Читать книгу Genetic Disorders and the Fetus - Группа авторов - Страница 72
Approaches to preimplantation genetic testing
ОглавлениеWhen prenatal genetic diagnosis was first considered in perspective, in 1984, the World Health Organization (WHO) emphasized the relevance of developing earlier approaches for genetic analysis with the possibility of diagnosis before implantation.9, 10 The following possibilities for PGT were mentioned: genetic analysis of the first or second polar bodies and embryo biopsy at the cleavage or blastocyst stage.10, 11 However, these approaches became possible only after introduction of the PCR assay12 and success in micromanipulation and embryo biopsy.
First attempts at PGT were undertaken in mammalian embryos over 30 years ago,13–18 when it was demonstrated that cells could be removed from mammalian preimplantation embryos and analyzed successfully without destroying the viability of the embryo in in vitro fertilization (IVF). PGT for human genetic disease was first demonstrated by Handyside et al.19 for X‐linked diseases and by Verlinsky et al.20 for autosomal recessive disorders. Tens of thousands of children without detectable birth defects have been born following these procedures,21–25 demonstrating that PGT can be performed safely in humans. Initially, PGT was based on polar body sampling and embryo biopsy at the cleavage stage, but the present standard shifted to blastocyst biopsy. The polar body approach is still, however, the only possibility for the ethnic groups where no embryos micromanipulation is allowed. The Preimplantation Genetic Diagnosis International Society (PGDIS) and the European Society of Human Reproduction and Embryology (ESHRE) Consortium have published an extensive set of best practice guidelines for PGT.26, 27 These recommendations cover PGT organization, genetic and treatment‐related counseling, psychologic evaluation, patient selection, all applicable technical issues, and quality control. The developments of preconception and PGT and the existing problems in the application of these early approaches to clinical practice are presented in this chapter, based on our 30 years' experience of over 22,000 PGT cycles, including 15,700 PGT‐A, 491 PGT‐HLA, and 6,778 PGT‐M, involving a spectrum of, approximately, 600 different monogenic conditions (Table 2.1).
Table 2.1 List of conditions for which preimplantation genetic testing (PGT) was performed and PGT‐M outcome: 30 years of original experience.
| Conditions | Gene | Type of inheritance | No. patients | No. cycles | No. embryo transfers | No. embryos transferred | Pregnancy % | No. deliveries |
|---|---|---|---|---|---|---|---|---|
| 3‐Hydroxyisobutyryl‐CoA hydrolase deficiency (HIBCHD) | HIBCH | AR | 1 | 1 | 1 | 2 | 0 | 0 |
| 3‐Methylglutaconic aciduria with deafness, encephalopathy, and Leigh‐like syndrome (MEGDEL) | SERAC1 | AR | 1 | 1 | 1 | 1 | 0 | 0 |
| Achondroplasia (ACH) | FGFR3 | AD | 8 | 17 | 11 | 14 | 7 | 6 |
| Achromatopsia 2 (ACHM2) | CNGA3 | AR | 1 | 1 | 1 | 1 | 1 | 1 |
| Achromatopsia 3 (ACHM3) | CNGB3 | AR | 3 | 4 | 4 | 5 | 2 | 2 |
| Acromesomelic dysplasia, Maroteaux type (AMDM) | NPR2 | AR | 1 | 1 | 2 | 2 | 1 | 1 |
| Acyl‐CoA dehydrogenase, medium‐chain, deficiency | ACADM | AR | 3 | 8 | 7 | 14 | 4 | 4 |
| Acyl‐CoA dehydrogenase, very long‐chain; (ACADVL) | ACADVL | AR | 5 | 6 | 6 | 11 | 2 | 2 |
| Adrenal hyperplasia, congenital, due to 21‐hydroxylase deficiency | CYP21A2 | AR | 23 | 34 | 26 | 42 | 17 | 17 |
| Adrenoleukodystrophy (ALD) | ABCD1 | XL | 17 | 33 | 20 | 29 | 11 | 11 |
| Agammaglobulinemia, X‐linked (XLA) | BTK | XL | 4 | 7 | 7 | 13 | 3 | 3 |
| Aicardi–Goutieres syndrome 5 (AGS5 + CF) | SAMHD1 | AR | 1 | 2 | 2 | 2 | 1 | 1 |
| Alagille syndrome 1 (ALGS1) | JAG1 | AD | 1 | 1 | 1 | 1 | 1 | 1 |
| Albinism, ocular, type i (OA1) | GPR143 | XL | 1 | 12 | 5 | 9 | 4 | 3 |
| Albinism, oculocutaneous, type ia (OCA1a) | TYR | AR | 4 | 7 | 6 | 9 | 3 | 3 |
| Albinism, oculocutaneous, type ii (OCA2) | OCA2 | AR | 3 | 6 | 5 | 9 | 3 | 3 |
| Albinism, oculocutaneous, type iii (OCA3) | TYRP1 | AR | 1 | 1 | 0 | 0 | 0 | 0 |
| Allan–Herndon–Dudley syndrome (AHDS) | SLC16A2 | XL | 1 | 2 | 2 | 2 | 1 | 1 |
| Alopecia universalis congenita (ALUNC) | HR | AR | 1 | 1 | 1 | 2 | 1 | 1 |
| Alpha‐1‐antitrypsin deficiency (A1ATD) | SERPINA1 | AR | 9 | 16 | 14 | 18 | 9 | 8 |
| Alport syndrome, autosomal dominant | COL4A3 | AR | 1 | 4 | 0 | 0 | 0 | 0 |
| Alport syndrome, X‐linked (ATS) | COL4A5 | XL | 8 | 16 | 15 | 22 | 10 | 9 |
| Alzheimer disease 3 | PSEN1 | AD | 2 | 3 | 3 | 6 | 3 | 3 |
| Alzheimer disease 4 | PSEN2 | AD | 1 | 1 | 1 | 2 | 0 | 0 |
| Alzheimer disease (AD) | APP | AD | 2 | 3 | 2 | 4 | 2 | 1 |
| Amegakaryocytic thrombocytopenia, congenital (CAMT) | MPL | AR | 1 | 1 | 0 | 0 | 0 | 0 |
| Amyloidosis, hereditary, transthyretin‐related | TTR | AD | 3 | 7 | 5 | 6 | 3 | 2 |
| Amyotrophic lateral sclerosis 1 (ALS1) | SOD1 | XL | 2 | 2 | 2 | 3 | 2 | 1 |
| Amyotrophic lateral sclerosis 4, juvenile (ALS4) | SETX | AD | 1 | 1 | 1 | 1 | 1 | 1 |
| Anemia, nonspherocytic hemolytic, due to g6pd deficiency | G6PD | XL | 9 | 12 | 12 | 15 | 6 | 6 |
| Angelman syndrome (AS) | UBE3A | AD | 2 | 2 | 2 | 3 | 1 | 1 |
| Angioedema, hereditary, type i (HAE1) | C1NH | AD | 3 | 4 | 3 | 4 | 1 | 1 |
| Aniridia (AN) | PAX6 | AD | 4 | 7 | 5 | 6 | 4 | 4 |
| Aortic valve disease 1 (AOVD1) | NOTCH1 | AD | 1 | 1 | 2 | 2 | 1 | 1 |
| Argininosuccinic aciduria | ASL | AR | 2 | 3 | 3 | 4 | 1 | 1 |
| Arterial tortuosity syndrome (ATS) | SLC2A10 | AR | 1 | 2 | 2 | 2 | 1 | 1 |
| Arthrogryposis, distal, type 2a (DA2a) | MYH3 | AD | 1 | 2 | 2 | 2 | 1 | 1 |
| Arthrogryposis, distal, type 2b (DA2b) | TNNI2 | AD | 1 | 2 | 1 | 1 | 0 | 0 |
| Arthrogryposis, distal, type 2b (DA2b) | TNNT3 | AD | 1 | 3 | 2 | 3 | 2 | 1 |
| Arthrogryposis, distal, type 9 (DA9) | FBN2 | AD | 1 | 2 | 2 | 2 | 2 | 2 |
| Ataxia‐telangiectasia (AT) | ATM | AD | 5 | 12 | 7 | 8 | 6 | 5 |
| Auriculocondylar syndrome 2 (ARCND2) | PLCB4 | AR | 1 | 1 | 0 | 0 | 0 | 0 |
| Axenfeld–rieger syndrome, type 1 (RIEG1) | PITX2 | AD | 3 | 13 | 13 | 15 | 5 | 4 |
| Bardet–Biedl syndrome 10 (BBS10) | BBS10 | AR | 1 | 2 | 3 | 4 | 1 | 1 |
| Bardet–Biedl syndrome 2 (BBS2) | BBS2 | AR | 1 | 1 | 2 | 2 | 2 | 1 |
| Bardet–Biedl syndrome 4 (BBS4) | BBS4 | AR | 1 | 1 | 2 | 2 | 1 | 1 |
| Bartter syndrome, type 3 (BARTS3) | CLCNKB | AR | 1 | 1 | 2 | 2 | 1 | 1 |
| Basal cell nevus syndrome (BCNS) (Gorlin) | PTCH1 | AD | 6 | 7 | 6 | 10 | 4 | 4 |
| Benign chronic pemphigus (BCPM) | ATP2C1 | AD | 1 | 1 | 1 | 1 | 1 | 0 |
| Beta‐ureidopropionase deficiency (UPB1D) | UPB1 | AR | 1 | 1 | 2 | 2 | 2 | 1 |
| Biotinidase deficiency | BTD | AR | 3 | 5 | 2 | 3 | 2 | 2 |
| Birt–Hogg–Dube syndrome (BHD) | FLCN | AD | 1 | 2 | 1 | 1 | 1 | 1 |
| Bleeding disorder, platelet‐type, 16 (BDPLT16) | ITGB3 | AD | 1 | 1 | 0 | 0 | 0 | 0 |
| Blepharophimosis, ptosis, and epicanthus inversus (BPES) | FOXL2 | AD | 3 | 7 | 5 | 7 | 3 | 3 |
| Blood group – Kell–Cellano system | KEL | AR | 14 | 32 | 19 | 32 | 5 | 5 |
| Brachydactyly, type B1 (BDB1) | ROR2 | AD | 1 | 3 | 2 | 4 | 2 | 2 |
| Branchiooculofacial syndrome (BOFS) | TFAP2A | AD | 1 | 1 | 1 | 2 | 0 | 0 |
| Breast cancer | PALB2 | AD | 2 | 4 | 2 | 2 | 1 | 1 |
| Breast–ovarian cancer, familial, susceptibility to, 1 (BROVCA1) | BRCA1 | AD | 93 | 175 | 128 | 183 | 89 | 83 |
| Breast–ovarian cancer, familial, susceptibility to, 2 (BROVCA2) | BRCA2 | AD | 64 | 123 | 87 | 122 | 55 | 51 |
| Campomelic dysplasia with autosomal sex reversal | SOX9 | AD | 1 | 1 | 0 | 0 | 0 | 0 |
| Camurati–Engelmann disease (CAEND) | TGFB1 | AD | 1 | 1 | 1 | 1 | 0 | 0 |
| Canavan disease | ASPA | AR | 4 | 6 | 5 | 7 | 5 | 5 |
| Carbamoyl phosphate synthetase i deficiency | CPS1 | AR | 1 | 1 | 1 | 2 | 0 | 0 |
| Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1 | SCO2 | AR | 2 | 5 | 5 | 10 | 3 | 3 |
| Cardiomyopathy, dilated, 1A (CMD1A) | LMNA | AR | 7 | 17 | 16 | 25 | 10 | 8 |
| Cardiomyopathy, dilated, 1DD (CMD1DD) | RBM20 | AD | 1 | 2 | 2 | 2 | 2 | 2 |
| Cardiomyopathy, dilated, 1E (CMD1E) | SCN5A | AD | 1 | 2 | 2 | 2 | 1 | 1 |
| Cardiomyopathy, dilated, 1G (CMD1G) | TTN | AD | 2 | 2 | 3 | 3 | 1 | 1 |
| Cardiomyopathy, dilated, 1S (CMD1S) | MYH7 | AD | 3 | 6 | 4 | 4 | 2 | 2 |
| Cardiomyopathy, dilated, with woolly hair, keratoderma, and tooth agenesis (DCWHKTA) | DSP | AD | 2 | 3 | 2 | 3 | 2 | 1 |
| Cardiomyopathy, familial hypertrophic, 2 (CMH2) | TNNT2 | AD | 1 | 2 | 1 | 1 | 1 | 0 |
| Cardiomyopathy, familial hypertrophic, 4 (CMH4) | MYBPC3 | AD | 14 | 22 | 16 | 23 | 11 | 9 |
| Cardiomyopathy, familial hypertrophic, 7 (CMH7) | TNNI3 | AD | 1 | 1 | 1 | 1 | 0 | 0 |
| Cardiomyopathy, familial hypertrophic, 8 (CMH8) | MYL3 | AD | 1 | 2 | 0 | 0 | 0 | 0 |
| Carnitine deficiency, systemic primary (CDSP) | SLC22A5 | AR | 1 | 2 | 1 | 2 | 1 | 1 |
| Carnitine palmitoyltransferase II deficiency, infantile | CPT2 | AR | 4 | 7 | 4 | 4 | 2 | 2 |
| Cerebral arteriopathy, autosomal dominant | NOTCH3 | AD | 3 | 7 | 6 | 6 | 6 | 4 |
| Cerebral creatine deficiency syndrome 1 (CCDS1) | SLC6A8 | XL | 1 | 1 | 1 | 2 | 1 | 1 |
| Ceroid lipofuscinosis, neuronal 2, late infantile (CLN2) | TPP1 | AR | 2 | 3 | 2 | 2 | 2 | 1 |
| Ceroid lipofuscinosis, neuronal, 10 (CLN10) | CTSD | AR | 1 | 1 | 2 | 3 | 1 | 1 |
| Ceroid lipofuscinosis, neuronal, 5 (CLN5) | CLN5 | AR | 1 | 1 | 2 | 3 | 0 | 0 |
| Ceroid lipofuscinosis, neuronal, 6 (CLN6) | CLN6 | AR | 2 | 2 | 1 | 2 | 0 | 0 |
| Charcot–Marie–Tooth disease, axonal, type 2A2 (CMT2A2) | MFN2 | AD | 2 | 9 | 6 | 7 | 2 | 2 |
| Charcot–Marie–Tooth disease, axonal, type 2B (CMT2B) | RAB7A | AD | 1 | 1 | 2 | 4 | 2 | 1 |
| Charcot–Marie–Tooth disease, axonal, type 2E (CMT2E) | NEFL | AD | 1 | 4 | 4 | 7 | 1 | 1 |
| Charcot–Marie–Tooth disease, axonal, type 2F (CMT2F) | HSPB1 | AD | 1 | 1 | 1 | 1 | 0 | 0 |
| Charcot–Marie–Tooth disease, demyelinating, type 1A (CMT1A) | PMP22 | AD | 28 | 56 | 38 | 51 | 25 | 21 |
| Charcot–Marie–Tooth disease, demyelinating, type 1B (CMT1B) | MPZ | AD | 2 | 5 | 2 | 5 | 0 | 0 |
| Charcot–Marie–Tooth disease, X‐linked, 1 (CMTX1) | GJB1 | XL | 6 | 9 | 9 | 14 | 5 | 5 |
| Cholestasis, benign recurrent intrahepatic, 2 (BRIC2) | ABCB11 | AR | 1 | 2 | 2 | 4 | 1 | 1 |
| Cholestasis, progressive familial intrahepatic, 3 (PFIC3) | ABCB4 | AR | 1 | 1 | 1 | 2 | 1 | 1 |
| Chondrodysplasia punctata 1, X‐linked recessive (CDPX1) | ARSE | XL | 1 | 2 | 2 | 3 | 0 | 0 |
| Choroideremia (CHM) | CHM | XL | 3 | 5 | 5 | 9 | 3 | 3 |
| Ciliary dyskinesia, primary, 15 (CILD15) | CCDC40 | AR | 1 | 1 | 1 | 1 | 1 | 1 |
| Ciliary dyskinesia, primary, 3 (CILD3) | DNAH5 | AR | 2 | 2 | 1 | 2 | 1 | 1 |
| Citrullinemia, classic | ASS1 | AR | 4 | 7 | 6 | 8 | 3 | 3 |
| Cleidocranial dysplasia (CCD) | RUNX2 | AD | 1 | 3 | 5 | 5 | 2 | 2 |
| Cockayne syndrome A (CSA) | ERCC8 | AR | 1 | 1 | 2 | 2 | 1 | 1 |
| Coenzyme Q10 deficiency, primary, 7 (COQ10D7) | COQ4 | AR | 1 | 1 | 1 | 1 | 1 | 1 |
| Cohen syndrome (COH1) | VPS13B | AR | 2 | 2 | 2 | 4 | 2 | 2 |
| Colorectal cancer, hereditary nonpolyposis, type 1 (HNPCC1) | MSH2 | AD | 11 | 21 | 14 | 17 | 7 | 6 |
| Colorectal cancer, hereditary nonpolyposis, type 2 (HNPCC2) | MLH1 | AD | 10 | 18 | 15 | 25 | 9 | 9 |
| Colorectal cancer, hereditary nonpolyposis, type 4 (HNPCC4) | PMS2 | AD | 1 | 2 | 1 | 1 | 0 | 0 |
| Colorectal cancer, hereditary nonpolyposis, type 5 (HNPCC5) | MSH6 | AD | 5 | 10 | 8 | 11 | 5 | 5 |
| Combined oxidative phosphorylation deficiency 13 (COXPD13) | PNPT1 | AR | 1 | 1 | 3 | 5 | 0 | 0 |
| Cone–rod dystrophy 6 (CORD6) | GUCY2D | AD | 1 | 1 | 1 | 0 | 0 | 0 |
| Congenital disorder of deglycosylation (CDDG) | NGLY1 | AR | 1 | 1 | 2 | 2 | 1 | 1 |
| Congenital disorder of glycosylation, type Ia (CDG1A) | PMM2 | AR | 5 | 5 | 4 | 4 | 3 | 3 |
| Congenital disorder of glycosylation, type IIc (CDG2C) | SLC35C1 | AR | 1 | 1 | 2 | 3 | 0 | 0 |
| Congenital disorder of glycosylation, type IIL (CDG2L) | COG6 | AR | 1 | 2 | 2 | 2 | 0 | 0 |
| Congenital disorder of glycosylation, type In (CDG1N) | RFT1 | AR | 2 | 2 | 2 | 4 | 1 | 1 |
| Cranioectodermal dysplasia 2 (CED2) | WDR35 | AR | 1 | 1 | 1 | 1 | 1 | 1 |
| Craniofrontonasal syndrome (CFNS) | EFNB1 | XL | 1 | 1 | 1 | 1 | 0 | 0 |
| Creutzfeldt–Jakob disease (CJD); Gerstmann–Straussler disease (GSD) | PRNP | AD | 6 | 9 | 9 | 12 | 8 | 7 |
| Crouzon syndrome | FGFR2 | AD | 8 | 16 | 14 | 23 | 9 | 8 |
| Currarino syndrome | MNX1 | AD | 1 | 1 | 1 | 2 | 1 | 1 |
| Cutis laxa, autosomal dominant 1 (ADCL1) | ELN | AD | 1 | 4 | 3 | 4 | 2 | 2 |
| Cutis laxa, autosomal recessive, type IIB (ARCL2B) | PYCR1 | AR | 1 | 1 | 2 | 2 | 1 | 1 |
| Cutis laxa, autosomal recessive, type IIIA (ARCL3A) | ALDH18A1 | AR | 1 | 1 | 1 | 1 | 1 | 1 |
| Cystic fibrosis (CF) | CFTR | AR | 496 | 748 | 627 | 1072 | 354 | 314 |
| Cystinosis, nephropathic (CTNS) | CTNS | AR | 1 | 1 | 1 | 1 | 0 | 0 |
| Danon disease | LAMP2 | XL | 1 | 2 | 2 | 2 | 2 | 2 |
| Darier–White disease (DAR) | ATP2A2 | AD | 1 | 1 | 1 | 1 | 1 | 1 |
| D‐bifunctional protein deficiency | HSD17B4 | AR | 1 | 1 | 1 | 1 | 0 | 0 |
| Deafness, autosomal dominant 3b (DFNA3b) | GJB6 | AD | 1 | 2 | 2 | 3 | 1 | 1 |
| Deafness, neurosensory, autosomal recessive 1 (DFNB1) | GJB2 | AR | 51 | 68 | 56 | 80 | 33 | 30 |
| Dentinogenesis imperfecta, shields type III | DSPP | AD | 1 | 2 | 2 | 2 | 2 | 1 |
| Developmental delay | DHX35 | AR | 1 | 1 | 2 | 2 | 1 | 1 |
| Diabetes insipidus, nephrogenic, X‐linked | AVPR2 | XL | 1 | 3 | 3 | 3 | 1 | 1 |
| Diabetes mellitus, permanent neonatal (PNDM) | INS | AD | 1 | 1 | 1 | 1 | 1 | 1 |
| Diamond–Blackfan anemia 1 (DBA1) | RPS19 | AD | 1 | 1 | 1 | 2 | 1 | 1 |
| Digeorge syndrome (DGS) | TBX1 | AD | 1 | 1 | 1 | 1 | 1 | 1 |
| Dihydrolipoamide dehydrogenase deficiency (DLDD) | DLD | AR | 1 | 1 | 1 | 1 | 1 | 1 |
| Donnai–Barrow syndrome | LRP2 | AR | 1 | 1 | 0 | 0 | 0 | 0 |
| Dyskeratosis congenita, autosomal dominant 3 (DKCA3) | TINF2 | AD | 1 | 2 | 2 | 3 | 1 | 1 |
| Dyskeratosis congenita, autosomal dominant 2 (DKCA2) | TERT | AD | 1 | 3 | 1 | 1 | 0 | 0 |
| Dyskeratosis congenita, autosomal recessive 5 (DKCB5) | RTEL1 | AR | 1 | 1 | 2 | 2 | 1 | 1 |
| Dyskeratosis congenita, X‐linked (DKCX) | DKC1 | XL | 1 | 1 | 1 | 2 | 1 | 1 |
| Dyskinesia, seizures, and intellectual developmental disorder (DYSEIDD) | DEAF1 | AR | 1 | 1 | 1 | 1 | 0 | 0 |
| Dystonia 1, torsion, autosomal dominant (DYT1) | TOR1A | AD | 16 | 36 | 35 | 63 | 18 | 18 |
| Dystonia 28, childhood‐onset (DYT28) | KMT2B | AD | 1 | 1 | 1 | 1 | 0 | 0 |
| Dystonia 3, torsion, X‐linked (DYT3) | TAF1 | XL | 1 | 1 | 1 | 2 | 1 | 1 |
| Ectodermal dysplasia 10b, hypohidrotic/hair/tooth type, autosomal recessive (ECTD10B) | EDAR | AR | 1 | 1 | 1 | 2 | 1 | 1 |
| Ectodermal dysplasia, hypohidrotic, X‐linked (XHED) | EDA | XL | 6 | 8 | 8 | 10 | 4 | 4 |
| Ehlers–Danlos syndrome, classic type | COL5A1 | AD | 2 | 4 | 3 | 4 | 3 | 2 |
| Ehlers–Danlos syndrome, type IV, autosomal dominant | COL3A1 | AD | 4 | 6 | 4 | 7 | 4 | 3 |
| Ehlers–Danlos syndrome, type VI (EDS6) | PLOD1 | AR | 1 | 1 | 2 | 3 | 0 | 0 |
| Emery–Dreifuss muscular dystrophy 1, X‐linked (EDMD1) | EMD | XL | 3 | 4 | 4 | 7 | 3 | 3 |
| Epidermolysis bullosa dystrophica, autosomal dominant (DDEB) | COL7A1 | AR | 8 | 9 | 8 | 13 | 4 | 4 |
| Epidermolysis bullosa simplex with pyloric atresia (EBSPA) | PLEC1 | AR | 1 | 2 | 1 | 3 | 1 | 1 |
| Epidermolysis bullosa simplex, dowling‐meara type (EBSDM) | KRT5 | AD | 1 | 2 | 1 | 2 | 1 | 1 |
| Epidermolysis bullosa, junctional, Herlitz type | LAMA3 | AR | 4 | 9 | 7 | 13 | 7 | 7 |
| Epidermolysis bullosa, junctional, non‐herlitz type | LAMB3 | AR | 5 | 6 | 5 | 9 | 2 | 2 |
| Epidermolytic hyperkeratosis (EHK) | KRT10 | AD | 2 | 3 | 2 | 2 | 2 | 2 |
| Epileptic encephalopathy, early infantile, 2 (EIEE2) | CDKL5 | XL | 1 | 1 | 1 | 2 | 1 | 1 |
| Epileptic encephalopathy, early infantile, 3 (EIEE3) | SLC25A22 | AR | 1 | 1 | 0 | 0 | 0 | 0 |
| Epileptic encephalopathy, early infantile, 5 (EIEE5) | SPTAN1 | AR | 1 | 1 | 0 | 0 | 0 | 0 |
| Epiphyseal dysplasia, multiple, 1 (EDM1) | COMP | AD | 3 | 4 | 2 | 2 | 1 | 1 |
| Exostoses, multiple, type I | EXT1 | AD | 11 | 21 | 17 | 29 | 12 | 10 |
| Exostoses, multiple, type II | EXT2 | AD | 3 | 8 | 6 | 10 | 3 | 3 |
| Fabry disease | GLA | XL | 12 | 19 | 14 | 22 | 9 | 7 |
| Facioscapulohumeral muscular dystrophy 1 (FSHD1) | FRG1 | AD | 25 | 51 | 42 | 71 | 23 | 20 |
| Factor VII deficiency | F7 | AR | 1 | 1 | 1 | 1 | 0 | 0 |
| Familial adenomatous polyposis 1 (FAP1) | APC | AD | 23 | 44 | 36 | 57 | 17 | 15 |
| Familial cold autoinflammatory syndrome 1 (FCAS1) | NLPR3 | AD | 1 | 1 | 1 | 1 | 1 | 1 |
| Familial Mediterranean fever (FMF) | MEFV | AR | 10 | 18 | 16 | 22 | 11 | 8 |
| Fanconi anemia, complementation group A (FANCA) | FANCA | AR | 2 | 5 | 2 | 3 | 2 | 2 |
| Fanconi anemia, complementation group C (FANCC) | FANCC | AR | 2 | 5 | 4 | 8 | 1 | 1 |
| Fetal akinesia deformation sequence (FADS) | NUP88 | AR | 1 | 1 | 1 | 2 | 1 | 1 |
| Fetal akinesia deformation sequence (FADS) | RAPSN | AR | 1 | 1 | 1 | 2 | 1 | 0 |
| Fragile‐X mental retardation syndrome | FMR1 | XL | 312 | 608 | 450 | 662 | 243 | 214 |
| Fraser syndrome 1 (FRASRS1) | FRAS1 | AR | 2 | 2 | 2 | 2 | 1 | 1 |
| Friedreich ataxia 1 (FRDA) | FXN | AR | 2 | 6 | 4 | 7 | 2 | 2 |
| Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 (FTDALS1) | c9orf72 | AD | 1 | 1 | 1 | 1 | 1 | 1 |
| Fructose intolerance, hereditary | ALDOB | AR | 2 | 7 | 6 | 7 | 3 | 3 |
| Fumarase deficiency (FMRD) | FH | AR | 1 | 1 | 0 | 0 | 0 | 0 |
| Galactosemia | GALT | AR | 3 | 7 | 5 | 6 | 2 | 2 |
| Gastric cancer, hereditary diffuse (HDGC) | CDH1 | AD | 1 | 1 | 1 | 2 | 1 | 1 |
| Gaucher disease, type I | GBA | XL | 39 | 52 | 34 | 57 | 24 | 19 |
| Geroderma osteodysplasticum (GO) | GORAB | AR | 1 | 2 | 2 | 4 | 1 | 1 |
| Gitelman syndrome (GTLMNS) | SLC12A3 | AR | 1 | 1 | 1 | 1 | 0 | 0 |
| Glaucoma 3, primary congenital, A (GLC3A) | CYP1B1 | AR | 1 | 1 | 2 | 2 | 1 | 1 |
| Glut1 deficiency syndrome 1 (GLUT1DS1) | SLC2A1 | AD | 1 | 2 | 1 | 2 | 0 | 0 |
| Glutaric acidemia I | GCDH | AR | 1 | 1 | 1 | 2 | 0 | 0 |
| Glycine encephalopathy (GCE) | GLDC | AR | 6 | 7 | 6 | 11 | 6 | 6 |
| Glycogen storage disease Ia (GSD1A) | G6PC | AR | 1 | 1 | 2 | 2 | 0 | 0 |
| Glycogen storage disease II (GSD2) | GAA | AR | 5 | 7 | 4 | 9 | 1 | 1 |
| Glycogen storage disease IXa1 (GSD9A1) | PHKA2 | XL | 1 | 1 | 0 | 0 | 0 | 0 |
| Glycogen storage disease VII (GSD7) | PFKM | AR | 1 | 1 | 1 | 1 | 1 | 1 |
| Gm1‐gangliosidosis, type I | GLB1 | AR | 5 | 5 | 5 | 10 | 4 | 4 |
| Granulomatous disease, chronic, X‐linked (CDGX) | CYBB | XL | 4 | 5 | 4 | 6 | 3 | 2 |
| Greig cephalopolysyndactyly syndrome (GCPS) | GLI3 | AD | 1 | 1 | 2 | 2 | 0 | 0 |
| Harel–Yoon syndrome (HAYOS) | ATAD3A | AR | 1 | 3 | 3 | 3 | 1 | 1 |
| Hemoglobin‐alpha locus 1 (HBA1) | HBA | AR | 14 | 23 | 21 | 38 | 10 | 10 |
| Hemoglobin‐beta locus (HBB) | HBB | AR | 301 | 470 | 402 | 762 | 192 | 161 |
| Hemophagocytic lymphohistiocytosis, familial, 2 (FHL2) | PRF1 | AR | 1 | 1 | 0 | 0 | 0 | 0 |
| Hemophagocytic lymphohistiocytosis, familial, 3 (FHL3) | UNC13D | AR | 3 | 4 | 4 | 5 | 4 | 3 |
| Hemophilia A (HEMA) | F8 | XL | 62 | 103 | 88 | 145 | 50 | 42 |
| Hemophilia B (HEMB) | F9 | XL | 5 | 6 | 6 | 9 | 6 | 6 |
| Hereditary leiomyomatosis and renal cell cancer (HLRCC) | FH | AD | 1 | 1 | 1 | 2 | 0 | 0 |
| Hereditary motor and sensory neuropathy, type IIC (HMSN2C) | TRPV4 | AD | 1 | 1 | 2 | 2 | 1 | 1 |
| Hermansky–Pudlak syndrome 1 (HPS1) | HPS1 | AR | 1 | 4 | 3 | 6 | 2 | 2 |
| HLA + myelodysplastic syndrome (MDS) | GATA2 | AD | 1 | 2 | 1 | 1 | 1 | 1 |
| HLA + Shwachman–Diamond syndrome (SDS) | SBDS | AR | 4 | 10 | 3 | 4 | 2 | 2 |
| HLA + adenosine deaminase deficiency (ADA) | ADA | AR | 1 | 1 | 1 | 1 | 1 | 1 |
| HLA + adrenoleukodystrophy | ABCD1 | XL | 3 | 7 | 2 | 2 | 1 | 1 |
| HLA + Diamond–Blackfan anemia 1 (DBA1) | RPS19, | AD | 6 | 13 | 10 | 15 | 5 | 5 |
| HLA + Diamond–Blackfan anemia 2 (DBA2) | RPS20 | AD | 1 | 1 | 1 | 1 | 1 | 1 |
| HLA + Diamond–Blackfan anemia 3 (DBA3) | RPS 24 | AD | 1 | 1 | 1 | 1 | 0 | 0 |
| HLA + Diamond–Blackfan anemia 5 (DBA5) | RPL35A | AD | 1 | 1 | 1 | 1 | 1 | 1 |
| HLA + Diamond–Blackfan anemia 9 (DBA9) | RPS10 | AD | 1 | 1 | 2 | 2 | 1 | 1 |
| HLA + ectodermal dysplasia, hypohidrotic, with immune deficiency | IKBKG | XL | 2 | 9 | 6 | 8 | 2 | 2 |
| HLA + Fanconi anemia, complementation group A (FANCA) | FANCA | AR | 18 | 52 | 29 | 43 | 14 | 10 |
| HLA + Fanconi anemia, complementation group C (FANCC) | FANCC | AR | 2 | 5 | 5 | 8 | 1 | 1 |
| HLA + Fanconi anemia, complementation group D2 (FANCD2) | FANCD2 | AR | 1 | 3 | 2 | 3 | 1 | 1 |
| HLA + Fanconi anemia, complementation group F (FANCF) | FANCF | AR | 2 | 5 | 2 | 3 | 0 | 0 |
| HLA + Fanconi anemia, complementation group G (FANCG) | FANCG | AR | 2 | 2 | 2 | 3 | 2 | 2 |
| HLA + Fanconi anemia, complementation group I (FANCI) | FANCI | AR | 1 | 2 | 2 | 3 | 0 | 0 |
| HLA + Fanconi anemia, complementation group J (FANCJ) | BRIP1 | AR | 1 | 1 | 1 | 1 | 1 | 1 |
| HLA + Fanconi anemia, complementation group JI (FANCJ) | BRIP1 | AR | 1 | 3 | 1 | 3 | 0 | 0 |
| HLA + Glanzmann thrombasthenia (GT, +DMD) | ITGA2B DMD | 1 | 2 | 2 | 4 | 1 | 0 | |
| HLA + granulomatous disease, chronic, autosomal recessive, cytochrome b‐positive, type I (CDG1) | NCF1 | AR | 1 | 3 | 2 | 2 | 1 | 1 |
| HLA + granulomatous disease, chronic, X‐linked (CDGX) | CYBB | XL | 6 | 16 | 13 | 17 | 7 | 6 |
| HLA + hemoglobin‐beta locus (HBB) | HBB | AR | 92 | 188 | 119 | 177 | 41 | 31 |
| HLA + hyper‐IgE recurrent infection syndrome, autosomal recessive | DOCK8 | AR | 1 | 1 | 0 | 0 | 0 | 0 |
| HLA + Krabbe disease | GALC | AR | 1 | 1 | 1 | 2 | 1 | 1 |
| HLA + myotonic dystrophy 1 (DM1) | DMPK | AD | 1 | 2 | 1 | 2 | 1 | 1 |
| HLA + neutropenia, severe congenital, 1, autosomal dominant (SCN1) | ELANE | AD | 2 | 3 | 2 | 5 | 2 | 1 |
| HLA + polycystic kidney disease 1 (PKD1) | PKD1 | AD | 1 | 1 | 1 | 2 | 1 | 1 |
| HLA + sickle cell anemia | HBB | AR | 18 | 29 | 18 | 27 | 12 | 8 |
| HLA + thrombocythemia 1 (THCYT1) | SH2B3 | AR | 1 | 2 | 2 | 2 | 2 | 1 |
| HLA + thrombotic thrombocytopenic purpura, congenital (TTP) | ADAMTS13 | AR | 1 | 2 | 2 | 4 | 1 | 1 |
| HLA + Wiskott–Aldrich syndrome (WAS) | WAS | XL | 1 | 1 | 0 | 0 | 0 | 0 |
| HLA immunodeficiency with hyper‐IgM, type 1 (HIGM1) | CD40LG | XL | 8 | 15 | 9 | 13 | 5 | 4 |
| HLA + pyruvate kinase deficiency of red cells | PKLR | AD | 1 | 2 | 1 | 1 | 0 | 0 |
| Holoprosencephaly 2 (HPE2) | SIX3 | AD | 1 | 1 | 1 | 2 | 0 | 0 |
| Holt–Oram syndrome (HOS) | TBX5 | AD | 5 | 8 | 8 | 9 | 4 | 4 |
| Homocystinuria due to cystathionine beta‐synthase deficiency | CBS | AR | 4 | 6 | 4 | 9 | 3 | 3 |
| Homocystinuria due to deficiency of n(5,10)‐methylenetetrahydrofolate reductase activity | MTHFR | AR | 1 | 1 | 1 | 2 | 0 | 0 |
| Homocystinuria‐megaloblastic anemia, cblG complementation type (HMAG) | MTR | AR | 1 | 2 | 1 | 1 | 0 | 0 |
| Human leukocyte antigens | HLA | AR | 60 | 119 | 73 | 108 | 25 | 20 |
| Huntington disease (HD) | HTT | AD | 141 | 209 | 171 | 267 | 107 | 97 |
| Hurler syndrome | IDUA | AR | 7 | 10 | 8 | 13 | 3 | 3 |
| Hyaline fibromatosis syndrome (HFS) | ANTXR2 | AR | 1 | 1 | 1 | 2 | 1 | 1 |
| Hydrocephalus due to congenital stenosis of aqueduct of Sylvius (HSAS) | L1CAM | XL | 11 | 16 | 16 | 34 | 8 | 6 |
| Hydroxyacyl‐CoA dehydrogenase/3‐ketoacyl‐CoA thiolase/enoyl‐CoA hydratase, alpha subunit (HADHA) | HADHA | AR | 4 | 4 | 4 | 13 | 3 | 3 |
| Hyperinsulinemic hypoglycemia, familial, 1 (HHF1) | ABCC8 | AR | 2 | 11 | 8 | 19 | 4 | 2 |
| Hyperuricemic nephropathy, familial juvenile, 1 (HNFJ1) | UMOD | AD | 1 | 1 | 1 | 1 | 0 | 0 |
| Hypogonadotropic hypogonadism 1 with or without anosmia (HH1) | ANOS1 | XL | 1 | 1 | 2 | 2 | 0 | 0 |
| Hypogonadotropic hypogonadism 1 with or without anosmia (HH1) | KAL1 | XL | 1 | 2 | 1 | 1 | 1 | 1 |
| Hypoparathyroidism–retardation–dysmorphism syndrome (HRDS) | TBCE | 1R | 1 | 1 | 1 | 2 | 0 | 0 |
| Hypophosphatasia, infantile | ALPL | AR | 6 | 7 | 6 | 9 | 4 | 4 |
| Ichthyosis, congenital, autosomal recessive 1 (ARCI1) | TGM1 | AD | 2 | 9 | 7 | 10 | 1 | 1 |
| Ichthyosis, lamellar, 2 (LI2) | ABCA12 | AR | 2 | 2 | 1 | 2 | 0 | 0 |
| Ichthyosis, spastic quadriplegia, and mental retardation (ISQMR) | ELOVL4 | AR | 1 | 1 | 1 | 1 | 0 | 0 |
| Ichthyosis, X‐linked (XLI) | STS | XL | 2 | 3 | 3 | 4 | 1 | 1 |
| Ifap syndrome with or without Bresheck syndrome | MBTPS2 | XL | 2 | 3 | 2 | 5 | 2 | 1 |
| Immunodeficiency with hyper‐IgM, type 1 (HIGM1) | CD40LG | XL | 4 | 14 | 14 | 22 | 6 | 6 |
| Immunodysregulation, polyendocrinopathy, and enteropathy, X‐linked (IPEX) | FOXP3 | XL | 2 | 3 | 3 | 3 | 1 | 1 |
| Incontinentia pigmenti (IP) | IKBKG | XL | 15 | 35 | 28 | 43 | 11 | 11 |
| Infantile cerebellar‐retinal degeneration (ICRD) | ACO2 | AR | 1 | 1 | 1 | 2 | 2 | 2 |
| Infantile liver failure syndrome 1 (ILFS1) | LARS | AR | 1 | 1 | 2 | 2 | 1 | 1 |
| Isovaleric acidemia (IVA) | IVD | AR | 1 | 1 | 1 | 2 | 0 | 0 |
| Joubert syndrome 1 (JBTS1) | INPP5E | AR | 1 | 1 | 2 | 2 | 1 | 1 |
| Joubert syndrome 17 (JBTS17) | CPLANE1 | AD | 1 | 1 | 1 | 2 | 1 | 1 |
| Joubert syndrome 2 (JBTS2) | TMEM216 | AR | 1 | 1 | 2 | 2 | 1 | 1 |
| Joubert syndrome 21 (JBTS21) | CSPP1 | AR | 2 | 5 | 4 | 7 | 1 | 1 |
| Joubert syndrome 23 (JBTS23) | KIAA0586 | AR | 1 | 1 | 1 | 2 | 1 | 1 |
| Joubert syndrome 3 (JBTS3) | AHI1 | AR | 1 | 1 | 0 | 0 | 0 | 0 |
| Joubert syndrome 6 (JBTS6) | TMEM67 | AR | 2 | 3 | 2 | 2 | 2 | 2 |
| Krabbe disease | GALC | AR | 11 | 12 | 11 | 19 | 7 | 5 |
| Larsen syndrome (LRS) | FLNB | AD | 2 | 2 | 1 | 1 | 1 | 1 |
| Leber congenital amaurosis 2 (LCA2) | RPE65 | AR | 1 | 1 | 0 | 0 | 0 | 0 |
| Leigh syndrome (LS) | NDUFS8 | AR | 1 | 1 | 0 | 0 | 0 | 0 |
| Leigh syndrome (LS) | SURF1 | AR | 1 | 1 | 1 | 3 | 0 | 0 |
| Lesch–Nyhan syndrome (LNS) | HPRT1 | XL | 1 | 4 | 3 | 3 | 2 | 2 |
| Leukoencephalopathy with vanishing white matter (VWM) | EIF2B2 | AR | 1 | 1 | 1 | 2 | 1 | 0 |
| Li–Fraumeni syndrome 1 (LFS1) | TP53 | AD | 16 | 22 | 17 | 24 | 13 | 11 |
| Lipoid congenital adrenal hyperplasia (LCAH) | STAR | AR | 1 | 2 | 2 | 3 | 1 | 1 |
| Lissencephaly, X‐linked, 2 (LISX2) | ARX | XL | 1 | 1 | 1 | 2 | 0 | 0 |
| Loeys–Dietz syndrome 1 (LDS1) | TGFBR2 | AD | 2 | 5 | 4 | 6 | 2 | 1 |
| Long QT syndrome 1 (LQT1) | KCNQ1 | AD | 4 | 5 | 2 | 2 | 2 | 2 |
| Long QT syndrome 2 (LQT2) | KCNH2 | AD | 3 | 3 | 2 | 2 | 1 | 1 |
| Long QT syndrome 8 (LQT8) | CACNA1C | AD | 1 | 1 | 1 | 1 | 1 | 1 |
| Lymphedema, hereditary, III (LMPH3) | PIEZO1 | AR | 1 | 1 | 0 | 0 | 0 | 0 |
| Lymphoproliferative syndrome, X‐linked, 1 (XLP1) | SH2D1A | XL | 1 | 1 | 2 | 3 | 2 | 2 |
| Lysosomal acid lipase deficiency | LIPA | AR | 2 | 2 | 2 | 4 | 2 | 2 |
| Machado–Joseph disease (MJD) | ATXN3 | AD | 4 | 7 | 6 | 8 | 6 | 6 |
| Macular dystrophy, vitelliform, 2 (VMD2) | BEST1 | AD | 1 | 1 | 1 | 1 | 1 | 1 |
| Maple syrup urine disease (MSUD) | BCKDHB | AR | 1 | 2 | 2 | 2 | 1 | 1 |
| Marfan syndrome (MFS) | FBN1 | AD | 30 | 58 | 46 | 78 | 27 | 21 |
| Marinesco–Sjogren syndrome (MSS) | SIL1 | AR | 1 | 3 | 3 | 5 | 1 | 1 |
| Meckel syndrome, type 1 (MKS1) | MKS1 | AR | 2 | 5 | 5 | 9 | 2 | 2 |
| Meckel syndrome, type 4 (MKS4) | CEP290 | 4 | 6 | 6 | 10 | 4 | 4 | |
| Meckel syndrome, type 6 (MKS6) | CC2D2A | AR | 2 | 5 | 5 | 9 | 2 | 2 |
| Meckel syndrome, type 6 (MKS6) | CCD2DA2 | AR | 1 | 1 | 1 | 2 | 1 | 1 |
| Meckel syndrome, type 8 (MKS8) | TCTN2 | AR | 1 | 1 | 2 | 2 | 1 | 1 |
| Mental retardation, autosomal dominant 35 (MRD35) | PPP2R5 | AD | 1 | 1 | 2 | 2 | 1 | 1 |
| Mental retardation, autosomal recessive 38 (MRT38) | HERC2 | AR | 1 | 2 | 2 | 3 | 1 | 1 |
| Metachromatic leukodystrophy due to saposin B deficiency | PSAP | AR | 1 | 1 | 0 | 0 | 0 | 0 |
| Metachromatic leukodystrophy (MLD) | ARSA | AR | 3 | 4 | 3 | 4 | 4 | 2 |
| Metaphyseal chondrodysplasia, Schmid type (MCDS) | COL10A1 | AD | 2 | 7 | 3 | 4 | 2 | 2 |
| Methylmalonic aciduria and homocystinuria, cblC type | MMACHC | AR | 3 | 6 | 6 | 11 | 5 | 5 |
| Methylmalonic aciduria due to methylmalonyl‐CoA mutase deficiency | MUT | AR | 2 | 4 | 4 | 4 | 2 | 2 |
| Methylmalonic aciduria, cblB type | MMAB | AR | 3 | 3 | 2 | 3 | 1 | 1 |
| Microcephalic osteodysplastic primordial dwarfism, type I (MOPD1) | RNU4ATAC | AR | 1 | 1 | 1 | 1 | 1 | 1 |
| Microcephaly 2, primary, autosomal recessive (MCPH2) | WDR62 | AR | 1 | 1 | 1 | 1 | 0 | 0 |
| Microcephaly 5, primary, autosomal recessive (MCPH5) | ASPM | AR | 2 | 3 | 2 | 3 | 2 | 2 |
| Microcephaly 6, primary, MCPH6) | CENPJ | AR | 1 | 2 | 2 | 2 | 1 | 1 |
| Microphthalmia, isolated, with coloboma 3 (MCOPCB3) | VSX2 | AR | 2 | 2 | 1 | 1 | 1 | 1 |
| Midface hypoplasia, hearing impairment, elliptocytosis, and nephrocalcinosis (MFHIEN) | AMMECR1 | XL | 2 | 8 | 6 | 9 | 2 | 2 |
| Migraine, familial hemiplegic, 1 (FHM1) | CACNA1A | AD | 1 | 1 | 1 | 2 | 1 | 1 |
| Mitochondrial complex i deficiency due to acad 9 deficiency | ACAD9 | AR | 1 | 1 | 1 | 2 | 1 | 1 |
| Mitochondrial DNA depletion syndrome 13 | FBXL4 | AD | 1 | 1 | 3 | 4 | 1 | 1 |
| Mitochondrial DNA depletion syndrome 4a (Alpers type) (MTDPS4A) | POLG | AR | 3 | 5 | 5 | 5 | 4 | 4 |
| Molybdenum cofactor deficiency, complementation group B (MOCODB) | MOCS2 | AR | 1 | 1 | 3 | 4 | 0 | 0 |
| Mosaic variegated aneuploidy syndrome 1 (MVA1) | BUB1B | AR | 1 | 1 | 1 | 2 | 1 | 0 |
| Mucolipidosis II alpha/beta | GNPTAB | AR | 2 | 3 | 2 | 2 | 2 | 2 |
| Mucopolysaccharidosis, type II (MPS2) | IDS | XL | 9 | 20 | 15 | 29 | 10 | 6 |
| Mucopolysaccharidosis, type IIIA (MPS3A) | SGSH | AR | 2 | 2 | 2 | 3 | 0 | 0 |
| Mucopolysaccharidosis, type IVA (MPS4A) | GALNS | AR | 1 | 4 | 4 | 12 | 2 | 2 |
| Multinucleated neurons, anhydramnios, renal dysplasia, cerebellar hypoplasia | CEP55 | AR | 1 | 1 | 1 | 2 | 1 | 1 |
| Multiple congenital anomalies–hypotonia–seizures syndrome 2 (MCAHS2) | PIGA | XL | 1 | 1 | 0 | 0 | 0 | 0 |
| Multiple endocrine neoplasia, type I (MEN1) | MEN1 | AD | 8 | 21 | 16 | 23 | 7 | 4 |
| Multiple endocrine neoplasia, type IIA (MEN2A) | RET | AD | 6 | 11 | 11 | 17 | 8 | 8 |
| Multiple endocrine neoplasia, type IV (MEN4) | CDKN1B | AD | 1 | 3 | 1 | 1 | 1 | 1 |
| Muscular dystrophy, congenital merosin‐deficient, 1A (MDC1A) | LAMA2 | AR | 6 | 7 | 7 | 14 | 7 | 6 |
| Muscular dystrophy, Duchenne type (DMD) | DMD | XL | 69 | 115 | 103 | 169 | 57 | 48 |
| Muscular dystrophy, limb‐girdle, type 2A (LGMD2A) | CAPN3 | AR | 1 | 1 | 0 | 0 | 0 | 0 |
| Muscular dystrophy, limb‐girdle, type 2S (LGMD2S) | TRAPPC11 | AR | 1 | 1 | 2 | 2 | 2 | 2 |
| Muscular dystrophy–dystroglycanopathy (congenital with brain and eye anomalies), type A, 5 (MDDGA5) | FKRP | AR | 1 | 3 | 3 | 3 | 1 | 1 |
| Muscular dystrophy–dystroglycanopathy (congenital with brain and eye anomalies), type A, 4 (MDDGA4) | FKTN | AR | 2 | 2 | 2 | 3 | 2 | 2 |
| Myoglobinuria, acute recurrent, autosomal recessive | LPIN1 | AR | 1 | 1 | 1 | 1 | 1 | 1 |
| Myopathy, areflexia, respiratory distress, and dysphagia, early‐onset (EMARDD) | MEGF10 | AR | 1 | 1 | 1 | 1 | 1 | 1 |
| Myopathy, centronuclear, X‐linked (CNMX) | MTM1 | XL | 5 | 6 | 4 | 6 | 4 | 4 |
| Myopathy, myofibrillar, 1 (MFM1) | DES | AD | 1 | 1 | 1 | 1 | 1 | 1 |
| Myotonia congenita, autosomal dominant | CLCN1 | AD | 1 | 1 | 1 | 2 | 1 | 1 |
| Myotonic dystrophy 1 (DM1) | DMPK | AD | 94 | 147 | 107 | 188 | 55 | 46 |
| Myotonic dystrophy 2 (DM2) | CNBP | AD | 1 | 2 | 2 | 4 | 2 | 2 |
| Nail–patella syndrome (NPS) | LMX1B | AD | 3 | 4 | 3 | 4 | 1 | 1 |
| Nemaline myopathy 2 (NEM2) | NEB | AR | 6 | 6 | 6 | 10 | 3 | 3 |
| Nephrotic syndrome, type 1 (NPHS1) | NPHS1 | AR | 1 | 3 | 3 | 7 | 1 | 0 |
| Nephrotic syndrome, type 2 (NPHS2) | NPHS2 | AR | 1 | 1 | 1 | 1 | 1 | 1 |
| Nephrotic syndrome, type 5 | LAMB2 | AR | 1 | 2 | 2 | 4 | 2 | 1 |
| Neurofibromatosis, type I (NF1) | NF1 | AD | 51 | 90 | 80 | 123 | 46 | 41 |
| Neurofibromatosis, type II (NF2) | NF2 | AD | 7 | 10 | 9 | 17 | 7 | 7 |
| Neuropathy, hereditary sensory and autonomic, type III (HSAN3) | IKBKAP | AR | 13 | 19 | 17 | 28 | 9 | 9 |
| Neuropathy, hereditary sensory and autonomic, type VI (HSAN6) | DST | AD | 1 | 2 | 2 | 2 | 2 | 2 |
| Neutropenia, severe congenital, 1, autosomal dominant (SCN1) | ELANE | AD | 1 | 1 | 1 | 1 | 1 | 1 |
| Niemann–Pick disease, type A | SMPD1 | AR | 3 | 5 | 3 | 6 | 2 | 2 |
| Nijmegen breakage syndrome (NBS) | NBN | AR | 1 | 1 | 2 | 2 | 1 | 1 |
| Noonan syndrome 1 (NS1) | PTPN11 | AD | 5 | 7 | 7 | 9 | 4 | 3 |
| Norrie disease (ND) | NDP | XL | 5 | 8 | 6 | 12 | 2 | 2 |
| Omenn syndrome | RAG1 | AD | 2 | 6 | 5 | 12 | 1 | 1 |
| Optic atrophy 1 (OPA1) | OPA1 | AD | 3 | 5 | 5 | 9 | 1 | 1 |
| Ornithine transcarbamylase deficiency | OTC | XL | 11 | 24 | 19 | 32 | 11 | 10 |
| Osteogenesis imperfecta, type I (OI1) | COL1A1 | AD | 24 | 61 | 44 | 72 | 17 | 17 |
| Osteogenesis imperfecta, type II (OI2) | COL1A2 | AD | 5 | 5 | 5 | 5 | 3 | 2 |
| Osteogenesis imperfecta, type IX (OI9) | PPIB | AR | 1 | 2 | 2 | 4 | 2 | 2 |
| Osteopathia striata with cranial sclerosis (OSCS) | AMER1 | XL | 1 | 1 | 1 | 1 | 1 | 1 |
| Osteopetrosis, autosomal recessive 1 (OPTB1) | TCIRG1 | AR | 5 | 7 | 7 | 13 | 3 | 3 |
| Pachyonychia congenita 3 (PC3) | KRT6A | AD | 1 | 2 | 2 | 2 | 2 | 1 |
| Pancreatitis, hereditary (PCTT) | PRSS1 | AD | 1 | 1 | 1 | 2 | 1 | 1 |
| Paraganglioma and gastric stromal sarcoma | SDHB | AD | 1 | 1 | 0 | 0 | 0 | 0 |
| Paramyotonia congenita of von Eulenburg (PMC) | SCN4A | AD | 3 | 3 | 3 | 4 | 3 | 2 |
| Pelizaeus–Merzbacher disease (PMD) | PLP1 | XL | 7 | 12 | 10 | 15 | 7 | 7 |
| Periventricular nodular heterotopia 1 (PVNH1) | FLNA | XL | 1 | 3 | 3 | 5 | 2 | 1 |
| Peroxisome biogenesis disorder 1A (Zellweger) (PBD1A) | PEX1 | AR | 3 | 3 | 3 | 6 | 3 | 3 |
| Peroxisome biogenesis disorder 2A (Zellweger) (PBD2A) | PEX5 | AR | 1 | 2 | 2 | 4 | 0 | 0 |
| Peroxisome biogenesis disorder 3A (Zellweger) (PBD3A) | PEX12 | AR | 1 | 3 | 3 | 4 | 2 | 1 |
| Peroxisome biogenesis disorder 5A (Zellweger) (PBD5A) | PEX2 | AR | 1 | 4 | 3 | 5 | 2 | 2 |
| Peutz–Jeghers syndrome (PJS) | STK11 | AD | 4 | 9 | 7 | 9 | 6 | 4 |
| Pfeiffer syndrome | FGFR1 | AD | 2 | 2 | 2 | 4 | 2 | 2 |
| Phenylketonuria (PKU) | PAH | AR | 15 | 20 | 14 | 16 | 8 | 7 |
| Platelet disorder, familial, with associated myeloid malignancy (FPDMM) | RUNX1 | AD | 1 | 1 | 1 | 1 | 1 | 1 |
| Pleuropulmonary blastoma (PPB) | DICER1 | AD | 1 | 1 | 1 | 1 | 1 | 1 |
| Polycystic kidney disease 1 (PKD1) | PKD1 | AD | 48 | 84 | 64 | 98 | 37 | 34 |
| Polycystic kidney disease 2 (PKD2) | PKD2 | AD | 7 | 10 | 9 | 15 | 3 | 3 |
| Polycystic kidney disease, autosomal recessive (ARPKD) | PKHD1 | AR | 16 | 29 | 26 | 42 | 17 | 16 |
| Polymicrogyria, bilateral frontoparietal (BFPP) | ADGRG1 | AR | 2 | 2 | 1 | 2 | 1 | 1 |
| Polymicrogyria, bilateral frontoparietal (BFPP) | GPR56 | AR | 1 | 1 | 1 | 2 | 0 | 0 |
| Pontocerebellar hypoplasia, type 1B (PCH1B) | EXOSC3 | AR | 1 | 1 | 2 | 2 | 1 | 1 |
| Popliteal pterygium syndrome (PPS) | IRF6 | AD | 2 | 2 | 1 | 2 | 1 | 1 |
| Porphyria, congenital erythropoietic | UROS | AR | 1 | 1 | 1 | 1 | 1 | 1 |
| Propionic acidemia | PCCA, | AR | 3 | 3 | 3 | 5 | 2 | 2 |
| PCCB | ||||||||
| Prothrombin deficiency, congenital; | F2 F5 | AR | 2 | 3 | 3 | 3 | 2 | 2 |
| Factor V deficiency | ||||||||
| Pseudovaginal perineoscrotal hypospadias (PPSH) | SRD5A2 | AR | 1 | 2 | 2 | 4 | 1 | 1 |
| Rap guanine nucleotide exchange factor 6 (RAPGEF6) | RAPGEF6 | AD | 1 | 2 | 3 | 4 | 3 | 1 |
| Renal cell carcinoma, papillary, 1 (RCCP1) | MET | AD | 1 | 1 | 2 | 2 | 1 | 1 |
| Renal tubular acidosis, distal, autosomal recessive (RTADR) | ATP6V0A4 | AR | 1 | 1 | 2 | 3 | 2 | 1 |
| Renal tubular dysgenesis (RTD) | ACE | AR | 1 | 4 | 3 | 4 | 2 | 2 |
| Restrictive dermopathy, lethal | ZMPSTE24 | AR | 2 | 2 | 2 | 3 | 1 | 1 |
| Retinal dystrophy, early‐onset, with or without pituitary dysfunction, included | OTX2 | AD | 1 | 1 | 0 | 0 | 0 | 0 |
| Retinitis pigmentosa 2 (RP2) | RP2 | XL | 1 | 1 | 1 | 2 | 1 | 1 |
| Retinitis pigmentosa 3 (RP3) | RPGR | XL | 5 | 6 | 6 | 8 | 4 | 3 |
| Retinitis pigmentosa 4 (RP4) | RHO | AD | 3 | 5 | 2 | 4 | 1 | 0 |
| Retinoblastoma (RB1) | RB1 | AD | 17 | 31 | 26 | 43 | 14 | 13 |
| Retinoschisis 1, X‐linked, juvenile (RS1) | RS1 | XL | 1 | 2 | 1 | 2 | 1 | 0 |
| Rett syndrome (RTT) | MECP2 | XL | 3 | 5 | 4 | 4 | 3 | 1 |
| Rhabdoid tumor predisposition syndrome 1 (RTPS1) | SMARCB1 | AD | 1 | 1 | 1 | 1 | 0 | 0 |
| Rhesus blood group, D antigen (RHD) | RHD | AD | 7 | 9 | 9 | 16 | 6 | 6 |
| Sandhoff disease | HEXB | AR | 4 | 6 | 5 | 8 | 4 | 4 |
| Seckel syndrome 1 (SCKL1) | ATR | AR | 1 | 1 | 2 | 2 | 0 | 0 |
| Severe combined immunodeficiency, autosomal recessive | IL7R | AR | 1 | 1 | 2 | 4 | 1 | 1 |
| Severe combined immunodeficiency, autosomal recessive | RAG2 | AR | 2 | 5 | 4 | 5 | 3 | 3 |
| Severe combined immunodeficiency, X‐linked (SCIDX1) | IL2RG | XL | 3 | 4 | 3 | 3 | 2 | 2 |
| Short stature, idiopathic, X‐linked (ISS) | SHOX | XL | 2 | 2 | 2 | 3 | 2 | 2 |
| Short‐rib thoracic dysplasia 3 with or without polydactyly (SRTD3) | DYNC2H1 | AR | 1 | 1 | 1 | 1 | 1 | 1 |
| Smith–Lemli–Opitz syndrome (SLOS) | DHCR7 | AR | 18 | 30 | 23 | 32 | 15 | 15 |
| Sonic hedgehog (SHH) | SHH | AD | 1 | 2 | 2 | 3 | 1 | 1 |
| Sotos syndrome 1 (SOTOS1) | NSD1 | AD | 2 | 3 | 2 | 2 | 2 | 2 |
| Spastic paraplegia 3, autosomal dominant (SPG3A) | ATL1 | AD | 1 | 1 | 1 | 1 | 1 | 1 |
| Spastic paraplegia 4, autosomal dominant (SPG4) | SPAST | AD | 6 | 10 | 8 | 12 | 7 | 5 |
| Spherocytosis, type 2 (SPH2) | SPTB | AD | 1 | 1 | 2 | 2 | 2 | 1 |
| Spinal and bulbar muscular atrophy, X‐linked 1 (SMAX1) | AR | XL | 3 | 5 | 5 | 6 | 2 | 1 |
| Spinal muscular atrophy, distal, autosomal recessive, 1 (DSMA1) | IGHMBP2 | AR | 2 | 3 | 2 | 4 | 1 | 1 |
| Spinal muscular atrophy, type I (SMA1) | SMN1 | AR | 102 | 151 | 125 | 199 | 78 | 69 |
| Spinocerebellar ataxia 1 (SCA1) | ATXN1 | AD | 4 | 7 | 6 | 8 | 4 | 4 |
| Spinocerebellar ataxia 2 (SCA2) | ATXN2 | AD | 7 | 14 | 14 | 27 | 6 | 8 |
| Spinocerebellar ataxia 6 (SCA6) | CACNA1A | AD | 2 | 5 | 2 | 3 | 1 | 1 |
| Spinocerebellar ataxia 7 (SCA7) | ATXN7 | AD | 2 | 3 | 3 | 7 | 2 | 1 |
| Spinocerebellar ataxia 8 (SCA8) | ATXN80S | AD | 1 | 1 | 1 | 1 | 1 | 1 |
| Spondyloepiphyseal dysplasia tarda, X‐linked (SEDT) | TRAPPC2 | AD | 1 | 1 | 2 | 2 | 1 | 1 |
| Stargardt disease 1 (STGD1) | ABCA4 | AR | 4 | 10 | 5 | 6 | 2 | 2 |
| Stickler syndrome, type I (STL1) | Col2A1 | AD | 4 | 4 | 3 | 5 | 2 | 2 |
| Stickler syndrome, type II (STL2) | COL11A1 | AD | 2 | 7 | 6 | 15 | 1 | 1 |
| Stickler syndrome, type II (STL2) | COL18A1 | AR | 1 | 1 | 1 | 1 | 1 | 1 |
| Succinic semialdehyde dehydrogenase deficiency (SSADHD) | ALDH5A1 | AR | 3 | 4 | 4 | 9 | 2 | 2 |
| Sulfocysteinuria | SUOX | AR | 1 | 1 | 2 | 2 | 1 | 1 |
| Supranuclear palsy, progressive, 1 (PSNP1) | MAPT | AD | 2 | 3 | 3 | 5 | 1 | 1 |
| Surfactant metabolism dysfunction, pulmonary, 3 (SMDP3) | ABCA3 | AR | 1 | 2 | 2 | 4 | 1 | 1 |
| Symphalangism, proximal (SYM1) | NOG | AD | 1 | 3 | 3 | 7 | 2 | 2 |
| Tay–Sachs disease (TSD) | HEXA | AR | 25 | 46 | 29 | 52 | 19 | 17 |
| Telangiectasia, hereditary hemorrhagic, of Rendu, Osler, and Weber (HHT) | ENG | AD | 4 | 11 | 6 | 7 | 3 | 3 |
| Telangiectasia, hereditary hemorrhagic, type 2 (HHT2) | ACVRL1 | AD | 4 | 8 | 7 | 8 | 4 | 4 |
| Temtamy syndrome (TEMTYS) | C12orf57 | AR | 1 | 1 | 1 | 2 | 0 | 0 |
| Thrombocytopenia‐absent radius syndrome (TAR) | RBM8A | AR | 4 | 6 | 5 | 7 | 4 | 4 |
| Treacher Collins syndrome 1 (TCS1) | TCOF1 | AD | 6 | 8 | 8 | 14 | 7 | 7 |
| Treacher Collins syndrome 2 (TCS2) | POLR1D | AD | 1 | 1 | 1 | 1 | 0 | 0 |
| Tuberous sclerosis 1 (TSC1) | TSC1 | AD | 20 | 30 | 27 | 52 | 16 | 14 |
| Tuberous sclerosis 2 (TSC2) | TSC2 | AD | 8 | 14 | 10 | 14 | 5 | 4 |
| Tyrosinemia, type I (TYRSN1) | FAH | AR | 1 | 7 | 7 | 13 | 5 | 3 |
| Ulnar–Mammary syndrome (UMS) | TBX3 | AD | 1 | 3 | 3 | 4 | 1 | 1 |
| Usher syndrome, type I (USH1) | MYO7A | AD | 1 | 3 | 2 | 2 | 1 | 1 |
| Usher syndrome, type IF (USH1F) | PCDH15 | AR | 2 | 4 | 4 | 6 | 4 | 2 |
| Usher syndrome, type IIA (USH2A) | USH2A | AR | 3 | 4 | 5 | 6 | 2 | 2 |
| Usher syndrome, type IIC (USH2C) | ADGRV1 | AR | 1 | 1 | 1 | 2 | 1 | 1 |
| Usher syndrome, type IIC (USH2C) | GPR98 | AR | 1 | 1 | 0 | 0 | 0 | 0 |
| Van der Woude syndrome 1 (VWS1) | IRF6 | AD | 3 | 3 | 3 | 3 | 3 | 3 |
| Von Hippel–Lindau syndrome (VHL) | VHL | AD | 19 | 25 | 21 | 30 | 15 | 14 |
| Waardenburg syndrome, type 2A (WS2A) | MITF | AD | 2 | 6 | 6 | 6 | 4 | 4 |
| Wilson disease | ATP7B | AR | 3 | 3 | 3 | 5 | 3 | 2 |
| Wiskott–Aldrich syndrome (WAS) | WAS | XL | 6 | 15 | 13 | 20 | 9 | 8 |
| Wolfram syndrome 1 (WFS1) | WFS1 | AR | 1 | 2 | 1 | 1 | 1 | 1 |
| Xeroderma pigmentosum, complementation group g (XPG) | ERCC5 | AR | 1 | 1 | 0 | 0 | 0 | 0 |
| TOTAL | 3463 | 5869 | 4683 | 7443 | 2644 | 2332 | ||
| 1.59 | 56.4% |
