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CBA HoliRD REPORT: Williams Syndrome Marina Esteban Medina María Peña-Chilet Carlos Loucera Joaquín Dopazo Clinical Bioinformatics Area - FPS Sevilla, January 13, 2020 Collaborators: Dra.Victoria Campuzano’s group - U735 CIBERER Research group at Universidad Pompeu Fabra, Barcelona. CBA Objectives and methodology: The Holistic Rare Disease project (HoliRD) aims to build Diseases Maps for as many Rare Diseases as possible and to model them to systematize research in drug repurposing. In order to achieve this purpose several databases such as ORPHANET, OMIM, HPO, PubMed, KEGG, STRING, as well as the literature is used to collect all the up-to-date knowledge of the diseases under study and defining a Disease Map that contains the functional relationships among the known disease genes, as well as the functional consequences of their activity. Then, a mechanistic model that accounts for the activity of such map is used. The HiPathia algorithm, which has successfully proven to predict cell activities related to cancer hallmarks (Hidalgo et al., Oncotarget 2017; 8:5160-5178; Hidalgo et al., Biol Direct. 2018;13:16) as well as the effect of protein inhibitions on cell survival (Cubuk et al., Cancer Res. 2018; 78:6059-6072) is used to simulate the activity of the disease map. Finally, machine learning algorithms are used to find other proteins, already target of drugs with another indication, which display a potential causal effect on the activity of the previously defined disease map. The drugs that target these proteins are potential candidates for repurposing. Schematic representation of the method used. Examples of the use of this approach can be found in Esteban-Medina et al., BMC Bioinformatics. 2019, 20(1):370. CBA Report This report describes the results of the different steps of the HoliRD approach applied to Williams Syndrome Identification of genes highly related to the rare disease (RD) under study in Orphanet/OMIM A total of 9 genes annotated as Williams Syndrome (WS) were found in the OMIM/ORPHANET database. WS highly related genes Disease ID Entrez ID Gene Symbol OMIM:194050 2006 ELN OMIM:194050 51085 MLXIPL ORPHA:904 26608 TBL2 ORPHA:904 3984 LIMK1 ORPHA:904 9569 GTF2IRD1 ORPHA:904 7461 CLIP2 ORPHA:904 9031 BAZ1B ORPHA:904 2969 GTF2I ORPHA:904 5982 RFC2 CBA Identification of highly related HPO to the RD under study: A total of 143 HPO codes associated to WS with specificity >=7 were selected. WS highly related HPOs HPO ID HPO term Specificity level HP:0000010 Recurrent urinary tract infections 10 HP:0000015 Bladder diverticulum 8 HP:0000023 Inguinal hernia 9 HP:0000025 Functional abnormality of male internal genitalia 7 HP:0000028 Cryptorchidism 10 HP:0000044 Hypogonadotrophic hypogonadism 9 HP:0000075 Renal duplication 8 HP:0000076 Vesicoureteral reflux 11 HP:0000083 Renal insufficiency 9 HP:0000089 Renal hypoplasia 9 HP:0000093 Proteinuria 9 HP:0000121 Nephrocalcinosis 8 HP:0000125 Pelvic kidney 10 HP:0000147 Polycystic ovaries 12 HP:0000154 Wide mouth 10 HP:0000158 Macroglossia 15 HP:0000179 Thick lower lip vermilion 12 HP:0000212 Gingival overgrowth 11 HP:0000232 Everted lower lip vermilion 12 HP:0000252 Microcephaly 19 HP:0000275 Narrow face 8 CBA HP:0000280 Coarse facial features 7 HP:0000286 Epicanthus 10 HP:0000307 Pointed chin 7 HP:0000337 Broad forehead 7 HP:0000343 Long philtrum 12 HP:0000347 Micrognathia 16 HP:0000348 High forehead 7 HP:0000368 Low-set, posteriorly rotated ears 9 HP:0000389 Chronic otitis media 11 HP:0000400 Macrotia 7 HP:0000407 Sensorineural hearing impairment 10 HP:0000411 Protruding ear 7 HP:0000431 Wide nasal bridge 8 HP:0000485 Megalocornea 8 HP:0000486 Strabismus 7 HP:0000518 Cataract 7 HP:0000581 Blepharophimosis 12 HP:0000627 Posterior embryotoxon 8 HP:0000635 Blue irides 9 HP:0000668 Hypodontia 12 HP:0000670 Carious teeth 11 HP:0000682 Abnormality of dental enamel 14 HP:0000689 Dental malocclusion 11 HP:0000691 Microdontia 11 HP:0000716 Depressivity 7 HP:0000717 Autism 7 CBA HP:0000739 Anxiety 8 HP:0000767 Pectus excavatum 8 HP:0000787 Nephrolithiasis 8 HP:0000938 Osteopenia 9 HP:0000939 Osteoporosis 9 HP:0000960 Sacral dimple 14 HP:0001052 Nevus flammeus 9 HP:0001081 Cholelithiasis 9 HP:0001136 Retinal arteriolar tortuosity 20 HP:0001181 Adducted thumb 14 HP:0001249 Intellectual disability 7 HP:0001257 Spasticity 11 HP:0001260 Dysarthria 7 HP:0001297 Stroke 10 HP:0001310 Dysmetria 8 HP:0001337 Tremor 7 HP:0001347 Hyperreflexia 7 HP:0001361 Nystagmus-induced head nodding 8 HP:0001387 Joint stiffness 7 HP:0001531 Failure to thrive in infancy 7 HP:0001537 Umbilical hernia 10 HP:0001582 Redundant skin 9 HP:0001618 Dysphonia 8 HP:0001629 Ventricular septal defect 9 HP:0001631 Atrial septal defect 9 HP:0001634 Mitral valve prolapse 9 CBA HP:0001636 Tetralogy of Fallot 13 HP:0001639 Hypertrophic cardiomyopathy 8 HP:0001642 Pulmonic stenosis 7 HP:0001643 Patent ductus arteriosus 9 HP:0001645 Sudden cardiac death 8 HP:0001647 Bicuspid aortic valve 9 HP:0001653 Mitral regurgitation 8 HP:0001800 Hypoplastic toenails 10 HP:0001822 Hallux valgus 16 HP:0001969 Tubulointerstitial abnormality 10 HP:0002020 Gastroesophageal reflux 11 HP:0002024 Malabsorption 8 HP:0002027 Abdominal pain 8 HP:0002035 Rectal prolapse 11 HP:0002120 Cerebral cortical atrophy 14 HP:0002141 Gait imbalance 7 HP:0002150 Hypercalciuria 10 HP:0002183 Phonophobia 7 HP:0002205 Recurrent respiratory infections 11 HP:0002253 Colonic diverticula 10 HP:0002308 Arnold-Chiari malformation 11 HP:0002575 Tracheoesophageal fistula 13 HP:0002623 Overriding aorta 10 HP:0002637 Cerebral ischemia 15 HP:0002650 Scoliosis 8 HP:0002808 Kyphosis 8 CBA HP:0002857 Genu valgum 19 HP:0002974 Radioulnar synostosis 21 HP:0002999 Patellar dislocation 13 HP:0003028 Abnormality of the ankles 9 HP:0003072 Hypercalcemia 9 HP:0003196 Short nose 8 HP:0003236 Elevated serum creatine kinase 8 HP:0003298 Spina bifida occulta 11 HP:0003307 Hyperlordosis 8 HP:0003312 Abnormal form of the vertebral bodies 8 HP:0003422 Vertebral segmentation defect 8 HP:0004209 Clinodactyly of the 5th finger 19 HP:0004295 Abnormality of the gastric mucosa 8 HP:0004381 Supravalvular aortic stenosis 8 HP:0004398 Peptic ulcer 7 HP:0004428 Elfin facies 7 HP:0004969 Peripheral pulmonary artery stenosis 15 HP:0005113 Aortic arch aneurysm 13 HP:0005344 Abnormal carotid artery morphology 8 HP:0005562 Multiple renal cysts 9 HP:0005692 Joint hyperflexibility 7 HP:0005978 Type II diabetes mellitus 9 HP:0007018 Attention deficit hyperactivity disorder 9 Atrophy/Degeneration involving the corticospinal HP:0007372 9 tracts HP:0007477 Abnormal dermatoglyphics 7 CBA HP:0007495 Prematurely aged appearance 7 HP:0007720 Flat cornea 8 HP:0007957 Corneal opacity 7 HP:0008053 Aplasia/Hypoplasia of the iris 12 HP:0008499 High hypermetropia 7 HP:0008661 Urethral stenosis 13 HP:0008736 Hypoplasia of penis 12 HP:0010526 Dysgraphia 7 HP:0010662 Abnormality of the diencephalon 8 HP:0010669 Hypoplasia of the zygomatic bone 12 HP:0010780 Hyperacusis 7 HP:0010807 Open bite 11 HP:0010880 Increased nuchal translucency 8 HP:0011001 Increased bone mineral density 8 HP:0100025 Overfriendliness 7 HP:0100539 Periorbital edema 13 HP:0100785 Insomnia 7 HP:0100817 Renovascular hypertension 14 HP:0200021 Down-sloping shoulders 9 CBA Identification of genes that shared at least HPO-RD codes Genes with >= 25 WS-HPO codes Gene Symbol Entrez Gene Symbol Entrez Gene Symbol Entrez ACTB 60 COX2 4513 SMC1A 8243 ARVCF 421 COX3 4514 NAA10 8260 RERE 473 ND1 4535 OFD1 8481 ATP6V1A 523 ND4 4538 TP63 8626 ATRX 546 ND5 4540 BAZ1B 9031 BRCA1 672 ND6 4541 SMC3 9126 BRAF 673 TRNF 4558 GTF2IRD1 9569 COMT 1312 TRNH 4564 SEC24C 9632 DHCR7 1717 TRNL1 4567 SEMA3E 9723 DVL1 1855 TRNQ 4572 MED12 9968 DVL3 1857 TRNS1 4574 CPLX1 10815 ELN 2006 TRNS2 4575 POLR3A 11128 ERCC2 2068 TRNW 4578 KAT6B 23522 ERCC3 2071 NOTCH2 4853 PIGN 23556 ERCC4 2072 NOTCH3 4854 RAB3GAP2 25782 ERCC6 2074 NRAS 4893 NIPBL 25836 FBN1 2200 ROR2 4920 SETBP1 26040 FGFR1 2260 OCRL 4952 TBL2 26608 FGFR3 2261 PIK3CA 5290 MLXIPL 51085 FGFR2 2263 MAP2K1 5604 BCOR 54880 FLNA 2316 PTCH1 5727 NSUN2 54888 GABRD 2563 PTEN 5728 SETD5 55209 CBA GATA4 2626 PTPN11 5781 FANCI 55215 GJA1 2697 ALDH18A1 5832 CHD7 55636 GP1BB 2812 RAD21 5885 HDAC8 55869 GTF2E2 2961 RAF1 5894 ARID1B 57492 GTF2I 2969 RFC2 5982 PIEZO2 63895 HRAS 3265 RPS6KA3 6197 PRDM16 63976 HSPG2 3339 RREB1 6239 NSD1 64324 KRAS 3845 SKI 6497 NXN 64359 LETM1 3954 TBX1 6899 MPLKIP 136647 LIG4 3981 HIRA 7290 B3GLCT 145173 LIMK1 3984 UFD1 7353 ARX 170302 LMNA 4000 CLIP2 7461 ARID2 196528 MECP2 4204 NSD2 7468 JMJD1C 221037 KMT2A 4297 RNF113A 7737 GTF2H5 404672 COX1 4512 Genes with >= 50 WS-HPO codes Gene Symbol Entrez Gene Symbol Entrez ELN 2006 CLIP2 7461 GTF2I 2969 BAZ1B 9031 KRAS 3845 GTF2IRD1 9569 LIMK1 3984 TBL2 26608 RFC2 5982 MLXIPL 51085 CBA Genes with >= 143 (all) WS-HPO codes Gene Symbol Entrez ELN 2006 GTF2I 2969 LIMK1 3984 RFC2 5982 CLIP2 7461 BAZ1B 9031 GTF2IRD1 9569 TBL2 26608 In order to maintain the specificity and not over expand the Disease Map of action only genes with >= 50 WS-HPO codes were selected. **Take into account that not all genes can be found in HiPathia pathways. We have selected those genes that expand the affected HiPathia circuits within a certain threshold for the model** Location of the selected disease related genes in KEGG pathways to define the Disease Map of action. After locating the RD associated genes within KEGG pathways, a total of 177 circuits belonging to 36 KEGG pathways were found as part of the disease map. KEGG-pathway KEGG-pathway KEGG pathway KEGG pathway code code Natural
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    PATIENT TUMOR TYPE QRF# Uterus carcinosarcoma PPAATIENTTIENT PHYPHYSICIANSICIAN SPECIMEN DISEASE ORDERING PHYSICIAN SPECIMEN SITE NAME MEDICAL FACILITY SPECIMEN ID DATE OF BIRTH ADDITIONAL RECIPIENT SPECIMEN TYPE SEX MEDICAL FACILITY ID DATE OF COLLECTION MEDICAL RECORD # PATHOLOGIST SPECIMEN RECEIVED NO REPORTREPORTABLE ALABLE ALTERATERATIONSTIONS WITH CCOMPOMPANIONANION DIADIAGNOGNOSSTIC (TIC (CDCDx)x) CLAIMS See professional services section for additional information OOTHER ALTHER ALTERATERATIONSTIONS & BIOMARKERS IDENTIFIED Results reported in this section are not prescriptive or conclusive for labeled use of any specific therapeutic product. See professional services section for additional information. MicrMicroossatatellitellite se sttatusatus MS-Stable § NT5C2NT5C2 R367Q TTumor Mutumor Mutational Burational Burdenden 53 Muts/Mb § PIK3CPIK3CAA R88Q AATRXTRX E259* PIK3CPIK3CAA M1043I CCAASP8SP8 E36* PPOLEOLE A456P FBFBXXW7W7 R465C PPTENTEN E7* FHFH splice site 1237-1G>T PPTENTEN S179I HSD3B1HSD3B1 T353M PPTENTEN F341V KDKDM5CM5C E448* RB1RB1 E323* MSH6MSH6 E908* TP53TP53 S127F MSH6MSH6 E1023* TP53TP53 Y327* § Refer to appendix for limitation statements related to detection of any copy number alterations, gene rearrangements, MSI or TMB result in this section. Please refer to appendix for Explanation of Clinical Significance Classification and for variants of unknown significance (VUS). FoundationOne CDx™ (F1CDx) is a next generation sequencing based TABLE 1 in vitro diagnostic device for detection of substitutions, insertion and