Variant annotation Extracted variants listed in dbsnp, OMIM, ClinVar, and HGMD 2434 variants

Transcription

1 Whole Genome Sequencing and Variant Calling Whole genome sequencing and variant calling of 128 healthy Ashkenazi Jews carried out by Complete Genomics. Merged 128 genomes using CGA tools, obtained exome variants. Panel Development Calculated expected prevalence from observed allele frequency, inheritance pattern, and the Hardy-Weinberg equilibrium. Variant annotation Extracted variants listed in dbsnp, OMIM, ClinVar, and HGMD 2434 variants Called, pathogenic in OMIM and ClinVar then scored per ACMG 80 Scored pathogenic very strong (PVS1) per ACMG 56 Measurable allele frequency in 1000 Genomes, ExAC 136 Trimmed variants based on disease prevalence and clinical utility. Figure 1S. Workflow for filtering genetic variants.

2 Chr Pos Ref Alt Variation dbsnpid Gene Symbol Phenotype ACMG score TAGC Frequency 1000 Genomes Frequency ExAC Frequency G A p.w610x rs CLCNKB Bartter syndrome type3 PVS1/PS T c.169dupa rs PPT1 Neuronal ceroid lipofuscinosis, infantile PVS E T c.1085dupt rs ZMPSTE24 Mandibuloacral dysplasia PVS T A c.79+2t>a rs MPL Amegakaryocytic thrombocytopaenia, congenital AG. c.1239_1240delga rs CPT2 Carnitine palmitoyltransferase 2 PVS PVS T c.886dupa RPE65 Leber congenital amaurosis PVS E A c.361dupt rs RPE65 Leber congenital amaurosis PVS C T p.t67i rs CTH Cystathioninuria PS3/PS4/PM C T p.g1961e rs ABCA4 Stargardt disease 1 PS4/PM C T c g>a rs DPYD Dihydropyrimidine dehydrogenase G A p.q45x rs AMPD1 Myoadenylate deaminase, myopathy due to G A p.v490m rs PHGDH Phosphoglycerate dehydrogenase PVS PVS1/PS PS3/PM E ACTG. c.2282_2285delcagt FLG Ichthyosis vulgaris PVS G A p.r501x rs FLG Ichthyosis vulgaris PVS1/PS4/PM T C p.n409s rs GBA Gaucher disease, type 1 PS1/PS C T c g>a SLC19A2 Megaloblastic anaemia, thiamine responsive T C c.492+2t>c rs DARS2 Leukoencephalopathy, brain & spine involvement, lactate elevation PVS E-05 PVS T C p.m467t rs SLC3A1 Cystinuria PS3/PM3/PP A c.2690dupa MSH6 Lynch syndrome PVS C. c.3261delc rs MSH6 Lynch syndrome PVS G A p.r307x rs PDE11A Adrenocortical hyperplasia PVS1/PS

3 A. c.171delt PDE11A Adrenocortical hyperplasia PVS G T p.p334h rs XPC Xeroderma pigmentosum, group C PS C T p.a1924t rs SCN5A Brugada syndrome 1 PS E G A p.t199m rs SLC6A20 Hyperglycinuria PS3/PM3/PP G c.5413dupg NBEAL2 Grey platelet syndrome PVS E C c.3942dupg COL7A1 Epidermolysis bullosa dystrophica G. c.1292delc SLCO2A1 Hypertrophic osteoarthropathy, primary A c.830dupt SLCO2A1 Hypertrophic osteoarthropathy, primary G A c g>a rs HPS3 Hermasky-Pudlak syndrome 3 PVS E-06 PVS E-06 PVS E-05 PVS1/PS3/PS E A C p.n48k rs CLRN1 Usher syndrome, type 3A PS3/PM3/PP A c.1158dupt BCHE Hypocholinesterasaemia PVS E T c.1027dupa BCHE Hypocholinesterasaemia PVS A CT c.435deltinsag rs BCHE Hypocholinesterasaemia PVS T c.401dupa BCHE Hypocholinesterasaemia PVS E G T p.g865x rs MTTP Abetalipoproteinemia PVS1/PM3/PP E T c.451dupt rs KLKB1 Prekallikrein PVS G A c g>a rs F11 Factor XI PVS E A G p.m1v rs SDHA Leigh syndrome due to mitochondrial comples II G A p.h412y rs TERT Bone marrow failure, telomere-related, 1 PVS1/PS E-05 PS3/PM T c.5563dupa DNAH5 Primary ciliary dyskinesia PVS E T c.8263dupa C5orf42 Joubert syndrome PVS E C A p.e13x rs ERCC8 Cockayne syndrome A PVS1/PS E C. c.1325delc MEGF10 Early-onset myopathy, areflexia, respiratory distress, and dysphagia T c.501dupa ZBTB24 Immuno, centromeric instability & facial anomalies syndrome PVS E-06 PVS E-05

4 C T c g>a rs LPA Lp(a) PVS1/benign phenotype A c.2052dupa rs CFTR Cystic fibrosis PVS E G A p.w1282x rs CFTR Cystic Fibrosis PVS1/PS4/PS A T p.n29i rs PRSS1 Pancreatitis, hereditary PS3/PP G A p.d36n rs LPL Combined hyperlipidemia, familial A G p.n318s rs268 LPL Combined hyperlipidemia, familial PS4/PS3/PP PS4/PS T c.4941dupt RP1 Retinitis pigmentosa PVS E C T p.r296x rs TG Thyroid dyshormonogenesis 3 PVS C G p.a150p rs ALDOB Fructose intolerance PS4/PS3/PP A c.1167dupa rs FKTN Muscular dystrophy, Fukuyama (AJ mutation) PVS A G c t>c rs IKBKAP Dysautonomia, familial PS4/PS3/PP C T p.p475s rs ADAMTS13 Thrombotic thrombocytopenic purpura, familial G A p.g530s rs COL5A1 Ehlers-Danlos syndrome, type II PS4/PS3/PP PS4/PS3/PP G A p.r175w rs PHYH Refsum disease PS4/PS A T p.y791f rs RET Thyroid carcinoma, familial medullary PS4/PM G A p.r245x rs PCDH15 Usher syndrome, type 1F PVS G T p.g287v rs HOGA1 Hyperoxaluria, primary, type 3 PM3/PP E G. c.972delc rs HPS1 Hermansky-Pudlak syndrome PVS G T p.r497l rs SMPD1 Niemann-pick disease, type A C T c g>a rs ABCC8 Hyperinsulinemic hypoglycemia, familial, A c.191dupa rs ANO5 Muscular dystrophy, limb girdle 2L GT. c.236_237deltg rs FSHB Follicle-stimulating hormone G A p.r81h rs BEST1 Vitelliform macular dystrophy, adult onset PS4/PS3/PP PS4/PS3/PP PVS PVS PS4/PS

5 C G c.964-1g>c rs DHCR7 Smith-Lemli-Opitz syndrome PVS C T p.p406l rs TYR Albinism, oculocutaneous, type IB G A p.g12s rs SDHD Carcinoid tumors /Cowden disease A G p.h50r rs SDHD Carcinoid tumors /Cowden disease 3 PS4/PP PS4/PS3/PP PS4/PS G A p.g490r rs CACNA1C Timothy syndrome PS4/PS3/PP C T p.r854q rs VWF Von Willebrand disease, type 2N A G p.w516r rs SCNN1A Bronchiectasis with or without elevated sweat chloride 2 PS4/PS3/PP PS4/PS A C p.y159x rs CLEC7A Candidiasis, familial, 4 PVS G A p.g2019s rs LRRK2 Parkinson disease 8, autosomal dominant PS4/PS3/PP G A p.v377i rs MVK Hyper IgD syndrome PS4/PS C T p.v84m rs GJB2 Deafness, autosomal recessive 1A A. c.167delt rs GJB2 Deafness, autosomal recessive 1A C T p.v37i rs GJB2 Deafness, autosomal recessive 1A A G p.m34t rs GJB2 Deafness, autosomal recessive 1A C. c.35delg rs GJB2 Deafness, autosomal recessive 1A PS4/PM E-06 PVS PS4/PM PS4/PM PVS A C p.t222p rs RXFP2 Cryptorchidism PS4/PS A c.5073dupa rs BRCA2 Breast and/or ovarian cancer PVS E G. c.722delg PCCA Propionic acidaemia PVS E T c.923dupt rs PCCA Propionic acidaemia PVS E C T p.v518m rs TGM1 Ichthyosis, congenital, autosomal recessive G T p.s42y rs TGM1 Ichthyosis, congenital, autosomal recessive C T p.a481t rs OCA2 Albinism oculocutaneous, type II PS4/PS3/PM PS4/PS3/PM E-06 PS4/PS3/PM C T p.v443i rs OCA2 Albinism oculocutaneous, PS4/PS3/PM

6 type II A c.2471dupt SPG11 Spastic paraplegia PVS E G A p.r311q rs NR2E3 Enhanced S-cone syndrome PS3/PM C G c g>c rs HEXA Tay-Sachs disease PVS E GATA c.1274_1277duptatc rs HEXA Tay-Sachs disease PVS A G p.v726a rs MEFV Familial Mediterranean fever PS4/PM3/PP T C p.k695r rs MEFV Familial Mediterranean fever PS4/PM3/PP C G p.e148q rs MEFV Familial Mediterranean fever PS4/PM3/PP C G p.s82c rs SCNN1B Bronchiectasis with or without elevated sweat chloride 1 PS4/PM C A p.d36y rs VKROC1 Warfarin resistance PS4/PP A c.244dupa ASPA Canavan disease PVS E C A p.y231x rs ASPA Canavan disease PVS E A C p.e285a rs ASPA Canavan disease PS4/PS3/PM C c.1353dupg CHRNE Congenital myasthenic syndrome C T p.r398w rs WRAP53 Dyskeratosis congenita, autosomal recessive, G A p.t118m rs PMP22 Charcot-Marie-Tooth disease, type 1A PVS PS3/PM PS4/PS3/PM C T p.r83c rs G6PC Glycogen storage disease Ia PS4/PS3/PM C T p.r14w rs CA4 Retinitis pigmentosa 17 PS4/PS3/PM C G p.l110v rs SLC9A3R1 Nephrolithiasis/osteoporosis, hypophosphatemic, C A c.753+1g>t rs UNC13D Haemophagocytic lymphohistiocytosis, familial TC c.2686_2687dupga rs DSC2 Arrhythmogenic right ventricular dysplasia/cardiomyopathy PS4/PS PVS E-05 PVS A c.5704dupt EPG5 Vici syndrome PVS E A G c t>c rs FECH Protoporphyria, erythropoietic PVS1/PS4/PS3/PP C T p.a175t rs MC4R Obesity PS4/PM3/PP C T p.e247k rs FUT6 Fucosyltransferase 6 PS4/PS

7 C T p.v1000m rs INSR Diabetes mellitus, noninsulin-dependent PS4/PP C T p.a182t rs SLC7A9 Cystinuria PS4/PS A C p.h59p rs GPI Hemolytic anemia, nonspherocytic, due to glucose phosphate isomerase PM1/PM E G. c.395delg DLL3 Spondylocostal dysostosis PVS E T C p.c130r rs APOE Hyperlipoprotenemia, type III PS3/PM A. c.939delt CCDC114 Primary ciliary dyskinesia PVS E C T p.g160d rs VSX1 Corneal dystrophy, hereditary polymorphous posterior C. c.4delg GSS Glutathione synthetase C T p.d85n rs KCNE1 Jervell and Lange-Nielsen syndrome 2 PS4/PS3/PP PVS PS4/PP T G c a>c rs CBS Homocystinuria PVS A G p.i278t rs CBS Homocysitnuria PS4/PM3/PP G A p.t358m rs PRODH Hyperprolinemia, type I PS4/PS A G p.l333p rs PRODH Hyperprolinemia, type I PS4/PS3/PP C T p.r323h rs PRODH Hyperprolinemia, type I PS4/PS A T p.l181m rs PRODH Hyperprolinemia, type I PS4/PS G A NM_ :c.917-1G>A rs UPB1 Beta-ureidopropionase PVS G A p.p92s rs MLC1 Megalencephalic leukoencephalopathy with subcortical cysts T C p.e289g rs TYMP Mitochondrial DNA depletion syndrome 1 PS4/PM3/PP PS1/PM X G A p.a180t rs BMP15 Premature ovarian failure 4 PS4/PM X C T p.r329q rs POF1B Premature ovarian failure 2B PS4/PS3/PP X G A p.r1677q rs COL4A5 Alport syndrome PS4/PS3/PP E-05

8 Table 1S: Variants identified in 128 Ashkenazi Jewish genomes and their allele frequencies in the source population, the 1000 Genomes population and the ExAC population. ACMG scores are as follows - PVS1: Truncating variant in a gene where LOF is a known mechanism of disease, PS1: Same amino acid change as an established pathogenic variant, PS3: Well-established functional studies show a deleterious effect, PS4: Prevalence in affecteds statistically increased over controls, PM1: Located in a mutational hot spot and/or known functional domain, PM2: Absent in 1000G and ESP, PM3: For recessive disorders, detected in trans with a pathogenic variant, PP1: Co-segregation with disease in multiple affected family members, PP2: Missense in gene with low rate of benign missense variants and pathogenic missenses common. Gene Symbol Phenotype dbsnp ID Variation Sensitivity AJ Sensitivity Gen. Pop. No. variants per disease Inheritance HBA1 Alpha thalassemia del 3.7Kb 1 5% 1 Recessive 1156 MTTP Abetalipoproteinemia rs p.g865x* 2 1 Recessive X X ACADS Acyl CoA dehydrogenase rs c.319c>t % 1 Recessive X X 900 PDE11A Adrenocortical hyperplasia rs p.r307x 2 Dominant X 128 PDE11A Adrenocortical hyperplasia c.171delt X OCA2 Albinism oculocutaneous, type II rs p.a481t 2 Recessive OCA2 Albinism oculocutaneous, type II rs p.v443i* 4 TYR Albinism, oculocutaneous, type IB rs p.p406l 1 Recessive X MPL Amegakaryocytic thrombocytopenia rs c.79+2t>a 5 1 Recessive X 4096 DSC2 Arrhythmogenic right ventricular dysplasia/cardiomyopathy rs c.2686_2687dupga* 1 Dominant X X X 127 CLCNKB Bartter syndrome type 3 rs p.w610x 1 Recessive X X 4110 UPB1 Beta-ureidopropionase rs c.917-1g>a* 1 Recessive X X Repr. Risk Pers Risk Dx Prevalence (1 in X)

9 BLM Bloom syndrome rs c.2207_2212 delatctga instagat 6 98% 1 Recessive X X TERT Bone marrow failure, telomere-related, 1 rs p.h412y 1 Dominant X X 33 BRCA1 Breast/ovarian cancer predisposition rs c.5266dupc 7 5% 3 Dominant X 56 BRCA1 Breast/ovarian cancer predisposition rs c.68_69delag 0.4 BRCA2 Breast/ovarian cancer predisposition rs c.6174 delt SCNN1B SCNN1A Bronchiectasis with or without elevated sweat chloride 1 Bronchiectasis with or without elevated sweat chloride 2 rs p.s82c 1 Recessive X X 7162 rs p.w516r 1 Recessive X X 2630 SCN5A Brugada syndrome 1 rs p.a1924t* 1 Dominant X 128 ASPA Canavan disease rs p.y231x 8 99% Recessive X X ASPA Canavan disease rs p.e285a X X ASPA Canavan disease rs p.a305e 30-60% X X CLEC7A Candidiasis, familial, 4 rs p.y159x 1 Recessive X 149 SDHD Carcinoid tumors /Cowden disease 3 rs p.g12s 2 Dominant X X 43 SDHD Carcinoid tumors /Cowden disease 3 rs p.h50r* X X CPT2 Carnitine palmitoyltransferase 2 CCM2 Cerebral cavernous malformations c.30+5delinstt 9 rs c.1239_1240delga* 1 Recessive X X Dominant X Unknown PMP22 Charcot-Marie-Tooth disease, type 1A rs p.t118m* 1 Recessive X X ERCC8 Cockayne syndrome A rs p.e13x 1 Recessive X APC Colon cancer predisposition rs p.i1307k 10 1 Dominant X 11 LPL Combined hyperlipidemia, familial rs p.d36n 2 Recessive X LPL Combined hyperlipidemia, familial rs268 p.n318s X CYP21A2 Congenital adrenal hyperplasia rs6471 p.v281l 11 63% 7 Recessive X X 9 CYP21A2 Congenital adrenal hyperplasia rs p.p30l CYP21A2 Congenital adrenal hyperplasia IVS2 13C>G (IVS 2) CYP21A2 Congenital adrenal hyperplasia rs6475 p.i172n CYP21A2 Congenital adrenal hyperplasia rs p.q318x CYP21A2 Congenital adrenal hyperplasia rs p.r356w CYP21A2 Congenital adrenal hyperplasia rs VSX1 Corneal dystrophy, hereditary polymorphous posterior 8 bp deletion in exon 3 rs p.g160d 1 Dominant X X X 28 RXFP2 Cryptorchidism rs p.t222p 1 Recessive X X 2000 CFTR Cystic Fibrosis rs p.w1282x 12 97% 75% 10 Recessive X X CFTR Cystic fibrosis rs p.508delf 2704 CFTR Cystic fibrosis rs p.g542x CFTR Cystic fibrosis rs p.n1303k CFTR Cystic fibrosis rs c C>T

10 CFTR Cystic fibrosis rs p.w1089x CFTR Cystic fibrosis rs p.d1152h CFTR Cystic fibrosis rs c.273+1g>a CFTR Cystic Fibrosis rs p.r1066h CFTR Cystic fibrosis rs c.2052dupa* X X SLC3A1 Cystinuria rs p.m467t 2 Recessive X X SLC7A9 Cystinuria rs p.a182t X X GJB2 Deafness, autosomal recessive 1A rs c.167delt % 6 Recessive X X 4110 GJB2 Deafness, autosomal recessive 1A rs c.35delg* GJB2 Deafness, autosomal recessive 1A rs p.v37i 4110 GJB2 Deafness, autosomal recessive 1A rs p.m34t GJB2 Deafness, autosomal recessive 1A rs p.v84m* LOXHD1 Deafness, autosomal recessive 1A rs p.r1572x % X X GJB6 Deafness, autosomal recessive 1B del 309kB 15 1 Recessive INSR Diabetes mellitus, noninsulin-dependent rs p.v1000m 1 Dominant X X 64 DLD DLD DPYD WRAP53 Dihydrolipoamide dehydrogenase Dihydrolipoamide dehydrogenase Dihydropyrimidine dehydrogenase Dyskeratosis congenita, autosomal recessive, 3 rs p.g229c 17 95% 2 Recessive X X p.y35x rs c g>a 1 Recessive X rs p.r398w 1 Recessive X X 7162 COL5A1 Ehlers-Danlos syndrome, type II rs p.g530s 1 Recessive X X 455 NR2E3 Enhanced S-cone syndrome rs p.r311q 1 Dominant X X 64 F11 Factor XI (PTA) rs p.f283l 18, % 3 Recessive X X 576 F11 Factor XI (PTA) rs p.e117x F11 Factor XI (PTA) rs c g>a* IKBKAP Familial dysautonomia rs c t>c >99% 2 Recessive X X 2630 IKBKAP Familial dysautonomia rs p.r696p 20,21 LDLR Familial hypercholesterolemia rs p.g197del % 1 Dominant X X 10 ABCC8 Familial hyperinsulinism rs c g>a* 23 90% 2 Recessive X X ABCC8 Familial hyperinsulinism rs p.f1387del X X MEFV Familial Mediterranean Fever rs p.v726a 24,25, % 6 Recessive X X MEFV Familial Mediterranean Fever rs p.m694i 100 MEFV Familial Mediterranean Fever rs p.m694v MEFV Familial Mediterranean Fever rs p.m680i MEFV Familial Mediterranean Fever rs p.k695r MEFV Familial Mediterranean Fever rs p.e148q

11 FANCC Fanconi anemia, complementation group C rs c.456+4a>t 27 99% 1 Recessive X X X FMR1 Fragile X syndrome CGG repeat 28 99% 1 X-linked X 250 ALDOB Fructose intolerance rs p.a149p 1 Recessive X FUT6 Fucosyltransferase 6 rs p.e247k 1 Recessive X X 164 GALT Galactosemia del 5kb 29,30 3 Recessive X GALT Galactosemia rs Q188R31 65% Euro GALT Galactosemia rs K285N 8%, 25-40% Euro GBA Gaucher disease, type 1 rs p.n409s* 32,33 98% 50-60% 4 Recessive X X X GBA Gaucher disease, type 1 rs p.l444p 900 GBA Gaucher disease, type 1 rs c.115+1g>a GBA Gaucher disease, type 1 rs c.84dupg GSS Glutathione synthetase c.4delg 1 Recessive X X G6PC Glycogen storage disease Ia rs p.r83c* 34, % Recessive X X HFE Hemochromatosis rs p.h63d % 1 Recessive X X 25 HPS3 Hermasky-Pudlak syndrome 3 rs c g>a* 1 Recessive X X CBS Homocystinuria rs c a>c 1 Recessive X 995 CBS Homocystinuria rs p.i278t 1 X X MVK Hyper IgD syndrome rs p.v377i* 37 1 Recessive X SLC6A20 Hyperglycinuria rs p.t199m 1 Dominant X X 5 APOE Hyperlipoprotenemia, type III rs p.c130r 1 Dominant X 6 HOGA1 Hyperoxaluria, primary, type 3 rs p.g287v* 38 2 Recessive X X HOGA1 Hyperoxaluria, primary, type 3 rs c.944_946delagg unknown PRODH Hyperprolinemia, type I rs p.r323h 4 Recessive X X 142 PRODH Hyperprolinemia, type I rs p.t358m PRODH Hyperprolinemia, type I rs p.l333p PRODH Hyperprolinemia, type I rs p.l181m BCHE Hypocholinesterasaemia rs c.435deltinsag 1 Recessive X X FLG Ichthyosis vulgaris rs p.r501x* 1 Recessive TGM1 TGM1 Ichthyosis, congenital, autosomal recessive 1 Ichthyosis, congenital, autosomal recessive 1 rs p.s42y 2 Recessive X X 7162 rs p.v518m* DYT1 Idiopathic torsion dystonia [3-BP DEL, GLU DEL] 39 1 Dominant 2965 TMEM216 Joubert Syndrome rs p.r73l 40 95% 1 Recessive X X LCA5 Leber congenital amaurosis rs c.835c>t 41 1% NDUFS4 Leigh Syndrome rs c.462dela Recessive Recessive DARS2 Leukoencephalopathy, brain & spine involvement, lactate elevation rs c.492+2t>c* 1 Recessive X X 65544

12 KCNE1 Long QT syndrome 5 rs p.d85n 1 Dominant X X X 19 MSH2 Lynch syndrome rs p.a636p 43 30% 3 Dominant X 18 MSH6 Lynch syndrome rs c.3984_3987dupgtca 44 X MSH6 Lynch syndrome rs c.3959_3962delcaag X ZMPSTE24 Mandibuloacral dysplasia rs c.1085dupt 1 Recessive X X BCKDHB Maple syrup urine disease rs p.r183p 45 >95% 2 Recessive X X BCKDHB Maple syrup urine disease rs p.g278s X X MLC1 Megalencephalic leukoencephalopathy with subcortical cysts rs p.p92s* 46 1 Recessive X X MCOLN1 Mucolipidosis IV rs c.406-2a>g 47 95% 2 Recessive X X MCOLN1 Mucolipidosis IV g.511_6943del ANO5 Muscular dystrophy, limb girdle 2L rs c.191dupa* 48 1 Recessive X X AMPD1 Myoadenylate deaminase, myopathy due to rs p.q45x 1 Recessive X 235 NEB Nemaline myopathy p.r2478_d2512del % 1 Recessive X X SLC9A3R1 Nephrolithiasis/osteoporosis, hypophosphatemic, 2 rs p.l110v 1 Dominant X X 15 SMPD1 Niemann-Pick disease, type A rs p.r610del33 50,51 99% 3 Recessive X X SMPD1 Niemann-Pick disease, type A rs c.996delc SMPD1 Niemann-Pick disease, type A rs p.l304p SMPD1 Niemann-Pick disease, type B rs p.r496l* 1 Recessive MC4R Obesity rs p.a175t 1 Dominant X 43 LRRK2 Parkinson disease 8 rs p.g2019s* 52 1 Dominant X 125 PHGDH Phosphoglycerate dehydrogenase rs p.v490m* 53 1 Recessive X X POF1B Premature ovarian failure 2B rs p.r329q 1 X-linked X X 50 BMP15 Premature ovarian failure 4 rs p.a180t* 1 X-linked X X 250 CCDC114 Primary ciliary dyskinesia c.939delt 54 1 Recessive X X FECH Protoporphyria, erythropoietic rs c t>c 1 Recessive X X 334 PHYH Refsum disease rs p.r175w* 1 Recessive X FAM161A Retinitis pigmentosa 28 rs c.1355_1356delca 55 2 Recessive X X unknown FAM161A Retinitis pigmentosa 28 rs p.r596x X X unknown DHDDS Retinitis pigmentosa 59 rs c.124a>g % 1 Recessive X X MAK Retinitis pigmentosa bp Alu ins Ex Recessive X X 3018 DHCR7 Smith-Lemli-Opitz syndrome rs c.964-1g>c 58 2 Recessive DHCR7 Smith-Lemli-Opitz syndrome p.m1v >75% X X 5184 SMN1 Spinal muscular atrophy37 Exon 7, copy number 59 >94% 1 Recessive X X 6724 ABCA4 Stargardt disease 1 rs p.g1961e 1 Recessive X 2380

13 HEXA Tay-Sachs disease rs HEXA Tay-Sachs disease rs c g>c* HEXA Tay-Sachs disease rs p.g269s % DAMTS13 Thrombotic thrombocytopenic purpura, familial c.1277_1281 instatc33, 60,61 95% 3 Recessive X X 3600 rs p.p475s 1 Recessive X RET Thyroid carcinoma, familial medullary rs p.y791f 1 Dominant X 19 CACNA1C Timothy syndrome rs p.g490r 1 Dominant X X 43 PCDH15 Usher syndrome, type 1F rs p.r245x 63 75% 1 Recessive X X CLRN1 Usher syndrome, type 3A rs p.n48k* % 1 Recessive X BEST1 Vitelliform macular dystrophy, adult onset rs p.r81h* 1 Dominant X 129 VWF Von Willebrand disease, type 2N rs p.r854q* 1 Dominant X X X 128 FKTN Walker-Warburg syndrome rs c.1167_1168insa 65 95% 1 Recessive X X 3906 XPC Xeroderma pigmentosum, group C rs p.p334h* 1 Recessive X X Table 2S. List of mutations found that would be useful on a screening panel. Alleles with shading were identified in Table 1S. Unshaded alleles were identified in the literature. Sensitivity AJ = sensitivity for picking up this disease in the AJ population. Sensitivity Gen. Pop. = sensitivity for picking up this disease in the general population. No. variants per disease = Number of variants (mutations) listed for this disease. Repr. Risk = An X indicates that this variant would be tested to determine reproductive (carrier) risk. Pers. Risk = An X indicates that this variant would be tested to determine a person's personal risk of developing a disease. Dx = Diagnostic. Prevalence, calculated = Prevalence for which this variant's frequency would predict, based on the Hardy-Weinberg equations. Note that references refer to references in supplemental materials. * = this variant was only present in one allele in our test population, but was found in other populations.

14 Disease ACMG recs ACOG recs Quest LabCorp Mount Sinai Counsyl Arup Lab Center for Human Genetics (MA) Emory Mayo University Hospitals Case Medical Center Bloom X X* X X X X X X X X X Canavan X X X X X X X X X X X Cystic Fibrosis X X X X X X X Dihydrolipoamide dehydrogenase def X X X Factor XI X Familial Dysautonomia X X X X X X X X X X X Familial hyperinsulinism X X X X Fanconi Anemia Group C X X* X X X X X X X X X Fragile X X Gaucher X X* X X X X X X X X X Glycogen Storage Disease Type 1a X X X X X X Joubert Syndrome 2 X X X X Maple Syrup Urine Disease X X X X X X Mucolipidosis IV X X* X X X X X X X X X Nemaline Myopathy X X X Niemann-Pick Type A X X* X X X X X X X X X Niemann-Pick Type B X X Spinal Muscular Atrophy X X Tay Sachs X X X X X X X X X X X Usher syndrome type 1F X X X X Usher syndrome type III X X X X Walker-Warburg syndrome X X Reference Table 3S. Ashkenazi screening panels and recommendations referenced in our paper. An asterisk indicates that this test is optional.

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