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Blueprint Genetics Comprehensive Short Stature Syndrome Panel

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Blueprint Genetics Comprehensive Short Stature Syndrome Panel Comprehensive Short Stature Syndrome Panel Test code: MA2101 Is a 98 gene panel that includes assessment of non-coding variants. Is ideal for patients with a clinical suspicion of short stature and associated disorders. About Comprehensive Short Stature Syndrome The clinical phenotypes of the disorders covered by this panel range in the severity of growth retardation and microcephaly, as well as in the degree of developmental delay, but there can be significant clinical overlap among syndromes. In addition to the disorders covered by the sub-panels, this comprehensive panel covers several other diseases associated with short stature, such as growth delay due to insulin-like growth factor I resistance or IGF1 deficiency (mutations in IGF1R and IGF1), hypothyroidism due to deficient transcription factors involved in pituitary development or function (HESX1, LHX3, LHX4, POU1F1 and PROP1), Rubinstein-Taybi syndrome (CREBBP and EP300), Cornelia de Lange syndrome (NIPBL, RAD21, SMC3, HDAC8 and SMC1A) and different forms of disproportionate short stature. Disproportionate short stature can manifest itself as short-limbed dwarfism or short-trunk dwarfism. Achondroplasia (autosomal dominant, mutations is FGFR3) is the most common form of disproportionate growth retardation, its estimated incidence is at about 1/25,000 live births worldwide. Identification of rare monogenic causes of short stature is critical since the genetic diagnosis may alert the clinician to other medical comorbidities for which the patient is at risk. For example, a male patient with 3-M syndrome will need to be monitored for the development of hypogonadism. Based on genetic studies in children with severe short stature of unknown etiology it has been suggested that monogenic causes of short stature are underdiagnosed in the pediatric endocrine clinic. Factors that increase the likelihood for a monogenic cause of short stature are severe GH deficiency, multiple pituitary hormone deficiency, unequivocal GH insensitivity, small for gestational age without catch-up growth, additional congenital anomalies or dysmorphic features, associated intellectual disability, microcephaly and height below −3 SD. Availability 4 weeks Gene Set Description Genes in the Comprehensive Short Stature Syndrome Panel and their clinical significance Gene Associated phenotypes Inheritance ClinVar HGMD ACTB* Baraitser-Winter syndrome AD 55 60 ACTG1* Deafness, Baraitser-Winter syndrome AD 27 47 AMMECR1 Midface hypoplasia, hearing impairment, elliptocytosis, and XL 4 5 nephrocalcinosis ARCN1 Rhizomelic short stature with microcephaly, micrognathia, and AD 3 3 developmental delay (SRMMD) ATR Cutaneous telangiectasia and cancer syndrome, Seckel syndrome AD/AR 10 33 B3GAT3* Multiple joint dislocations, short stature, craniofacial dysmorphism, and AR 6 13 congenital heart defects BCS1L Bjornstad syndrome, GRACILE syndrome, Leigh syndrome, Mitochondrial AR 42 37 complex III deficiency, nuclear type 1 BRAF* LEOPARD syndrome, Noonan syndrome, Cardiofaciocutaneous syndrome AD 134 65 https://blueprintgenetics.com/ CBL Noonan syndrome-like disorder with or without juvenile myelomonocytic AD 24 43 leukemia CCDC8 Three M syndrome 3 AR 2 3 CDC45 Meier-Gorlin syndrome 7 AR 10 19 CDC6 Meier-Gorlin syndrome (Ear-patella-short stature syndrome) AR 2 2 CDT1 Meier-Gorlin syndrome (Ear-patella-short stature syndrome) AR 6 12 CENPJ Seckel syndrome, Microcephaly AR 34 9 CEP152# Seckel syndrome, Microcephaly AR 20 20 CEP63 Seckel syndrome AR 7 2 COL27A1 Steel syndrome AR 7 7 CREBBP Rubinstein-Taybi syndrome AD 175 362 CUL7 3-M syndrome, Yakut short stature syndrome AR 26 83 DHCR7 Smith-Lemli-Opitz syndrome AR 88 217 DONSON Microcephaly, short stature, and limb abnormalities (MISSLA), 10 19 Microcephaly-Micromelia syndrome EP300 Rubinstein-Taybi syndrome AD 63 101 FGD1 Aarskog-Scott syndrome, Mental retardation, syndromic XL 29 51 FGFR3 Lacrimoauriculodentodigital syndrome, Muenke syndrome, Crouzon AD/AR 54 77 syndrome with acanthosis nigricans, Camptodactyly, tall stature, and hearing loss (CATSHL) syndrome, Achondroplasia, Hypochondroplasia, Thanatophoric dysplasia type 1, Thanatophoric dysplasia type 2, SADDAN FN1 Glomerulopathy with fibronectin deposits 2 AD 14 25 GH1* Isolated growth hormone deficiency, Kowarski syndrome AD/AR 25 90 GHR Growth hormone insensitivity syndrome (Laron syndrome) AD/AR 35 115 GHRHR Isolated growth hormone deficiency AR 13 51 GHSR Short stature AD/AR 2 12 GLI2 Culler-Jones syndrome AD 29 82 GNAS McCune-Albright syndrome, Progressive osseous heteroplasia, AD 64 274 Pseudohypoparathyroidism, Albright hereditary osteodystrophy HDAC8 Cornelia de Lange syndrome XL 41 50 HESX1 Septooptic dysplasia, Pituitary hormone deficiency, combined AR/AD 15 26 HRAS Costello syndrome, Congenital myopathy with excess of muscle spindles AD 43 31 IDUA Mucopolysaccharidosis AR 105 282 IGF1 Insulin-like growth factor I deficiency AD/AR 4 8 https://blueprintgenetics.com/ IGF1R Insulin-like growth factor I, resistance AD/AR 12 64 IGFALS Insulin-like growth factor-binding protein, acid-labile subunit, deficiency AR 5 34 INSR Hyperinsulinemic hypoglycemia, familial, Rabson-Mendenhall syndrome, AD/AR 44 190 Donohoe syndrome IRS1 Diabetes mellitus, noninsulin-dependent AD/AR 3 17 KRAS* Noonan syndrome, Cardiofaciocutaneous syndrome AD 63 35 LARP7 Alazami syndrome AR 19 10 LFNG Spondylocostal dysostosis, autosomal recessive 3 AR 1 5 LHX3 Pituitary hormone deficiency, combined AR 9 16 LHX4 Pituitary hormone deficiency, combined AD 10 23 LZTR1 Schwannomatosis, Noonan syndrome AD/AR 34 71 MAP2K1 Cardiofaciocutaneous syndrome AD 45 23 MAP2K2 Cardiofaciocutaneous syndrome AD 21 35 NIPBL Cornelia de Lange syndrome AD 311 425 NOTCH2* Alagille syndrome, Hajdu-Cheney syndrome AD 37 70 NRAS Noonan syndrome AD 31 14 OBSL1 3-M syndrome AR 13 33 ORC1 Meier-Gorlin syndrome (Ear-patella-short stature syndrome) AR 9 10 ORC4 Meier-Gorlin syndrome (Ear-patella-short stature syndrome) AR 24 6 ORC6 Meier-Gorlin syndrome (Ear-patella-short stature syndrome) AR 7 6 OSGEP Galloway-Mowat syndrome AR 11 17 OTX2 Microphthalmia, syndromic, Pituitary hormone deficiency, combined, AD 23 73 Retinal dystrophy, early-onset, and pituitary dysfunction PCNT Microcephalic osteodysplastic primordial dwarfism AR 49 88 PISD AR PITX2 Axenfeld-Rieger syndrome, Ring dermoid of cornea, AD 23 101 Iridogoniodysgenesis, Peters anomaly POC1A Short stature, onychodysplasia, facial dysmorphism, and hypotrichosis AR 4 8 (SOFT syndrome) POP1 Anauxetic dysplasia 2 AR 5 6 POU1F1 Pituitary hormone deficiency, combined AR 20 41 PPP3CA Epilepitic encephalopathy AD 8 11 https://blueprintgenetics.com/ PRMT7 Short stature, brachydactyly, intellectual developmental disability, and AR 10 11 seizures (SBIDDS) PROP1 Pituitary hormone deficiency, combined AR 33 37 PTPN11 Noonan syndrome, Metachondromatosis AD 135 140 PUF60 Short stature, Microcephaly AD 24 30 RAD21* Cornelia de Lange syndrome 4 AD 14 11 RAF1 LEOPARD syndrome, Noonan syndrome, Dilated cardiomyopathy (DCM) AD 45 53 RALA Intellectual disability AD 1 RASA2# Noonan syndrome AD 1 3 RBBP8 Seckel syndrome, Jawad syndrome AR 6 6 RIT1 Noonan syndrome AD 23 26 RNU4ATAC Roifman syndrome, Microcephalic osteodysplastic primordial dwarfism AR 15 24 type 1, Microcephalic osteodysplastic primordial dwarfism type 3 RRAS Noonan-syndrome like phenotype AD/AR 2 RTTN Microcephaly, short stature, and polymicrogyria with or without seizures AR 16 16 SGMS2 Osteoporosis and osteoporotic fractures, Skeletal dysplasia and disorders AD SHOC2 Noonan-like syndrome with loose anagen hair AD 2 4 SHOX* Leri-Weill dyschondrosteosis, Langer mesomelic dysplasia, Short stature XL/PAR 25 431 SMARCA2 Nicolaides-Baraitser syndrome AD 41 73 SMARCE1 Coffin-Siris syndrome AD 14 12 SMC1A Cornelia de Lange syndrome XL 73 87 SMC3 Cornelia de Lange syndrome AD 25 21 SOS1 Noonan syndrome AD 44 71 SOX11 Mental retardation, autosomal dominant 27 AD 11 14 SOX2* Microphthalmia, syndromic AD 34 104 SOX3 Panhypopituitarism XL 4 26 SRCAP Floating-Harbor syndrome AD 16 43 STAT5B* Growth hormone insensitivity with immunodeficiency AR 9 13 TALDO1 Transaldolase deficiency AR 6 10 TBX19 Adrenocorticotropic hormone deficiency AR 12 27 TBX2 AD 1 12 TBX3 Ulnar-Mammary syndrome AD 6 20 https://blueprintgenetics.com/ TOP3A 8 TRIM37 Mulibrey nanism AR 19 23 TRMT10A Microcephaly, short stature, and impaired glucose metabolism 1 AR 2 7 XRCC4 Short stature, microcephaly, and endocrine dysfunction AR 9 10 *Some regions of the gene are duplicated in the genome. Read more. # The gene has suboptimal coverage (means <90% of the gene’s target nucleotides are covered at >20x with mapping quality score (MQ>20) reads), and/or the gene has exons listed under Test limitations section that are not included in the panel as they are not sufficiently covered with high quality sequence reads. The sensitivity to detect variants may be limited in genes marked with an asterisk (*) or number sign (#). Due to possible limitations these genes may not be available as single gene tests. Gene refers to the HGNC approved gene symbol; Inheritance refers to inheritance patterns such as autosomal dominant (AD), autosomal recessive (AR), mitochondrial (mi), X-linked (XL), X-linked dominant (XLD) and X-linked recessive (XLR); ClinVar refers to the number of variants in the gene classified as pathogenic or likely pathogenic in this database (ClinVar); HGMD refers to the number of variants with possible disease association in the gene listed in Human Gene Mutation Database (HGMD). The list of associated,
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