with lipodystrophy 357175 hypotonia-intellectual disability 4 Cases Severe neurodevelopmental syndrome disorder with feeding difficulties- 500545 6 Cases Short-limb skeletal dysplasia with stereotypic hand movement- 935 19 Cases severe combined immunodeficiency bilateral cataract Severe X-linked intellectual 2462 Shprintzen-Goldberg syndrome 60 Cases 3078 7 Cases disability, Gustavson type 811 Shwachman-Diamond syndrome 0.28 P Severe X-linked mitochondrial 238329 2 Cases encephalomyopathy 811 Shwachman-Diamond syndrome 0.5 BP 363489 Sex cord-stromal tumor of testis 0.02 I * 309294 Sialidosis 0.05 BP * 810 Shigellosis 1.68 I * 3166 Sialuria 5 Cases 99063 Shone complex 100 Cases 232 Sickle cell anemia 22.0 P * 104008 Short bowel syndrome 3.4 P * 3167 Siegler-Brewer-Carey syndrome 2 Cases Short fifth metacarpals-insulin 71276 98 Cases 66518 6 Cases Silent sinus syndrome resistance syndrome 3168 Sillence syndrome 5 Cases Short rib-polydactyly syndrome 498497 2 Cases type 5 813 Silver-Russell syndrome 0.7 BP * Short rib-polydactyly syndrome, 93269 34 Cases 813 Silver-Russell syndrome 15.5 I * Majewski type Short stature due to GHSR Silver-Russell syndrome due to a 314811 8 Cases 397590 8 Cases deficiency point mutation Short stature due to growth 373 Simpson-Golabi-Behmel syndrome 250 Cases 629 3 Cases hormone qualitative anomaly SIN3A-related intellectual disability 500163 15 Cases 2867 Short stature, Brussels type 2 Cases syndrome Short stature-advanced bone age- 85191 Singleton-Merten dysplasia 22 Cases 435804 3 Families early-onset osteoarthritis syndrome Sinoatrial node dysfunction and 324321 8 Cases Short stature-auditory canal deafness 397623 atresia-mandibular hypoplasia- 4 Cases 3169 Sirenomelia 0.01 P skeletal anomalies syndrome Short stature-brachydactyly- 3169 Sirenomelia 0.98 BP 464288 obesity-global developmental delay 6 Cases 2882 Sitosterolemia 100 Cases syndrome Short stature-craniofacial 488437 SIX2-related frontonasal dysplasia 1 Family 2994 anomalies-genital hypoplasia 3 Families Skeletal dysplasia-epilepsy-short 1858 7 Cases syndrome stature syndrome Short stature-deafness-neutrophil Skeletal dysplasia-T-cell 2866 dysfunction-dysmorphism 2 Cases 508533 immunodeficiency-developmental 12 Cases syndrome delay syndrome Short stature-onychodysplasia- Skeletal overgrowth-craniofacial 314394 facial dysmorphism-hypotrichosis 14 Cases 477831 dysmorphism-hyperelastic skin- 2 Cases syndrome white matter lesions syndrome Short stature-optic atrophy-Pelger- Skin fragility-woolly hair- 391677 34 Cases Huët anomaly syndrome 293165 palmoplantar keratoderma 7 Cases Short stature-pituitary and syndrome 85442 cerebellar defects-small sella turcica 5 Families 238459 SLC35A1-CDG 3 Cases syndrome Short stature-valvular heart 356961 SLC35A2-CDG 4 Cases 2868 disease-characteristic facies 3 Cases 468699 SLC39A8-CDG 10 Cases syndrome 70573 Small cell lung cancer 11.2 P *

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families SMARCA4-deficient sarcoma of Spectrin-associated autosomal 466962 19 Cases 352403 2 Families thorax recessive cerebellar ataxia 93974 Smith-Fineman-Myers syndrome 11 Families 99865 Spermatocytic seminoma 0.03 I * Spigelian hernia-cryptorchidism 818 Smith-Lemli-Opitz syndrome 3.7 BP * 314432 15 Cases syndrome 819 Smith-Magenis syndrome 4.0 P Spinal atrophy-ophthalmoplegia- 1217 2 Cases 178355 Smith-McCort dysplasia 16 Cases pyramidal syndrome 90058 Spinal cord injury 32.0 P * 820 Sneddon syndrome 0.4 I * Snowflake vitreoretinal Spinal muscular atrophy with 91496 50 Cases 98920 128 Cases degeneration respiratory distress type 1 Sodium channelopathy-related Spinal muscular atrophy with 306577 8 Cases 404521 1 Case small fiber neuropathy respiratory distress type 2 Spinal muscular atrophy-Dandy- 3394 Soft tissue sarcoma 30.0 P * 73245 Walker malformation-cataracts 2 Cases 3394 Soft tissue sarcoma 4.74 I * syndrome Spinal muscular atrophy- 97230 Solar urticaria 36.0 P * 2590 progressive myoclonic epilepsy 10 Cases 209964 Solitary rectal ulcer syndrome 1.0 I * syndrome 97283 Somatostatinoma 0.0025 I * 98755 Spinocerebellar ataxia type 1 1.5 P 821 Sotos syndrome 7.1 BP 98756 Spinocerebellar ataxia type 2 1.5 P Sparse hair-short stature-skin 98757 Spinocerebellar ataxia type 3 1.5 P 79132 4 Cases anomalies syndrome 98766 Spinocerebellar ataxia type 5 3 Families Spastic ataxia with congenital 1182 3 Families miosis 98767 Spinocerebellar ataxia type 11 51 Cases Spastic ataxia-corneal dystrophy 2572 1 Family 98762 Spinocerebellar ataxia type 12 40 Families syndrome Spastic paraparesis-deafness 98768 Spinocerebellar ataxia type 13 20 Cases 2815 6 Cases syndrome 98763 Spinocerebellar ataxia type 14 20 Families 99015 Spastic paraplegia type 2 100 Cases 98769 Spinocerebellar ataxia type 15/16 80 Cases 99013 Spastic paraplegia type 7 4.0 P * 98759 Spinocerebellar ataxia type 17 100 Families Spastic paraplegia-facial-cutaneous 2819 5 Cases lesions syndrome 98771 Spinocerebellar ataxia type 18 26 Cases Spastic paraplegia-glaucoma- 2818 2 Families 98772 Spinocerebellar ataxia type 19/22 12 Cases intellectual disability syndrome 101110 Spinocerebellar ataxia type 20 20 Cases Spastic paraplegia-intellectual 521390 disability-nystagmus-obesity 4 Cases 98773 Spinocerebellar ataxia type 21 35 Cases syndrome 101108 Spinocerebellar ataxia type 23 4 Families Spastic paraplegia-nephritis- 2820 4 Cases deafness syndrome 101111 Spinocerebellar ataxia type 25 10 Cases Spastic paraplegia-neuropathy- 2821 1 Family 101112 Spinocerebellar ataxia type 26 1 Family poikiloderma syndrome Spastic paraplegia-optic atrophy- 98764 Spinocerebellar ataxia type 27 30 Cases 320406 75 Cases neuropathy syndrome 208513 Spinocerebellar ataxia type 29 50 Cases Spastic paraplegia-Paget disease of 329475 1 Family bone syndrome 211017 Spinocerebellar ataxia type 30 6 Cases Spastic paraplegia-precocious 2826 2 Cases 217012 Spinocerebellar ataxia type 31 30 Families puberty syndrome 276183 Spinocerebellar ataxia type 32 1 Family Spastic paraplegia-severe 464282 developmental delay-epilepsy 16 Cases 1955 Spinocerebellar ataxia type 34 27 Cases syndrome 276193 Spinocerebellar ataxia type 35 3 Families Spastic tetraplegia-retinitis 3011 pigmentosa-intellectual disability 2 Cases 276198 Spinocerebellar ataxia type 36 100 Families syndrome 363710 Spinocerebellar ataxia type 37 9 Cases Spastic tetraplegia-thin corpus 447997 callosum-progressive postnatal 15 Cases 423296 Spinocerebellar ataxia type 38 4 Families microcephaly syndrome 423275 Spinocerebellar ataxia type 40 5 Cases

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families 458798 Spinocerebellar ataxia type 41 1 Case Spondyloepimetaphyseal dysplasia- 93358 short limb-abnormal calcification 27 Cases 458803 Spinocerebellar ataxia type 42 25 Cases syndrome Spondyloepiphyseal dysplasia 497764 Spinocerebellar ataxia type 43 7 Cases 94068 1.0 BP * congenita Spinocerebellar ataxia with axonal 94124 9 Cases Spondyloepiphyseal dysplasia neuropathy type 1 163665 3 Cases tarda, Kohn type Spinocerebellar ataxia- 1185 3 Cases Spondyloepiphyseal dysplasia, dysmorphism syndrome 163654 4 Cases Cantu type Spinocerebellar degeneration- 3177 2 Cases Spondyloepiphyseal dysplasia, corneal dystrophy syndrome 93283 1 Family Kimberley type 86854 Splenic marginal zone lymphoma 0.5 P * Spondyloepiphyseal dysplasia, 163668 4 Cases Splenogonadal fusion-limb defects- MacDermot type 2063 30 Cases micrognathia syndrome Spondyloepiphyseal dysplasia, 263482 10 Cases Split hand-split foot-deafness Maroteaux type 71271 22 Cases syndrome Spondyloepiphyseal dysplasia, Split-foot malformation-mesoaxial 163649 4 Cases 488232 5 Cases Nishimura type polydactyly syndrome Spondyloepiphyseal dysplasia, 163662 1 Family 93357 SPONASTRIME dysplasia 16 Cases Reardon type Spondylo-megaepiphyseal- Spondyloepiphyseal dysplasia, 228387 19 Cases 459051 7 Cases metaphyseal dysplasia Stanescu type 85194 Spondylo-ocular syndrome 7 Cases 254 Spondylometaphyseal dysplasia 1.0 BP * Spondylometaphyseal dysplasia, A4 3180 Spondylocamptodactyly syndrome 5 Cases 168555 3 Cases type 3275 Spondylocarpotarsal synostosis 24 Cases Spondylometaphyseal dysplasia, 93315 30 Cases Spondylocostal dysostosis-anal 'corner fracture' type 94095 atresia-genitourinary malformation 3 Cases Spondylometaphyseal dysplasia, 370019 2 Cases syndrome Czarny-Ratajczak type Spondylometaphyseal dysplasia, Spondylocostal dysostosis- 168544 3 Cases 329252 hypospadias-intellectual disability 2 Cases Golden type syndrome Spondylometaphyseal dysplasia, 93316 7 Cases 1855 Spondyloenchondrodysplasia 36 Cases Schmidt type Spondylometaphyseal dysplasia, Spondyloepimetaphyseal dysplasia 93317 9 Cases 93346 30 Cases Sedaghatian type congenita, Strudwick type Spondylometaphyseal dysplasia- Spondyloepimetaphyseal dysplasia, 171866 3 Cases 168552 bowed forearms-facial 2 Cases aggrecan type dysmorphism syndrome Spondyloepimetaphyseal dysplasia, 168448 7 Cases Spondylometaphyseal dysplasia- Bieganski type 85167 18 Cases cone-rod dystrophy syndrome Spondyloepimetaphyseal dysplasia, 168454 6 Families Spondyloperipheral dysplasia-short Geneviève type 1856 10 Families ulna syndrome Spondyloepimetaphyseal dysplasia, 99642 234 Cases Handigodu type 29822 Spontaneous periodic hypothermia 50 Cases Spondyloepimetaphyseal dysplasia, Sporadic adult-onset ataxia of 370015 2 Cases 247234 7.6 P * Isidor type unknown etiology Spondyloepimetaphyseal dysplasia, 156728 5 Cases 204 Sporadic Creutzfeldt-Jakob disease 0.1 P * matrilin-3 type 204 Sporadic Creutzfeldt-Jakob disease 0.15 I Spondyloepimetaphyseal dysplasia, 93356 14 Cases Missouri type Squamous cell carcinoma of Spondyloepimetaphyseal dysplasia, 424996 gallbladder and extrahepatic biliary 0.04 I * 93282 17 Cases PAPSS2 type tract Spondyloepimetaphyseal dysplasia, Squamous cell carcinoma of liver 93352 5 Cases 424975 0.01 I * Shohat type and intrahepatic biliary tract Spondyloepimetaphyseal dysplasia- Squamous cell carcinoma of 168451 2 Cases 424039 0.03 I * abnormal dentition syndrome pancreas Spondyloepimetaphyseal dysplasia- Squamous cell carcinoma of the 168443 5 Cases 424019 0.73 I * hypotrichosis syndrome anal canal Squamous cell carcinoma of the 213767 4.28 I * cervix uteri

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families Squamous cell carcinoma of the 423994 0.02 I * 506307 Stromme syndrome 11 Cases colon Squamous cell carcinoma of the 370921 STT3A-CDG 2 Cases 213716 0.12 I * corpus uteri 370924 STT3B-CDG 1 Case Squamous cell carcinoma of the 99977 5.2 I 3205 Sturge-Weber syndrome 3.5 BP * esophagus Squamous cell carcinoma of the 3206 Stüve-Wiedemann syndrome 56 Cases 494547 1.27 I * hypopharynx Subaortic stenosis-short stature Squamous cell carcinoma of the 3191 1 Family 494550 4.61 I * syndrome larynx 48377 Subcorneal pustular dermatosis 200 Cases 502366 Squamous cell carcinoma of the lip 1.02 I Subepithelial mucinous corneal Squamous cell carcinoma of the 98959 1 Family 500464 0.35 I dystrophy nasal cavity and paranasal sinuses Succinic semialdehyde Squamous cell carcinoma of the 22 450 Cases 502363 3.51 I * dehydrogenase deficiency oral cavity Succinyl-CoA:3-ketoacid CoA Squamous cell carcinoma of the 832 33 Cases 500478 3.12 I * transferase deficiency oropharynx Sudden infant death-dysgenesis of Squamous cell carcinoma of the 168593 21 Cases 398058 0.57 I * the testes syndrome penis 498602 Sugarman brachydactyly 1 Family Squamous cell carcinoma of the 424002 0.07 I * rectum 3210 Summitt syndrome 3 Cases Squamous cell carcinoma of the 423968 0.01 I * 57145 SUNCT syndrome 6.7 P * small intestine Squamous cell carcinoma of the 455 Superficial epidermolytic ichthyosis 20 Cases 418959 0.13 I * stomach 46485 Superficial pemphigus 1.2 P * 324737 SRD5A3-CDG 7 Families 247245 Superficial siderosis 300 Cases 370927 SSR4-CDG 9 Cases 141096 Supernumerary nostril 32 Cases 83484 St. Louis encephalitis 0.38 I * 466695 Supratip dysplasia 5 Cases STAG1-related intellectual 502434 disability-facial dysmorphism- 17 Cases 3193 Supravalvular aortic stenosis 13.3 P * gastroesophageal reflux syndrome 3193 Supravalvular aortic stenosis 4.0 BP * Stapes ankylosis with broad SURF1-related Charcot-Marie- 140917 6 Families 391351 3 Cases thumbs and toes Tooth disease type 4 827 Stargardt disease 10.0 P * 838 Susac syndrome 304 Cases STAT3-related early-onset Susceptibility to infection due to 438159 19 Cases 331226 8 Cases multisystem autoimmune disease TYK2 deficiency 438117 Steel syndrome 40 Cases 3243 Sweet syndrome 100 Cases 273 Steinert myotonic dystrophy 12.5 P Symbrachydactyly of hands and 1570 2 Cases Sterile multifocal osteomyelitis feet 210115 17 Cases with periostitis and pustulosis 1314 Symmetrical thalamic calcifications 30 Cases 2017 Sternal cleft 2.0 BP * 79098 Sympathetic ophthalmia 0.6 P * Steroid dehydrogenase deficiency- Symphalangism with multiple 3196 1 Family 3246 6 Cases dental anomalies syndrome anomalies of hands and feet 36426 Stevens-Johnson syndrome 0.36 I * 93402 Syndactyly type 1 25.0 BP * Stevens-Johnson syndrome/toxic 95455 0.19 I epidermal necrolysis spectrum 93405 Syndactyly type 4 4 Cases 828 Stickler syndrome 12.2 BP 93406 Syndactyly type 5 10 Cases 2833 Stiff skin syndrome 54 Cases Syndactyly-camptodactyly and 357332 clinodactyly of fifth fingers-bifid 26 Cases 3199 Stimmler syndrome 2 Cases toes syndrome STING-associated vasculopathy Syndactyly-nystagmus syndrome 425120 9 Cases 294026 2 Cases with onset in infancy due to 2q31.1 microduplication Stormorken-Sjaastad-Langslet Syndactyly-polydactyly-ear lobe 3204 17 Cases 3259 10 Cases syndrome syndrome 137599 Stromal keratitis 16.0 P *

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families Syndactyly-telecanthus-anogenital TBCK-related intellectual disability 140952 6 Cases 488632 25 Cases and renal malformations syndrome syndrome TCR-alpha-beta-positive T-cell 84064 Syndromic diarrhea 44 Cases 397959 2 Cases deficiency 178364 Syndromic microphthalmia type 5 20 Cases 3291 Teebi-Shaltout syndrome 5 Cases Syndromic multisystem Telecanthus-hypertelorism- 228426 autoimmune disease due to Itch 10 Cases 3293 2 Cases deficiency strabismus-pes cavus syndrome TELO2-related intellectual Syndromic orbital border 98606 2 Families 488642 disability-neurodevelopmental 6 Cases hypoplasia disorder Syndromic recessive X-linked 281090 1.3 P * Temperature-sensitive ichthyosis 352737 10 Cases oculocutaneous albinism type 1 Syndromic sensorineural deafness 457223 due to combined oxidative 2 Cases 284227 TEMPI syndrome 10 Cases phosphorylation defect 254516 Temple syndrome 53 Cases Syndromic X-linked intellectual 85274 10 Cases Temple syndrome due to maternal disability 7 96184 uniparental disomy of chromosome 64 Cases Syndromic X-linked intellectual 85279 10 Families 14 disability due to JARID1C mutation Temple syndrome due to paternal 254531 12 Cases 840 Syringocystadenoma papilliferum 300 Cases 14q32.2 hypomethylation Temple syndrome due to paternal 3280 Syringomyelia 8.4 P * 254525 9 Cases 14q32.2 microdeletion 188 Systemic capillary leak syndrome 150 Cases 420561 Temple-Baraitser syndrome 7 Cases 2467 Systemic mastocytosis 3.75 P Temtamy preaxial brachydactyly 363417 18 Cases 2467 Systemic mastocytosis 0.9 I * syndrome Systemic primary carnitine 1777 Temtamy syndrome 7 Families 158 3.2 BP * deficiency 141258 Tessier number 4 facial cleft 2 Cases 90291 Systemic sclerosis 15.4 P * Testicular seminomatous germ cell 842 1.71 I * Systemic-onset juvenile idiopathic 85414 5.0 P * tumor arthritis 3299 Tetanus 0.026 I * T-B+ severe combined Tetraamelia-multiple 169157 immunodeficiency due to CD45 3 Cases 3301 5 Families deficiency malformations syndrome T-cell immunodeficiency with 3303 Tetralogy of Fallot 34.0 BP 324294 2 Cases epidermodysplasia verruciformis 3310 Tetrasomy 9p 70 Cases T-cell large granular lymphocyte 86872 0.4 I * leukemia 884 Tetrasomy 12p 4.0 BP * 171918 T-cell non-Hodgkin lymphoma 0.99 I * 96055 Tetrasomy 21 13 Cases 457077 TAFRO syndrome 28 Cases 9 Tetrasomy X 50 Cases 3287 Takayasu arteritis 1.34 P * 1780 Thakker-Donnai syndrome 2 Cases 3287 Takayasu arteritis 0.084 I * 3312 Thalidomide embryopathy 0.77 P Tall stature-intellectual disability- 404443 17 Cases 2655 Thanatophoric dysplasia 3.5 BP * facial dysmorphism syndrome Thiamine-responsive Tall stature-intellectual disability- 199348 2 Cases 500095 4 Cases encephalopathy renal anomalies syndrome Thiamine-responsive megaloblastic Tall stature-scoliosis-macrodactyly 49827 80 Cases 329191 2 Families anemia syndrome of the great toes syndrome Thickened earlobes-conductive 2405 2 Families 50809 Talo-patello-scaphoid osteolysis 2 Cases deafness syndrome 31150 Tangier disease 100 Cases 98960 Thiel-Behnke corneal dystrophy 173 Cases Thin ribs-tubular bones- 2886 TARP syndrome 6 Families 1506 2 Cases dysmorphism syndrome 1412 Tarsal-carpal coalition syndrome 10 Families THOC6-related developmental Taurodontia-absent teeth-sparse 363444 delay-microcephaly-facial 4 Cases 2731 15 Cases hair syndrome dysmorphism syndrome 845 Tay-Sachs disease 0.28 BP 3316 Thomas syndrome 6 Cases

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families 614 Thomsen and Becker disease 1.0 P 101028 Transaldolase deficiency 23 Cases Thoracic dysplasia-hydrocephalus 1861 2 Cases 859 Transcobalamin deficiency 40 Cases syndrome Transient bullous dermolysis of the 79411 30 Cases 3317 Thoracolaryngopelvic dysplasia 10 Cases newborn 1803 Thoracomelic dysplasia 2 Cases Transient infantile 300293 hypertriglyceridemia and 11 Cases Thrombocythemia with distal limb 329319 3 Families hepatosteatosis defects Transient neonatal diabetes Thrombocytopenia with congenital 99886 0.3 BP * 67044 3 Families mellitus dyserythropoietic anemia Transient neonatal multiple acyl- Thrombocytopenia-absent radius 329942 1 Case 3320 0.5 BP * CoA dehydrogenase deficiency syndrome Thrombocytopenia-Robin sequence 488618 Transketolase deficiency 5 Cases 3323 2 Cases syndrome 216675 Transposition of the great arteries 31.7 BP * Thrombomodulin-related bleeding 436169 15 Cases disorder 861 Treacher-Collins syndrome 2.0 BP * Thrombotic thrombocytopenic Tremor-ataxia-central 54057 25.5 P * 447896 7 Cases purpura hypomyelination syndrome Thumb deformity-alopecia- Tremor-nystagmus-duodenal ulcer 2251 1 Family 3350 17 Cases pigmentation anomaly syndrome syndrome Thumb stiffness-brachydactyly- 863 Trichinellosis 0.06 I * 1078 6 Cases intellectual disability syndrome 3352 Tricho-dento-osseous syndrome 30 Cases 3398 Thymic epithelial neoplasm 0.17 I * Tricho-retino-dento-digital 1264 9 Cases 3326 Thymic-renal-anal-lung dysplasia 3 Cases syndrome 99867 Thymoma 0.14 I * 3351 Trichodental syndrome 5 Families Trichodermodysplasia-dental 3327 Thyrocerebrorenal syndrome 2 Cases 3353 3 Cases alterations syndrome 100088 Thyroid carcinoma 12.7 P Trichodysplasia-amelogenesis 79129 1 Family 100088 Thyroid carcinoma 3.1 I imperfecta syndrome Trichodysplasia-xeroderma 3361 1 Family 95712 Thyroid ectopia 14.3 P * syndrome Trichomegaly-retina pigmentary 95719 Thyroid hemiagenesis 25.0 P 3363 14 Cases degeneration-dwarfism syndrome 95720 Thyroid hypoplasia 3.5 P 3355 Trichoodontoonychial dysplasia 4 Cases 100087 Thyroid tumor 3.2 I Trichorhinophalangeal syndrome 77258 100 Cases Tibial aplasia-ectrodactyly type 1 and 3 3329 0.1 P * syndrome Trichorhinophalangeal syndrome 502 100 Cases 93322 Tibial hemimelia 0.1 BP * type 2 609 Tibial muscular dystrophy 6.0 P * 33364 Trichothiodystrophy 0.12 BP * 42665 Tietz syndrome 2 Families 1209 Tricuspid atresia 4.2 BP * Trigonocephaly-bifid nose-acral 65283 Timothy syndrome 20 Cases 3368 2 Cases anomalies syndrome 314667 TMEM165-CDG 6 Cases Trigonocephaly-broad thumbs 3365 2 Cases syndrome 466703 TMEM199-CDG 7 Cases Trigonocephaly-short stature- 3369 3 Cases 3460 Torg-Winchester syndrome 12 Cases developmental delay syndrome Triose phosphate-isomerase 3338 Toriello-Carey syndrome 59 Cases 868 50 Cases deficiency 3339 Toriello-Lacassie-Droste syndrome 19 Cases Triphalangeal thumb- 2950 15 Families Torticollis-keloids-cryptorchidism- polysyndactyly syndrome 3341 7 Cases renal dysplasia syndrome Triphalangeal thumbs- 2947 4 Families 227972 Toxic oil syndrome 20000 Cases brachyectrodactyly syndrome 869 Triple A syndrome 100 Cases 3346 Tracheal agenesis 2.0 BP * Tracheobronchopathia 3376 Triploidy 12.6 BP * 3348 400 Cases osteochondroplastica 261344 Trisomy 1q 18 Cases

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families Unclassified acute myeloid 1738 Trisomy 4p 85 Cases 167714 0.49 I * leukemia 1742 Trisomy 5p 40 Cases Undifferentiated carcinoma of 418951 0.07 I * 1752 Trisomy 8q 30 Cases esophagus Undifferentiated carcinoma of liver 236 Trisomy 9p 150 Cases 424970 0.02 I * and intrahepatic biliary tract 171929 Trisomy 10p 50 Cases Undifferentiated carcinoma of 423786 0.17 I * stomach 1699 Trisomy 12p 2.0 BP Undifferentiated pleomorphic 2023 0.9 I * 3378 Trisomy 13 3.7 BP * sarcoma Unilateral multicystic dysplastic 3380 Trisomy 18 16.7 BP 97363 23.2 BP kidney 1715 Trisomy 18p 25 Cases 1464 Univentricular heart 7.5 BP 3375 Trisomy X 42.5 P * Univentricular heart with single 99069 2 Cases 88629 Tritanopia 4.8 P * atrio-ventricular valve 3408 Upington disease 1 Family 3384 Truncus arteriosus 4.3 BP Upper limb defect-eye and ear 2489 2 Cases 3389 Tuberculosis 20.0 P * abnormalities syndrome 3389 Tuberculosis 139.0 I 2497 Upper limb mesomelic dysplasia 4 Cases 805 Tuberous sclerosis complex 12.0 P * 3409 Urban-Rogers-Meyer syndrome 3 Cases 805 Tuberous sclerosis complex 10.0 BP * 94059 Uremic pruritus 35.0 P * Tubular renal disease- 73224 2 Cases 210128 Urocanic aciduria 4 Cases cardiomyopathy syndrome 481665 USP18 deficiency 5 Cases 467166 Tubulinopathy-associated dysgyria 7 Cases 178338 UV-sensitive syndrome 7 Cases 1063 Tufted angioma 200 Cases Uveal coloboma-cleft lip and 1473 12 Cases 3392 Tularemia 2.0 P * palate-intellectual disability 3392 Tularemia 0.14 I * 39044 Uveal melanoma 0.5 I * Tumor necrosis factor receptor 1 32960 0.1 P * 98715 Uveitis 38.0 P * associated periodic syndrome 98715 Uveitis 17.0 I * 182130 Tumor of endocrine glands 64.0 P * 3412 VACTERL with hydrocephalus 10 Families 182130 Tumor of endocrine glands 3.75 I * 887 VACTERL/VATER association 6.25 BP * 363472 Tumor of testis and paratestis 3.15 I * Vacuolar myopathy with 881 Turner syndrome 5.5 BP * 88635 sarcoplasmic reticulum protein 4 Cases 99745 Typhoid 3.0 I * aggregates 3417 Van den Bosch syndrome 1 Family 882 Tyrosinemia type 1 0.9 BP 2460 Van den Ende-Gupta syndrome 29 Cases 28378 Tyrosinemia type 2 150 Cases Van Regemorter-Pierquin-Vamos 69723 20 Cases 3419 3 Cases Tyrosinemia type 3 syndrome 3403 Uhl anomaly 1.0 BP 314652 Variant ABeta2M amyloidosis 5 Cases 3404 Ulbright-Hodes syndrome 3 Cases 52759 Vasculitis 6.3 P * Ulna hypoplasia-intellectual 2249 2 Cases 404553 Vasculitis due to ADA2 deficiency 48 Cases disability syndrome Ulna metaphyseal dysplasia 3424 Velo-facial-skeletal syndrome 2 Cases 1837 3 Cases syndrome Ventriculomegaly-cystic kidney 443988 11 Cases Ulnar hypoplasia-split foot disease 1122 1 Family syndrome Verloove Vanhorick-Brubakk 3429 2 Cases 3138 Ulnar-mammary syndrome 117 Cases syndrome Ulnar/fibula ray defect- 70476 Vernal keratoconjunctivitis 32.0 P * 52056 1 Family brachydactyly syndrome 493342 Vibratory urticaria 37 Cases Umbilical cord ulceration-intestinal 3405 55 Cases atresia syndrome 1493 Vici syndrome 50 Cases

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families Virus-associated trichodysplasia 228379 7 Cases 319182 Wiedemann-Steiner syndrome 18 Cases spinulosa Visceral neuropathy-brain 85446 Wild type ABeta2M amyloidosis 4.5 P * 73246 anomalies-facial dysmorphism- 2 Cases 330001 Wild type ATTR amyloidosis 30.0 P * developmental delay syndrome 904 Williams syndrome 10.8 BP Vitamin B12-responsive 28 192 Cases methylmalonic acidemia 905 Wilson disease 3.3 P Vitamin B12-responsive 79310 60 Cases 905 Wilson disease 2.2 BP methylmalonic acidemia type cblA Vitamin B12-unresponsive 3459 Wilson-Turner syndrome 28 Cases 79312 450 Cases methylmalonic acidemia type mut- 906 Wiskott-Aldrich syndrome 0.1 P * 3439 Von Voss-Cherstvoy syndrome 10 Cases 1667 Wolcott-Rallison syndrome 60 Cases 903 Von Willebrand disease 12.5 P 280 Wolf-Hirschhorn syndrome 2.0 BP * VPS11-related autosomal recessive 466934 13 Cases hypomyelinating leukodystrophy 3463 Wolfram syndrome 0.13 P 137583 Vulvar intraepithelial neoplasia 20.0 P * 3464 Woodhouse-Sakati syndrome 30 Cases 83453 Vulvovaginal gingival syndrome 380 Cases Woolly hair-hypotrichosis-everted 1409 lower lip-outstanding ears 1 Family 2804 W syndrome 6 Cases syndrome Woolly hair-palmoplantar 3440 Waardenburg syndrome 0.37 BP * 420686 8 Cases keratoderma syndrome 897 Waardenburg-Shah syndrome 100 Cases Wormian bone-multiple fractures- WAC-related facial dysmorphism- 166277 dentinogenesis imperfecta-skeletal 3 Cases 466943 developmental delay-behavioral 22 Cases dysplasia abnormalities syndrome 3465 Worster-Drought syndrome 3.7 P * 898 Wagner disease 100 Cases 178475 Wound botulism 0.1 I * 893 WAGR syndrome 0.2 BP 2834 Wrinkly skin syndrome 30 Cases 33226 Waldenström macroglobulinemia 0.81 I * 3466 WT limb-blood syndrome 3 Families 899 Walker-Warburg syndrome 1.65 BP * 53719 Wyburn-Mason syndrome 90 Cases 280558 Warsaw breakage syndrome 4 Cases X-linked acrogigantism due to Xq26 448372 22 Cases 3447 Weaver syndrome 48 Cases microduplication 3448 Weaver-Williams syndrome 2 Cases 43 X-linked adrenoleukodystrophy 5.0 BP 3449 Weill-Marchesani syndrome 1.0 P 47 X-linked agammaglobulinemia 0.22 P 3344 Weismann-Netter syndrome 100 Cases 391327 X-linked calvarial hyperostosis 1 Family X-linked central congenital 99971 Well-differentiated liposarcoma 0.51 I * 329235 hypothyroidism with late-onset 27 Cases 901 Wells syndrome 200 Cases testicular enlargement 902 Werner syndrome 0.5 P * 596 X-linked centronuclear myopathy 0.2 P * X-linked cerebral-cerebellar- 3451 West syndrome 6.0 P * 163961 3 Cases coloboma syndrome 3451 West syndrome 3.7 BP X-linked Charcot-Marie-Tooth 64747 1.6 P * 83476 West-Nile encephalitis 0.036 I * disease X-linked Charcot-Marie-Tooth 101076 5 Cases 51636 WHIM syndrome 65 Cases disease type 2 X-linked Charcot-Marie-Tooth 2475 White forelock with malformations 2 Cases 101077 4 Families disease type 3 White matter hypoplasia-corpus X-linked Charcot-Marie-Tooth 3207 callosum agenesis-intellectual 4 Cases 101078 7 Cases disability syndrome disease type 4 X-linked Charcot-Marie-Tooth 370131 White platelet syndrome 1 Family 99014 9 Cases disease type 5 1489 Whooping cough 9.32 I * X-linked Charcot-Marie-Tooth 352675 8 Cases Wiedemann-Rautenstrauch disease type 6 3455 54 Cases syndrome

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families X-linked colobomatous X-linked intellectual disability, 85293 24 Families microphthalmia-microcephaly- Cabezas type 431140 1 Family intellectual disability-short stature X-linked intellectual disability, 85277 30 Cases syndrome Cantagrel type X-linked complicated corpus X-linked intellectual disability, 1497 11 Cases 163971 4 Cases callosum dysgenesis Cilliers type X-linked cone dysfunction X-linked intellectual disability, 90001 10 Families 93947 3 Cases syndrome with myopia Golabi-Ito-Hall type X-linked intellectual disability, 1661 X-linked corneal dermoid 6 Cases 93952 9 Cases Hedera type X-linked creatine transporter 52503 150 Cases X-linked intellectual disability, deficiency 85283 4 Cases Miles-Carpenter type X-linked distal spinal muscular 139557 2 Families X-linked intellectual disability, atrophy type 3 163937 35 Families Najm type X-linked dominant 35173 0.25 BP * X-linked intellectual disability, chondrodysplasia punctata 163956 8 Cases Nascimento type X-linked dominant X-linked intellectual disability, Pai 163966 chondrodysplasia, Chassaing- 10 Cases 85322 1 Family Lacombe type type X-linked intellectual disability, X-linked dyserythropoietic anemia 85285 4 Cases 363727 with abnormal platelets and 1 Family Schimke type X-linked intellectual disability, neutropenia 85323 4 Cases Seemanova type 75497 X-linked Ehlers-Danlos syndrome 2 Families X-linked intellectual disability, X-linked Emery-Dreifuss muscular 85286 9 Cases 98863 1.0 P Shashi type dystrophy X-linked intellectual disability, X-linked Emery-Dreifuss muscular 85324 3 Cases 98863 1.0 BP Shrimpton type dystrophy X-linked intellectual disability, X-linked endothelial corneal 85287 2 Families 293621 35 Cases Siderius type dystrophy X-linked intellectual disability, X-linked erythropoietic 3063 21 Cases 443197 50 Cases Snyder type protoporphyria X-linked intellectual disability, 85325 4 Cases X-linked external auditory canal Stevenson type 500188 4 Cases atresia-dilated internal auditory X-linked intellectual disability, 85288 1 Family canal-facial dysmorphism syndrome Stocco Dos Santos type X-linked female restricted facial X-linked intellectual disability, Stoll 480880 17 Cases 85326 4 Cases dysmorphism-short stature-choanal type atresia-intellectual disability X-linked intellectual disability, Van 163976 7 Cases X-linked hereditary sensory and Esch type 139583 autonomic neuropathy with 5 Families X-linked intellectual disability, deafness 85290 3 Cases Wilson type X-linked hypohidrotic ectodermal 181 0.75 BP * X-linked intellectual disability- dysplasia 85327 2 Cases acromegaly-hyperactivity syndrome 89936 X-linked hypophosphatemia 0.21 P * X-linked intellectual disability- 85338 9 Cases X-linked immunodeficiency with ataxia-apraxia syndrome 317476 magnesium defect, Epstein-Barr 7 Cases X-linked intellectual disability- virus infection and neoplasia 324410 cardiomegaly-congestive heart 2 Cases X-linked immunoneurologic failure syndrome 2571 5 Cases disorder X-linked intellectual disability- 137831 14 Families X-linked intellectual disability due cerebellar hypoplasia syndrome 364028 14 Cases to GRIA3 mutations X-linked intellectual disability- X-linked intellectual disability with 459070 cerebellar hypoplasia-spondylo- 2 Cases 67045 2 Families isolated growth hormone deficiency epiphyseal dysplasia syndrome X-linked intellectual disability, X-linked intellectual disability- 85273 8 Cases Abidi type 85330 corpus callosum agenesis-spastic 4 Cases X-linked intellectual disability, quadriparesis syndrome 85276 6 Cases Armfield type X-linked intellectual disability- 163979 9 Cases X-linked intellectual disability, craniofacioskeletal syndrome 3056 9 Cases Brooks type

Estimated Number of Estimated Number of ORPHA Disease prevalence/ published ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or Number or Group of diseases incidence cases or (/100,000) families (/100,000) families X-linked intellectual disability- X-linked mendelian susceptibility to 85280 cubitus valgus-dysmorphism 5 Cases 319612 mycobacterial diseases due to 6 Cases syndrome IKBKG deficiency X-linked intellectual disability- X-linked microcephaly-growth 1568 Dandy-Walker malformation-basal 10 Cases 435938 retardation-prognathism- 3 Cases ganglia disease-seizures syndrome cryptorchidism syndrome X-linked intellectual disability- X-linked myopathy with excessive 25980 18 Families 2958 dysmorphism-cerebral atrophy 8 Cases autophagy syndrome X-linked myopathy with postural 178461 7 Families X-linked intellectual disability- muscle atrophy epilepsy-progressive joint X-linked myotubular myopathy- 85319 2 Cases 456328 4 Cases contractures-dysmorphism abnormal genitalia syndrome syndrome X-linked neurodegenerative 85334 7 Cases X-linked intellectual disability- syndrome, Bertini type global development delay-facial X-linked neurodegenerative 480907 14 Cases 85336 11 Cases dysmorphism-sacral caudal syndrome, Hamel type remnant syndrome X-linked non progressive cerebellar 314978 3 Families X-linked intellectual disability- ataxia hypogammaglobulinemia- X-linked osteoporosis with 85317 3 Cases 391330 8 Families progressive neurological fractures deterioration syndrome X-linked parkinsonism-spasticity 363654 5 Cases X-linked intellectual disability- syndrome 3055 hypogonadism-ichthyosis-obesity- 4 Cases X-linked recessive intellectual short stature syndrome 83648 disability-macrocephaly-ciliary 1 Family X-linked intellectual disability- dysfunction syndrome 85329 hypotonia-facial dysmorphism- 10 Cases aggressive behavior syndrome 54 X-linked recessive ocular albinism 0.58 BP * X-linked reticulate pigmentary X-linked intellectual disability- 85453 6 Families 457260 hypotonia-movement disorder 38 Cases disorder syndrome 1852 X-linked retinal dysplasia 8 Cases X-linked intellectual disability-limb 792 X-linked retinoschisis 5.0 P 423479 spasticity-retinal dystrophy- 2 Cases diabetes insipidus syndrome X-linked scapuloperoneal muscular 431272 22 Cases X-linked intellectual disability- dystrophy X-linked severe congenital 85320 macrocephaly-macroorchidism 12 Cases 86788 45 Cases syndrome neutropenia X-linked intellectual disability- 2898 2 Cases 75563 X-linked sideroblastic anemia 200 Cases plagiocephaly syndrome X-linked sideroblastic anemia and 2802 5 Families X-linked intellectual disability- spinocerebellar ataxia 3077 psychosis-macroorchidism 6 Cases X-linked skeletal dysplasia- syndrome 1436 4 Cases intellectual disability syndrome X-linked intellectual disability- 3052 4 Cases seizures-psoriasis syndrome 100997 X-linked spastic paraplegia type 16 1 Family X-linked intellectual disability-short 171607 X-linked spastic paraplegia type 34 24 Cases 457240 20 Cases stature-overweight syndrome X-linked spasticity-intellectual 3175 6 Cases X-linked keloid scarring-reduced disability-epilepsy syndrome 482606 joint mobility-increased optic cup- 15 Cases X-linked spinocerebellar ataxia type 85297 5 Cases to-disc ratio syndrome 3 X-linked lethal multiple pterygium X-linked spinocerebellar ataxia type 79447 6 Families 85292 1 Family syndrome 4 X-linked lissencephaly with 452 30 Families 910 Xeroderma pigmentosum 0.23 BP * abnormal genitalia X-linked lymphoproliferative 90342 Xeroderma pigmentosum variant 50 Cases 2442 0.05 P * disease Xeroderma pigmentosum- 220295 30 Cases 1131 X-linked mandibulofacial dysostosis 7 Cases Cockayne syndrome complex X-linked mendelian susceptibility to 3469 XK aprosencephaly syndrome 10 Cases 319605 13 Cases mycobacterial diseases 261476 Xp21 microdeletion syndrome 100 Cases X-linked mendelian susceptibility to 319623 mycobacterial diseases due to CYBB 7 Cases 314389 Xq12-q13.3 duplication syndrome 3 Cases deficiency

Estimated Number of ORPHA Disease prevalence/ published Number or Group of diseases incidence cases or (/100,000) families 521258 Xq25 microduplication syndrome 28 Cases 261483 Xq27.3q28 duplication syndrome 8 Cases XY type gonadal dysgenesis- 1770 2 Cases associated anomalies syndrome 370930 XYLT1-CDG 2 Cases 662 Yellow nail syndrome 400 Cases Young adult-onset distal hereditary 314485 3 Cases motor neuropathy 2828 Young-onset Parkinson disease 15.0 P * 3472 Yunis-Varon syndrome 25 Cases 97240 Zebra body myopathy 10 Cases 217017 Zechi-Ceide syndrome 3 Cases Zellweger-like syndrome without 50812 2 Cases peroxisomal anomalies 3473 Zimmermann-Laband syndrome 52 Cases 3253 Zlotogora-Ogur syndrome 50 Cases 913 Zollinger-Ellison syndrome 0.125 I

To access the complete Orphanet epidemiological data sets visit Orphadata (www.orphadata.org). For any questions or comments, please contact us: [email protected] Editor-in-chief : Ana Rath – Editor of the report : Stéphanie NGUENGANG WAKAP - Technical support : Samuel Demarest and Valérie Lanneau The correct form when quoting this document is : «Prevalence of rare diseases: Bibliographic data », Orphanet Report Series, Rare Diseases collection, January 2019, Number 1 : Diseases listed in alphabetical order http://www.orpha.net/orphacom/cahiers/docs/GB/Prevalence_of_rare_diseases_by_diseases.pdf

This Orphanet Report Series is part of the joint action Direct Grant N°831390 which has received funding from the European Union’s Health Programme (2014-2020).

The content of this Orphanet Report Series represents the views of the author only and is his/her sole responsibility; it can not be considered to reflect the views of the European Commission and/or the Consumers, Health, Agriculture and Food Executive Agency or any other body of the European Union. The European Commission and the Agency do not accept any responsibility for use that may be made of the information it contains.