Table 2.
List of hereditary NMDs with associated genes and variants identified in the patient cohort
| NMD group | Disorder (Short name; MIM#) | Patients (#); Families (#) | Ages at Diagnosis (years or range in years with avgerage)† | Associated Gene or Genomic Region (MIM#) | Mutations identified (homozygous; heterozygous; compound heterozygous; hemizygous)† | References† |
| Motor Neuron Diseases | Amyotrophic Lateral Sclerosis 1 (ALS1; 105400) | 8; 6 | 50-51 | SOD1 (147450) | c.352C > G p.Leu118Val | – |
| Brown-Vialetto-Van Laere syndrome 2 (BVVL2; 614707) | 6; 2 | 12–19 (avg. 16) | SLC52A2 (607882) | c.916G4A p.Gly306Arg | [28, 29] | |
| Distal Spinal Muscular Atrophy 1 (DSMA1; 604320) | 6; 3 | < 1 | IGHMBP2 (600502) | c.1540G > A p.Glu514Lys | [14] | |
| Distal Spinal Muscular Atrophy (DSMA; Unknown subtype) | 1; 1 | – | – | – | ||
| Frontotemporal Dementia and/or Amyotrophic Lateral Sclerosis 4 (FTDALS4; 616439) | 2; 2 | 35; 39 | TBK1 (604834) | c.2079_2082del p.Glu695Argfs*16 | [8] | |
| c.2079_2082del p.Glu695Argfs*16 | ||||||
| Spinal Muscular Atrophy 1 (SMA1; 253300) | 190; – | < 1 | SMN1a (600354) | exon 7 &8 deletion | – | |
| Spinal Muscular Atrophy 2 (SMA2; 253550) | 7; 7 | 2–15 (avg. 6) | exon 8 deletion | |||
| Spinal Muscular Atrophy 3 (SMA3; 253550) | 7; 4 | 7–33 (avg. 20) | c.549del; p.Lys184Serfs* and exon 7 & 8 deletion | |||
| Hereditary Motor and Sensory Neuropathies | Charcot-Marie-Tooth Disease, Axonal, Type 2S (CMT2S; 616155) | 4b; 2 | 32–53 | IGHMBP2 (600502) | c.62G > T p.Arg21Ileb | [8] |
| Charcot-Marie-Tooth Disease, Axonal, Type 2T (CMT2T; 617017) | 2; 2 | – | MME (120520) | Under publication (Delague V. et al.) | ||
| Charcot-Marie-Tooth Disease, Demyelinating, Type 1A (CMT1A; 118220) | 4; 4 | 6 | PMP22 (601097) | 1.5-Mb duplication at 17p11.2 | – | |
| Charcot-Marie-Tooth Disease, Type 4A (CMT4A; 214400) | 5; 4 | 7–26 (avg. 13) | GDAP1 (606598) | c.668T > A p.Leu223* | [78] | |
| Charcot-Marie-Tooth Disease, Type 4B3 (CMT4B3; 615284) | 2; 1 | 7; 12 | SBF1 (615284) | c.1004T > C p.Lys335Pro | [65] | |
| Charcot-Marie-Tooth Disease, Type 4C (CMT4C; 601596) | 1; 1 | – | SH3TC2 (608206) | Unpublished data (Delague V. et al.) | ||
| Charcot-Marie-Tooth Disease, Demyelinating, Type 4F (CMT4F; 614895) | 10; 3 | 0–19 (avg. 6) | PRX (605725) | c.586C > T p.Arg196* | [67] | |
| Charcot-Marie-Tooth Disease, Demyelinating, Type 4H (CMT4H; 609311) | 2; 2 | 17 | FGD4 (611104) | c.1698G > A p.Met566Ile | [79] | |
| Charcot-Marie-Tooth Disease, Type 6C (CMT6C; 618511) | 4; 2 | – | PDXK (179020) | c.628G > A p.Ala228Thr | Under publication (Delague V. et al.) | |
| Charcot-Marie-Tooth Disease, Dominant Intermediate E (CMTDIE; 614455) | 1; 1 | – | INF2 (610982) | c.312C > G p.Cys104Trp | – | |
| Charcot-Marie-Tooth Disease, Recessive Intermediate C (CMTRIC; 615376) | 5; 4 | 7– 15 (avg. 12) | PLEKHG5 (611101) | c.909C > A p.Tyr303* | [14] Under publication | |
| c.1452_1453del p.His485Profs*169 | (Delague V. et al.) | |||||
| Charcot-Marie-Tooth Disease Type I (CMT1; Unknown subtype) | 3; 2 | 13; 28; 37 | – | – | ||
| Charcot-Marie-Tooth Disease Type I (CMT1; Associated with MTMR4 mutation) | 1; 1 | 0 | MTMR4 (603559) | Unpublished data (Delague V. et al.) | ||
| Charcot-Marie-Tooth Disease Type 2 (CMT2; Unknown subtype) | 3; 3 | 23; 44 | – | – | ||
| Charcot-Marie-Tooth Disease Type 2 (CMT2; Associated with BAG3 mutation) | 1; 1 | 25 | BAG3 (603883) | Under publication (Delague V. et al.) | ||
| Charcot-Marie-Tooth Disease, X-Linked Dominant, 1 (CMTX1; 302800) | 2; 2 | 7; 34 | GJB1 (304040) | c.164_184dup p.Thr55_Asn61dup | [8] | |
| c.G139A p.Glu47Lys | ||||||
| Charcot-Marie-Tooth Disease (CMT; Associated with DNAJB2 mutation) | 1; 1 | – | DNAJB2 (604139) | Under publication (Delague V. et al.) | ||
| Charcot-Marie-Tooth Disease (CMT; Associated with VRK1 mutation) | 1; 1 | – | VRK1 (602168) | |||
| Charcot-Marie-Tooth Disease (CMT; Unknown subtype) | 14; 14 | 14– 50 | – | – | ||
| Muscular Dystrophies | Becker Muscular Dystrophy (BMD; 300376) | 13c; 5 | 6– 30 (avg. 15) | DMD (300377) | See Fig. 2 for exonal deletions | – |
| Bethlem Myopathy 1 (BTHLM1; 158810) | 3; 2 | 12; 15; 43 | COL6A1 (120220) | c.928_930delAAG p.Lys310del | – | |
| c.868G > A p.Gly290Arg | ||||||
| Duchenne Muscular Dystrophy (DMD; 310200) | 73c; 62 | 0– 41 (avg. 10) | DMD (300377) | See Fig. 2 for exonal deletions and exonal positions of truncating variants | [8] | |
| exon 53 duplication | ||||||
| t(X;1)(p21;q23) | ||||||
| c.94-1G > T | ||||||
| c.4071 + 1G > A | ||||||
| Emery-Dreifuss Muscular Dystrophy 4 (EDMD4; 612998) | 1; 1 | 7 | SYNE1 (608441) | c.18445C > A p.Arg6149Ser | [14] | |
| Facioscapulohumeral Muscular Dystrophy 1 (FSHD1; 158900) | 21d; 13 | 12– 52 (avg. 27) | Chr.4q35 [DUX4] (606009) | 4qA haplotype with 3– 6 D4Z4 microsatellite repeats | – | |
| Limb Girdle Muscular Dystrophy Recessive 1 (LGMDR1; 253600) | 11; 5 | 7– 22 (avg. 19) | CAPN3 (114240) | c.257C > T p.Ser86Phe | – | |
| c.[257C > T];[956C > T] p.[Ser86Phe];[Pro319Leu] | ||||||
| c.[956C > T; 310-4_310-1delACAG] p.[Pro319Leu];[?] | ||||||
| Limb Girdle Muscular Dystrophy Recessive 2 (LGMDR2; 253601) | 2; 2 | 21; 42 | DYSF (603009) | c.5438T > C p.Leu1813Pro | – | |
| Limb Girdle Muscular Dystrophy Recessive 3 (LGMDR3; 608099) | 6; 4 | 3– 15 (avg. 11) | SGCA (600119) | c.[157G > A];[c.574C > T] p.[Ala53Thr];[Arg192*] | [8] | |
| Limb Girdle Muscular Dystrophy Recessive 4 (LGMDR4; 604286) | 3; 3 | 10 | SGCB (600900) | c.-10_22dup p.Ala8fs | – | |
| Limb Girdle Muscular Dystrophy Recessive 5 (LGMDR5; 253700) | 6; 4 | 2– 24 (avg. 13) | SGCG (608896) | exon 7 deletion | [8] | |
| Limb Girdle Muscular Dystrophy Recessive 6 (LGMDR6; 601287) | 1; 1 | 8 | SGCD (601411) | c.784G > A p.Glu262Lys | – | |
| Limb Girdle Muscular Dystrophy Recessive 10 (LGMDR10; 608807) | 1; 1 | 6 | TTN (188840) | c.36040A > T; p.Lys12014* | [8] | |
| Limb Girdle Muscular Dystrophy Recessive 23 (LGMDR23; 618138) | 8; 7 | 4– 30 (avg. 11) | LAMA2 (156225) | c.8244 + 3_8244 + 6del | [8] | |
| c.8244 + 2dupT | ||||||
| c.[3829C > T];[1300C > T] p.[Arg1277*];[Arg434*] | ||||||
| Limb Girdle Muscular Dystrophy Recessive (LGMDR; Unknown Subtype) | 12; 7 | 10– 45 (avg. 22) | – | – | ||
| Muscular Dystrophy-Dystroglycanopathy, Limb-Girdle, Type C, 1 (MDDGC1; 609308) | 6; 3 | 4– 22 (avg. 12) | POMT1 (607423) | c.[1858C > T];[221C > T] p.[Arg620*];[Ala74Val] | [8, 14] | |
| c.[200C > A];[2005G > A] p.[Pro67Gln];[Ala669Thr] | ||||||
| Muscular Dystrophy-Dystroglycanopathy, Limb-Girdle, Type C, 5 (MDDGC5; 607155) | 3; 3 | 1; 6; 15 | FKRP (606596) | c.823C > T p.Arg275Cys | [8] | |
| Congenital Muscular Dystrophies | Muscular Dystrophy-Dystroglycanopathy, Congenital with Impaired Intellectual Development, Type B, 6 (MDDGB6; 608840) | 2; 1 | 4; 8 | LARGE1 (603590) | Intron 10 42.9-KB insertion/4.1-KB deletion | [80] |
| Muscular Dystrophy, Congenital, LMNA-Related (MDCL; 613205) | 1; 1 | 6 | LMNA (150330) | c.1867A > G p.Thr623Ala | [14] | |
| Muscular Dystrophy, Congenital (CMD; Unknown subtype) | 4; 4 | 8 | – | – | ||
| Rigid Spine Muscular Dystrophy 1 (RSMD1; 602771) | 2; 2 | 14 | SELENON (606210) | c.1405C > T p.Arg469Trp | – | |
| Ullrich Congenital Muscular Dystrophy 1 (UCMD1; 254090) | 6e; 3 | 0– 3 | COL6A1 (120220) | COL6A1: c.2923G > C p.Gly975Arg | [14] | |
| COL6A2 (120240) | COL6A2: c.2611G > A p.Asp871Asne | |||||
| COL6A3 (120250) | COL6A3: c.8136del p.Arg2713Glyfs*3 | |||||
| Congenital Myopathies | Central Core Disease of Muscle (CCD; 117000) | 1; 1 | 25 | RYR1 (180901) | c.8758C > T p.Arg2920* | [8] |
| Myopathy, Centronuclear, X-Linked (CNMX; 310400) | 2; 2 | 0 | MTM1 (300415) | c.969dupA p.Val324Serfs*8 | – | |
| c.1190A > G; p.Tyr397Cys | ||||||
| Nemaline Myopathy 2 (NEM2; 256030) | 1; 1 | 5 | NEB (161650) | c.5452-1G > A | – | |
| Congenital Myopathy (CM; Unknown subtype) | 3; 3 | 1; 7; 9 | – | – | ||
| Metabolic Myopathies | Glycogen Storage Disease II (GSD2; 232300) | 2; 2 | 7 | GAA (606800) | c.266G > A p.Arg89His | [8] |
| c.1927G > A p.Gly643Arg | ||||||
| Neurodegeneration with Brain Iron Accumulation 2A (NBIA2A; 256600) | 3; 3 | 3; 4; 5 | PLA2G6 (603604) | c.2257G > T p.Val753Phe | [8] | |
| c.2370T > G p.Tyr790* | ||||||
| Other Myopathies | Tubular Aggregate Myopathy 1 (TAM1; 160565) | 1; 1 | 12 | STIM1 (605921) | c.57G > C p.Gln19His | – |
| Myotonic Syndromes | Myotonic Dystrophy 1 (MD1; 160900) | 3; 2 | 30; 33; 60 | DMPK (605377) | 3’ CTG triplet repeat expansion (> 400 repeats) | – |
| Other Neuromuscular Disorders | Mitochondrial DNA depletion syndrome (MTDPS; Unknown subtype) | 2; 1 | 15 | – | – | |
| Congenital Myasthenic Syndromes | Myasthenic Syndrome, Congenital, 25, Presynaptic (CMS25; 618323) | 1; 1 | 14 | VAMP1 (185880) | c.97C > T p.Arg33* | [8] |
| Unspecified | Mitochondrial Myopathy (MM; Associated with MTRNR2 mutation) | 1; 1 | 11 | MTRNR2 (561010) | m.2119T > Cf | – |
| Mitochondrial Trifunctional Protein Deficiency (MTPD; 609015) | 1; 1 | 28 | HADHA (600890) | c.703C > T p.Arg235Trpg | – | |
| Unclassified NMDs | 7; 6 | 3– 52 (avg. 27) | – | – | ||
†Patient data on age, variants, and relevant published studies are available only for independent subsets of patients. a: Spinal Muscular Atrophy patients presented with varying copy numbers of SMN2 b: One patient presented with uncharacteristic syndromic features including delayed motor language development, intellectual disability, microcephaly, and dysmorphic facial features; c: All female patients were manifesting carriers of DMD mutations; d: One patient presented with typical FSHD1 symptoms and a negative molecular test; e: One patient presented with uncharacteristic cognitive features in the form of psychomotor delay; f: Heteroplasmic MTRNR2 variant in a patient exhibiting features of mitochondrial myopathy; g: Variant position is based on the precursor from of the mitochondrial protein.