Publications about genetic testing for neurological disorders
  1. Home
  2. Science
  3. NGS Panel – Genetic Testing for Muscular Dystrophy

Muscular Dystrophy

August 18, 2017

Disease synonyms

Muscular dystrophy, MD

Inheritance pattern

Autosomal dominant, autosomal recessive, X-linked

Clinical features

Muscular dystrophies are inherited neuromuscular diseases characterized by weakness and wasting due to muscle dysfunction. Age of onset, severity, progression and histopathological findings are variable between different subtypes of muscular dystrophies.

Muscular dystrophies include a heterogeneous group of neuromuscular disorders:

Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene located on the X chromosome which encodes protein dystrophin. DMD affects boys in early childhood, causing progression of muscle weakness and resulting gait problems, general motor delay, and speech/learning difficulties. DMD is the most severe form of muscular dystrophy and it is characterized as follows1:

  • Rapid progression of muscle weakness, often with calf hypertrophy
  • Increased levels of serum CK concentration
  • Onset before age five years
  • Wheelchair dependency before age 13 years
  • Approximately one third of affected shows DMD-associated dilated cardiomyopathy in teenage years.

DMD has a prevalence from 15.9 to 19.5 per 100,000 live births2, 3. A milder form of disease occurs in very few female carriers, where mild form of muscle weakness develops in 2.5-20% of affected female carriers1.

Becker muscular dystrophy (BMD) is another, milder form of muscular dystrophy caused by mutations in DMD. BMD affects older boys and young men, and it occurs in about 1 in 30,000 male births1.

Becker muscular dystrophy is clinically characterized by the following:

  • Progressive symmetric muscle weakness and atrophy with calf hypertrophy
  • In some cases quadriceps femoris weakness is the only sign of disease
  • Activity-induced cramping in some patients
  • Flexion contractures of the elbows
  • Wheelchair dependency after age 16 years
  • Preservation of neck flexor muscle strength differentiates BMD from DMD
  • The most common cause of death in BMD-affected patients is dilated cardiomyopathy and heart failure.

Mutations in the DMD gene cause both DMD and BMD. Deletions of one or more exons of DMD account for approximately 60-70% of pathogenic variants in individuals with DMD and BMD 1, 4. Duplications that lead to in-frame transcripts account for mutations in 5-10% of males with DMD and BMD 4, 5. Single nucleotide variants (single-base changes, small deletions/insertions and splice site changes) account for approximately 25-35% of pathogenic variants in males with DMD and about 10-20% of males with BMD 4, 6.

Emery-Dreifuss muscular dystrophy (EDMD) is another X-linked form of muscular dystrophy that affects young boys, characterized by the following clinical features7:

  • Slowly progressive wasting and weakness, typically of the humero-peroneal/scapulo-peroneal muscles in the early stages
  • Early contractures of the elbow flexors, achilles tendons and neck extensors resulting in limitation of neck flexion, followed by limitation of extension of the spine
  • Cardiac disease with conduction defects and arrhythmias (atrial fibrillation, dilated or hypertrophic cardiomyopathy)
  • Serum CK levels are normal or mildly increased, and muscle histopathology shows nonspecific dystrophic changes.

EDMD is caused by mutations in one of the following genes: EMD (encoding emerin), FHL1 (encoding FHL1), and LMNA, encoding lamin A and C. Mutations in EMD are responsible for ~61%8 of XL-EDMD, mutations in FHL1 for ~10%8 of XL-EDMD, and mutations in LMNA account for ~45% of autosomal dominant EDMD9.

Limb-girdle muscular dystrophy (LGMD) is a large group of childhood to early adulthood-onset diseases, mostly characterized by non-syndromic involvement of skeletal muscles. LGMD affects both men and women and has an estimates of prevalence from 1/14,500 to 1/123,000 10. LGMD includes dystrophies caused by mutations in genes encoding sarcoglycans (SGCA, SGCB, SGCG, SGCD), calpain (CAPN3), dysferilin (DYSF), and other muscle-related genes 10.

Facioscapulohumeral muscular dystrophy (FSH), also known as Landouzy-Dejerine disease, is a late childhood to early adulthood-onset muscular dystrophy that affects both men and women, causing weakness in the muscles of the face, shoulders, and upper arms. FSH occurs in about 4-10/100,000 people11.

Approximately 95% of individuals with FSHD have “contraction” mutations of the D4Z4 macrosatellite locus (within subtelomeric region of chromosome 4q35) 11. The pathologic contraction of the D4Z4 repeat region is associated with an opening of the chromatin structure at the D4Z4 locus. The remaining 5% of FSHD patients do not have contraction of the D4Z4 locus, but were shown to have loss of CpG methylation at all D4Z4 repeat arrays on chromosomes 4 and 10, resulting in FSHD type 2 11.

Myotonic dystrophy type 1 (DM1, Steinert's disease) is an inherited form of muscular dystrophy that affects both men and women, characterized by myotonia and cataracts. Estimates of the prevalence of DM1 range from 1:100,000 in some areas of Japan to 1:10,000 in Iceland, with an overall estimated worldwide prevalence of 1:20,000 12, 13.

The disease has three major subtypes:

  • Mild DM1, characterized by cataract and mild myotonia and normal life span
  • Classic DM1, characterized by myotonia, cataracts, muscle weakness and cardiac conduction abnormalities, and shortened life span
  • Congenital DM1, severe form of disease, characterized by hypotonia and severe generalized weakness at birth, often with respiratory insufficiency and early death; intellectual disability is common.

DM1 should be suspected in newborns who present with one or any of the following:

  • Hypotonia
  • Facial muscle weakness
  • Generalized weakness
  • Positional malformations including club foot
  • Respiratory insufficiency.

Clinical symptoms and the most common signs of myotonic dystrophy type 1 in adult patients include the following:

  • Muscle weakness, starting in distal regions and progressing throughout the body and head
  • Myotonia, sustained muscle contraction, most commonly grip myotonia
  • Posterior subcapsular cataracts, detectable as red/green opacities on slit lamp examination.

DM1 is caused by expansion of a CTG trinucleotide repeat in the non-coding region of DMPK. It is considered that normal alleles have 5-34 CTG repeats, while fully penetrant alleles have more than 50 CTG repeats12.

Myotonic dystrophy type 2 (DM2) is another inherited muscular dystrophy characterized by myotonia (in~90% of affected DM2 patients) and muscle weakness (~82%), and in some patients by cardiac abnormalities, cataracts, insulin-insensitive type 2 diabetes mellitus, and testicular failure14. The prevalence of DM2 appears to differ in various populations, but a higher prevalence is observed in Germany, Poland and Finland 14, 15. Expansion of the CCTG repeat localized within intron 1 of the CNBP (ZNF9) gene causes DM2. The number of CCTG repeats in expanded alleles ranges from approximately 75 to more than 11,000, with a mean of approximately 5000 repeats14.

Oculopharyngeal muscular dystrophy (OPMD) is a rare inherited muscular dystrophy characterized by swallowing difficulties and ptosis. OPMD has an adult age of onset, affecting both males and females, causing weakness in the eye muscles and throat. The estimated prevalence of OPMD is 1/100,000 in France, 1/1000 in the French-Canadian population of Quebec, and 1/600 among Bukhara Jews in Israel15.

OPMD is caused by an expansion of a “GCN” trinucleotide repeat in the first exon of PABPN1 (N represent any of the 4 nucleotides). Normal alleles contain ten GCN trinucleotide repeats, while pathogenic alleles contain 11-17 repeats.

An overview of those genes most commonly associated with muscular dystrophies is listed in the table.

Gene OMIM (Gene) Associated diseases (OMIM) Inheritance
AARS1 601065 type 2N Charcot-Marie-Tooth disease; early infantile epileptic encephalopathy 29 AD, AR
ABHD5 604780 Chanarin-Dorfman syndrome AR
ACAD9 611103 Acyl-Coa Dehydrogenase Family, Member 9, Deficiency Of AR
ACADM 607008 medium chain acyl-CoA dehydrogenase deficiency AR
ACADVL 609575 very long chain acyl-CoA dehydrogenase deficiency AR
ACTA1 102610 Myopathy, nemaline, 3; Myopathy, congenital, with fiber-type disproportion AD, AR
AGL 610860 glycogen storage disease type III AR
AGRN 103320 congenital myasthenic syndrome type 8, with pre- and postsynaptic defects AR
AHCY 180960 Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase AR
AIFM1 300169 Deafness, X-linked 5; Combined oxidative phosphorylation deficiency 6; Cowchock syndrome XLR
ALDOA 103850 Glycogen storage disease XII AR
ALG14 612866 AR
ALG2 607905 congenital disorder of glycosylation type 1i AR
AMPD1 102770 Myopathy due to myoadenylate deaminase deficiency AR
ANO5 608662 gnathodiaphyseal dysplasia; limb-girdle muscular dystrophy type 2L AD, AR
ARHGEF10 608136 slowed nerve conduction velocity AD
ARHGEF9 300429 Epileptic encephalopathy, early infantile, 8 XLR
ASAH1 613468 Spinal muscular atrophy with progressive myoclonic epilepsy; Farber lipogranulomatosis AR
ATL1 606439 spastic paraplegia 3A AD
ATP2A1 108730 Brody myopathy AR
ATP7A 300011 X-linked distal spinal muscular atrophy type 3; Occipital horn syndrome; Menkes disease XLR
B3GALNT2 610194 congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies type A11 AR
B4GAT1 605517 congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies A13 AR
BAG3 603883 Myopathy, myofibrillar, 6; dilated cardiomyopathy-1HH AD
BICD2 609797 autosomal dominant lower extremity-predominant spinal muscular atrophy type 2 AD
BIN1 601248 centronuclear myopathy AR
BSCL2 606158 Lipodystrophy, congenital generalized, type 2; spastic paraplegia 17; Neuropathy, distal hereditary motor, type V; Encephalopathy, progressive, with or without lipodystrophy AD, AR
CACNA1S 114208 hypokalemic periodic paralysis 1; Thyrotoxic periodic paralysis Type 1; Malignant hyperthermia susceptibility 5 AD
CAPN3 114240 limb-girdle muscular dystrophy type 1; limb-girdle muscular dystrophy type 4 AD, AR
CASK 300172 Fg Syndrome 4; Mental retardation and microcephaly with pontine and cerebellar hypoplasia XLD
CAV1 601047 AD, AR
CAV3 601253 Creatine phosphokinase, elevated serum; familial hypertrophic cardiomyopathy 1; Rippling muscle disease; Rippling muscle disease 2; long QT syndrome 9 AD, DiD
CCDC78 614666 Myopathy, centronuclear, 4 AD
CFL2 601443 nemaline myopathy type 7 AR
CHAT 118490 Presynaptic congenital myasthenic syndrome type 6 AR
CHCHD10 615903 Frontotemporal dementia and/or amyotrophic lateral sclerosis 2 AD
CHKB 612395 Muscular dystrophy, congenital, megaconial type AR
CHRNA1 100690 Multiple pterygium syndrome, lethal type; Myasthenic syndrome, slow-channel congenital; Myasthenic syndrome, fast-channel congenital AD, AR
CHRNB1 100710 Myasthenic syndrome, congenital, 2A, slow-channel; Myasthenic syndrome, congenital, 2C, associated with acetylcholine receptor deficiency AD, AR
CHRND 100720 Multiple pterygium syndrome, lethal type; slow-channel congenital myasthenic syndrome type 3A; Congenital fast-channel myasthenic syndrome type 3B; ?Myasthenic syndrome, congenital, 3C, associated with acetylcholine receptor deficiency AD, AR
CHRNE 100725 slow-channel congenital myasthenic syndrome type 4A; congenital myasthenic syndrome type 4C, associated with acetylcholine receptor deficiency; fast-channel congenital myasthenic syndrome type 4B AD, AR
CHRNG 100730 Multiple pterygium syndrome, lethal type; Multiple Pterygium Syndrome, Escobar Variant AR
CHST14 608429 Ehlers-Danlos syndrome musculocontractural type 1 AR
CLCN1 118425 myotonia congenita (Thomsen myotonia); myotonia congenita (Becker myotonia) AD, AR
CNTN1 600016 Myopathy, congenital, Compton-North AR
COL12A1 120320 Ullrich congenital muscular dystrophy 2; Bethlem myopathy 2 AD
COL6A1 120220 Bethlem myopathy type 1; Ullrich congenital muscular dystrophy AD, AR
COL6A2 120240 Bethlem myopathy type 1; Ullrich congenital muscular dystrophy AD, AR
COL6A3 120250 Bethlem myopathy type 1; Ullrich congenital muscular dystrophy; dystonia 27 AD, AR
COLQ 603033 congenital myasthenic syndrome type 5 AR
COQ2 609825 Multiple system atrophy, susceptibility to; Coenzyme Q10 deficiency, primary, 1 AD, AR
COX6A1 602072 intermediate type D Charcot-Marie-Tooth AR
CPT2 600650 stress-induced myopathic CPT II deficiency; infantile CPT deficiency; lethal neonatal CPT II deficiency; susceptibility to infection-induced acute encephalopathy type 4 AD, AR
CRPPA 614631 congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies type A7; congenital limb-girdle muscular dystrophy-dystroglycanopathy type C7 AR
CRYAB 123590 Myopathy, myofibrillar, 2; Cataract 16, multiple types; Myopathy, Myofibrillar, Fatal Infantile Hypertonic, Alpha-B Crystallin-Related; dilated cardiomyopathy-1II AD, AR
CSRP3 600824 dilated cardiomyopathy-1M; Cardiomyopathy, familial hypertrophic, 12 AD
CTDP1 604927 Congenital cataracts, facial dysmorphism, and neuropathy AR
DAG1 128239 congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies type C9 AR
DCTN1 601143 amyotrophic lateral sclerosis 1; Perry syndrome; Neuronopathy, Distal Hereditary Motor, Type Viib AD, AR
DES 125660 Scapuloperoneal syndrome, neurogenic, Kaeser type; Myopathy, myofibrillar, 1; dilated cardiomyopathy-1I AD, AR
DGUOK 601465 mitochondrial DNA depletion syndrome 3 AR
DHCR24 606418 Desmosterolosis AR
DHTKD1 614984 2-aminoadipic 2-oxoadipic aciduria; type 2Q Charcot-Marie-Tooth disease AD, AR
DMD 300377 Becker muscular dystrophy; dilated cardiomyopathy type 3B; Duchenne muscular dystrophy XL, XLR
DMPK 605377 myotonic dystrophy type 1 AD
DNA2 601810 Progressive external ophthalmoplegia with mitochondrial dna deletions, autosomal dominant, 6 AD, AR
DNAJB2 604139 autosomal recessive distal spinal muscular atrophy type 5 AR
DNAJB6 611332 limb-girdle muscular dystrophy type 1E AD
DNM2 602378 Myopathy, centronuclear 1; CHARCOT-MARIE-TOOTH, DOMINANT INTERMEDIATE TYPE B; Lethal congenital contracture syndrome 5 AD, AR
DNMT1 126375 cerebellar ataxia, deafness and narcolepsy; Neuropathy, hereditary sensory, type IE AD
DOK7 610285 congenital myasthenic syndrome type 10 AR
DPAGT1 191350 congenital disorder of glycosylation type 1j; Myasthenic syndrome, congenital, with tubular aggregates 13 AR
DPM1 603503 Congenital disorder of glycosylation, type Ie AR
DPM2 603564 Congenital disorder of glycosylation, type Iu AR
DPM3 605951 congenital disorder of glycosylation, type Io AR
DYNC1H1 600112 lower extremity-predominant spinal muscular atrophy type 1; type 2O Charcot-Marie-Tooth disease; mental retardation-13 AD
DYSF 603009 limb-girdle muscular dystrophy type 2B; Miyoshi muscular dystrophy type 1; distal myopathy with anterior tibial onset AR
ECEL1 605896 distal arthrogryposis type 5D AR
EGR2 129010 Dejerine-Sottas syndrom; congenital hypomyelinating neuropathy; type 1D Charcot-Marie-Tooth disease AD, AR
ELP1 603722 hereditary sensory and autonomic neuropathy type III AR
EMD 300384 Emery-Dreifuss muscular dystrophy type 1 XLR
ENO3 131370 Glycogen storage disease XIII AR
ERCC5 133530 xeroderma pigmentosum complementation group G; cerebrooculofacioskeletal syndrome type 3 AR
ERCC6 609413 Cockayne syndrome, type B; Lung Cancer; Cerebrooculofacioskeletal syndrome 1 AD, AR
ETFA 608053 multiple acyl-CoA dehydrogenase deficiency AR
ETFB 130410 multiple acyl-CoA dehydrogenase deficiency AR
ETFDH 231675 multiple acyl-CoA dehydrogenase deficiency AR
EXOSC3 606489 pontocerebellar hypoplasia type 1B AR
EXOSC8 606019 AR
FBLN5 604580 Cutis laxa, autosomal recessive, type IA; hereditary neuropathy with or without age-related macular degeneration AD, AR
FBN2 612570 congenital contractural arachnodactyly; early-onset macular degeneration AD
FBXO38 608533 distal hereditary motor neuronopathy type IID AD
FGD4 611104 type 4H Charcot-Marie-Tooth disease AR
FHL1 300163 Scapuloperoneal myopathy, X-linked dominant; Myopathy, X-linked, with postural muscle atrophy; Emery-Dreifuss muscular dystrophy 6; Myopathy, Reducing Body, X-Linked, Early-Onset, Severe; Myopathy, reducing body, X-linked, childhood-onset XL, XLD, XLR
FIG4 609390 Yunis-Varon syndrome; type 4J Charcot-Marie-Tooth disease; amyotrophic lateral sclerosis 11; Polymicrogyria, bilateral temporooccipital AD, AR
FKBP10 607063 Bruck syndrome 1; osteogenesis imperfecta type 11 AR
FKRP 606596 Muscular dystrophy-dystroglycanopathy (congenital with or without mental retardation), type B5; Muscular dystrophy-dystroglycanopathy (limb-girdle), type C5; Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5 AR
FKTN 607440 congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies type A4; congenital limb-girdle muscular dystrophy-dystroglycanopathy type C4; dilated cardiomyopathy type 1X; congenital muscular dystrophy-dystroglycanopathy without mental retardation type B4 AR
FLNC 102565 Myopathy, myofibrillar, 5; distal myopathy type 4; Cardiomyopathy, Familial Hypertrophic, 26 AD
GAA 606800 Pompe disease AR
GAN 605379 giant axonal neuropathy AR
GARS1 600287 Neuropathy, distal hereditary motor, type V; type 2D Charcot-Marie-Tooth disease AD
GBA 606463 Lewy body dementia; Susceptibility to late-onset Parkinson disease; Gaucher disease type 1; Gaucher disease type 2 (acute); Gaucher disease type 3 (subacute/ chronic); Gaucher disease, cardiovascular form; Gaucher disease, perinatal-lethal form AD, AR
GBE1 607839 storage disease type 4; Polyglucosan body disease, adult form AR
GDAP1 606598 type 4A Charcot-Marie-Tooth disease; type 2K Charcot-Marie-Tooth disease AD, AR
GFPT1 138292 congenital myasthenic syndrome with tubular aggregates type 1 AR
GJB1 304040 Charcot-Marie-Tooth disease type 1 XLD
GLE1 603371 Lethal congenital, contracture syndrome 1 AR
GLRA1 138491 Hyperekplexia, hereditary 1, autosomal dominant or recessive AD, AR
GLRB 138492 Hyperekplexia 2, autosomal recessive AR
GMPPB 615320 Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 14; Muscular dystrophy-dystroglycanopathy (congenital with mental retardation), type B, 14; Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 14 AR
GNB4 610863 intermediate type F Charcot-Marie-Tooth AD
GNE 603824 Sialuria; Nonaka myopathy AD, AR
GPHN 603930 Molybdenum cofactor deficiency, complementation group c AR
GYG1 603942 Glycogen storage disease XV; Polyglucosan body myopathy 2 AR
GYS1 138570 Glycogen storage disease 0, muscle AR
HADHA 600890 mitochondrial trifunctional protein deficiency; long-chain 3-hydroxyl-CoA dehydrogenase deficiency AR
HADHB 143450 mitochondrial trifunctional protein deficiency AR
HINT1 601314 Neuromyotonia and axonal neuropathy, autosomal recessive AR
HK1 142600 Hemolytic anemia due to hexokinase deficiency; Neuropathy, hereditary motor and sensory, Russe type; Retinitis pigmentosa 79; Neurodevelopmental disorder with visual defects and brain anomalies AD, AR
HNRNPDL 607137 limb-girdle muscular dystrophy type 1G AD
HOXD10 142984 AD
HRAS 190020 Bladder Cancer; Melanocytic nevus syndrome, congenital, somatic; Nevus, Epidermal; Schimmelpenning-Feuerstein-Mims Syndrome; Thyroid Carcinoma, Follicular; Costello syndrome AD
HSPB1 602195 type 2F Charcot-Marie-Tooth disease; Neuropathy, distal hereditary motor, type IIB AD
HSPB3 604624 Neuronopathy, distal hereditary motor, type iic AD
HSPB8 608014 Neuropathy, distal hereditary motor, type IIA; type 2L Charcot-Marie-Tooth disease AD
HSPG2 142461 Silverman-Handmaker type of dyssegmental dysplasia; Schwartz-Jampel syndrome AR
IGHMBP2 600502 distal hereditary motor neuronopathy type VI; type 2S Charcot-Marie-Tooth disease AR
INF2 610982 Focal Segmental Glomerulosclerosis 5; intermediate type E Charcot-Marie-Tooth AD
ISCU 611911 AR
ITGA7 600536 Muscular dystrophy, congenital, due to ITGA7 deficiency AR
KARS1 601421 CHARCOT-MARIE-TOOTH, RECESSIVE INTERMEDIATE TYPE B; Deafness, autosomal recessive 89 AR
KAT6B 605880 Ohdo syndrome, SBBYS variant; Genitopatellar syndrome AD
KBTBD13 613727 Nemaline Myopathy 6 AD
KCNA1 176260 Episodic ataxia/myokymia syndrome AD
KCNE3 604433 Brugada syndrome 6
KIF1A 601255 spastic paraplegia 30; Neuropathy, hereditary sensory, type IIC; MENTAL RETARDATION, AUTOSOMAL DOMINANT 9 AD, AR
KIF1B 605995 type 2A1 Charcot-Marie-Tooth disease; pheochromocytoma AD
KIF5A 602821 spastic paraplegia 10; Neonatal intractable myoclonus AD
KLHL40 615340 Nemaline myopathy 8, autosomal recessive AR
KLHL41 607701 Nemaline myopathy 9 AR
LAMA2 156225 congenital muscular dystrophy type 1A; limb-girdle Muscular dystrophy type 23 AR
LAMB2 150325 Pierson syndrome; Nephrotic syndrome, type 5, with or without ocular abnormalities AR
LAMP2 309060 Danon disease XLD
LARGE1 603590 congenital muscular dystrophy-dystroglycanopathy with mental retardation type B6; congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies type A6 AR
LDB3 605906 dilated cardiomyopathy-1C; Myopathy, myofibrillar, 4 AD
LDHA 150000 Glycogen storage disease XI AR
LIMS2 607908 limb-girdle muscular dystrophy type 2W AR
LITAF 603795 type 1C Charcot-Marie-Tooth disease AD
LMNA 150330 dilated cardiomyopathy-1A; Lipodystrophy, familial partial, 2; Hutchinson-Gilford progeria; limb-girdle muscular dystrophy type 1B; Emery-Dreifuss muscular dystrophy 2; Malouf syndrome; Mandibuloacral dysplasia; Restrictive dermopathy, lethal; type 2B1 Charcot-Marie-Tooth disease; Heart-hand syndrome, Slovenian type; Muscular dystrophy, congenital; Emery-Dreifuss muscular dystrophy 3, AR AD, AR
LMOD3 616112 Nemaline myopathy 10 AR
LPIN1 605518 Myoglobinuria, acute recurrent, autosomal recessive AR
LRSAM1 610933 type 2P Charcot-Marie-Tooth disease AD, AR
MAGEL2 605283 Schaaf-Yang syndrome AD
MAMLD1 300120 Hypospadias 2, X-linked XLR
MARS1 156560 Interstitial lung and liver disease; type 2U Charcot-Marie-Tooth disease AD, AR
MATR3 164015 Myopathy, Distal, 2 AD
MED25 610197 Basel-Vanagait-Smirin-Yosef syndrome AR
MEGF10 612453 Myopathy, areflexia, respiratory distress, and dysphagia, early-onset AR
MFN2 608507 hereditary motor and sensory neuropathy type VIA with optic atrophy; axonal Charcot-Marie-Tooth disease type 2A2A; axonal Charcot-Marie-Tooth disease type 2A2B AD, AR
MICU1 605084 Myopathy with extrapyramidal signs AR
MPV17 137960 mitochondrial DNA depletion syndrome type 6 AR
MPZ 159440 type 1B Charcot-Marie-Tooth disease; Dejerine-Sottas syndrom; type 2I Charcot-Marie-Tooth disease; type 2J Charcot-Marie-Tooth disease AD, AR
MTM1 300415 X-linked myotubular myopathy XLR
MTMR14 611089 Myopathy, centronuclear 1 AD
MTMR2 603557 type 4B1 Charcot-Marie-Tooth disease AR
MUSK 601296 Fetal akinesia deformation sequence; myasthenic syndrome, congenital type 9, associated with acetylcholine receptor deficiency AR
MYBPC1 160794 Arthrogryposis, distal, type 1B; Lethal congenital contracture syndrome 4 AD, AR
MYBPC3 600958 familial hypertrophic cardiomyopathy 4; dilated cardiomyopathy-1MM AD, AR
MYH2 160740 Inclusion body myopathy 3, autosomal dominant AD, AR
MYH3 160720 distal arthrogryposis type 2A; Distal arthrogryposis type 2B3 (Sheldon-Hall) AD, AR
MYH7 160760 Liang distal myopathy; Scapuloperoneal syndrome, myopathic type; familial hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myopathy, myosin storage, autosomal dominant; dilated cardiomyopathy-1S AD, AR, DiD
MYH8 160741 distal arthrogryposis type 7; Carney complex variant AD
MYO18B 607295 Klippel-Feil syndrome 4, autosomal recessive, with myopathy and facial dysmorphism AR
MYOT 604103 Myopathy, spheroid body; Myopathy, myofibrillar, 3; limb-girdle muscular dystrophy type 1A AD
MYPN 608517 dilated cardiomyopathy-1KK; Autosomal recessive Nemaline myopathy type 11 AD, AR
NALCN 611549 Hypotonia, infantile, with psychomotor retardation and characteristic facies; Congenital contractures of the limbs and face, hypotonia, and developmental delay AD, AR
NDRG1 605262 type 4D Charcot-Marie-Tooth disease AR
NEB 161650 nemaline myopathy type 2 AR
NTRK1 191315 hereditary sensory and autonomic neuropathy type 4 AR
OPA1 605290 Optic atrophy plus syndrome; optic atrophy type 1; Behr syndrome; Glaucoma, normal tension, susceptibility to; Mitochondrial DNA depletion syndrome 14 AD, AR
OPA3 606580 Optic atrophy type 3 with cataract; 3-methylglutaconic aciduria type III AD, AR
PDK3 300906 type X6 Charcot-Marie-Tooth XLD
PFKM 610681 Glycogen storage disease type VII AR
PGAM2 612931 Glycogen storage disease X AR
PGK1 311800 Phosphoglycerate kinase 1 deficiency XLR
PGM1 171900 congenital disorder of glycosylation type 1t AR
PHKA1 311870 Muscle glycogenosis XLR
PIEZO2 613629 Arthrogryposis, distal, type 5; Marden-Walker syndrome; Arthrogryposis, distal, with impaired proprioception and touch AD, AR
PLEC 601282 epidermolysis bullosa simplex, Ogna type; epidermolysis bullosa simplex with muscular dystrophy; epidermolysis bullosa simplex with pyloric atresia; limb-girdle muscular dystrophy type 2Q AD, AR
PLEKHG5 611101 autosomal recessive distal spinal muscular atrophy type 4; recessive intermediate Charcot-Marie-Tooth disease type C AR
PLOD2 601865 Bruck syndrome 2 AR
PMM2 601785 congenital disorder of glycosylation type 1a AR
PMP22 601097 type 1A Charcot-Marie-Tooth disease; Dejerine-Sottas syndrom; Neuropathy, recurrent, with pressure palsies ?AD, AD, AR
PNPLA2 609059 Neutral lipid storage disease with myopathy AR
POLG 174763 progressive external ophthalmoplegia; mitochondrial DNA depletion syndrome type 4A; autosomal recessive progressive external ophthalmoplegia; sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome; mitochondrial DNA depletion syndrome type 4B AD, AR
POLG2 604983 Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4 AD, AR
POMGNT1 606822 congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies type A3; congenital muscular dystrophy-dystroglycanopathy with mental retardation type B3; congenital limb-girdle muscular dystrophy-dystroglycanopathy type C3; retinitis pigmentosa type 76 AR
POMGNT2 614828 congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies type A8 AR
POMK 615247 congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies A12; congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies type C12 AR
POMT1 607423 congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies type A1; congenital limb-girdle muscular dystrophy-dystroglycanopathy type C1; congenital muscular dystrophy-dystroglycanopathy with mental retardation type B1 AR
POMT2 607439 congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies type A2; congenital muscular dystrophy-dystroglycanopathy with mental retardation type B2; congenital limb-girdle muscular dystrophy-dystroglycanopathy type C2 AR
PREPL 609557 congenital myasthenic syndrome type 22 AR
PRKAG2 602743 Wolff-Parkinson-White syndrome; fatal congenital hypertrophic cardiomyopathy due to glycogen storage disease; familial hypertrophic cardiomyopathy 6 AD
PRPS1 311850 Phosphoribosylpyrophosphate synthetase superactivity; Arts syndrome; deafness type 1; type X5 Charcot-Marie-Tooth XL, XLR
PRX 605725 Dejerine-Sottas syndrom; type 4F Charcot-Marie-Tooth disease AD, AR
PYGM 608455 glycogen storage disease type 5 AR
QARS1 603727 Microcephaly, progressive, seizures, and cerebral and cerebellar atrophy AR
RAB7A 602298 type 2B Charcot-Marie-Tooth disease AD
RAPSN 601592 congenital myasthenic syndrome, type 11, associated with acetylcholine receptor deficiency AR
RBCK1 610924 Polyglucosan body myopathy 1 with or without immunodeficiency AR
REEP1 609139 spastic paraplegia 31; Neuronopathy, distal hereditary motor, type VB AD
RETREG1 613114 hereditary sensory and autonomic neuropathy type IIB AR
RRM2B 604712 mitochondrial DNA depletion syndrome 8A; progressive external ophthalmoplegia with mitochondrial DNA deletions 5 AD, AR
RXYLT1 605862 congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies A10 AR
RYR1 180901 central core disease; malignant hyperthermia; minicore myopathy with external ophthalmoplegia AD, AR
SBF1 603560 type 4B3 Charcot-Marie-Tooth disease AR
SBF2 607697 type 4B2 Charcot-Marie-Tooth disease AR
SCN4A 603967 Paramyotonia congenita; Hyperkalemic periodic paralysis, type 2; Atypical myotonia congenita, acetazolamide-responsive; Hypokalemic periodic paralysis, type 2; Myasthenic syndrome, acetazolamide-responsive AD, AR
SELENON 606210 Myopathy, congenital, with fiber-type disproportion; rigid spine syndrome AD, AR
SGCA 600119 limb-girdle Muscular dystrophy type 3 AR
SGCB 600900 limb-girdle muscular dystrophy type 2E AR
SGCD 601411 limb-girdle muscular dystrophy type 2F; dilated cardiomyopathy-1L AR
SGCE 604149 myoclonus-dystonia AD
SGCG 608896 limb-girdle muscular dystrophy type 2C AR
SH3TC2 608206 type 4C Charcot-Marie-Tooth disease; Mononeuropathy of the median nerve, mild AD, AR
SIL1 608005 Marinesco-Sjogren syndrome AR
SLC12A6 604878 Agenesis of the corpus callosum with peripheral neuropathy AR
SLC16A1 600682 Monocarboxylate transporter 1 deficiency AD, AR
SLC22A5 603377 systemic primary carnitine deficiency AR
SLC25A1 190315 Combined D-2- and L-2-hydroxyglutaric aciduria AR
SLC25A20 613698 Carnitine-acylcarnitine translocase deficiency AR
SLC25A46 610826 Neuropathy, hereditary motor and sensory, type VIB AR
SLC5A7 608761 Neuronopathy, distal hereditary motor, type VIIA; Myasthenic syndrome, congenital, 20, presynaptic AD, AR
SLC6A5 604159 Hyperekplexia 3 AD, AR
SMCHD1 614982 Fascioscapulohumeral muscular dystrophy 2, digenic AD
SMN1 600354 spinal muscular atrophy type 1; spinal muscular atrophy type 3; spinal muscular atrophy type 2; spinal muscular atrophy type 4 AR
SMN2 601627 spinal muscular atrophy type 3 AR
SPEG 615950 centronuclear myopathy type 5 AR
SPG11 610844 Amyotrophic lateral sclerosis 5, juvenile; spastic paraplegia type 11; Charcot-Marie-Tooth disease, axonal, type 2X AR
SPTLC1 605712 Neuropathy, hereditary sensory and autonomic, type IA AD
SPTLC2 605713 Neuropathy, hereditary sensory and autonomic, type ic AD
SUCLA2 603921 mitochondrial DNA depletion syndrome 5 AR
SYNE1 608441 autosomal recessive spinocerebellar ataxia 8; Emery-Dreifuss muscular dystrophy 4 AD, AR
SYNE2 608442 Emery-Dreifuss muscular dystrophy 5 AD
TAZ 300394 Barth syndrome XLR
TCAP 604488 limb-girdle muscular dystrophy type 2G; cardiomyopathy, familial hypertrophic, 25 AD, AR
TFG 602498 Hereditary motor and sensory neuropathy, Okinawa type; spastic paraplegia 57 AD, AR
TGFB3 190230 Arrhythmogenic right ventricular dysplasia 1; Loeys-Dietz syndrome 5 AD
TK2 188250 mitochondrial DNA depletion syndrome 2 AR
TMEM43 612048 arrhythmogenic right ventricular dysplasia 5 AD
TNNI2 191043 distal arthrogryposis type 2B AD
TNNT1 191041 Nemaline myopathy 5, Amish type AR
TNNT3 600692 AD
TNPO3 610032 limb-girdle muscular dystrophy type 1F AD
TOR1A 605204 dystonia 1 AD
TPM2 190990 Nemaline myopathy type 4, autosomal dominant AD
TPM3 191030 Myopathy, congenital, with fiber-type disproportion; Nemaline myopathy 1, autosomal dominant or recessive AD, AR
TRAPPC11 614138 limb-girdle muscular dystrophy type 2S AR
TRIM2 614141 type 2R Charcot-Marie-Tooth disease AR
TRIM32 602290 limb-girdle muscular dystrophy type 2H; Bardet-Biedl syndrome 11 AR
TRPV4 605427 Brachyolmia type 3; Metatropic dysplasia; Spondylometaphyseal dysplasia, Kozlowski type; Hereditary motor and sensory neuropathy, type IIc AD
TSEN2 608753 pontocerebellar hypoplasia type 2B AR
TSFM 604723 Combined oxidative phosphorylation deficiency 3 AR
TTN 188840 Tibial muscular dystrophy, tardive; Hereditary myopathy with early respiratory failure; dilated cardiomyopathy type 1G; limb-girdle muscular dystrophy type 2J; early-onset myopathy with fatal cardiomyopathy; familial hypertrophic cardiomyopathy type 9 AD, AR
TWNK 606075 Mitochondrial DNA depletion syndrome 7 (hepatocerebral type); Progressive external ophthalmoplegia, autosomal dominant, 3 AD, AR
TYMP 131222 mitochondrial DNA depletion syndrome 1 AR
UBA1 314370 X-linked infantile spinal muscular atrophy type 2 XLR
VAMP1 185880 Spastic ataxia 1, autosomal dominant; Myasthenic syndrome, congenital, 25 AD, AR
VAPB 605704 Finkel type late-onset spinal muscular atrophy; amyotrophic lateral sclerosis 8 AD
VCP 601023 inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 1; amyotrophic lateral sclerosis 14; Charcot-Marie-Tooth disease type 2Y AD
VIPAS39 613401 Arthrogryposis, renal dysfunction, and cholestasis 2 AR
VRK1 602168 pontocerebellar hypoplasia type 1A AR
WNK1 605232 Neuropathy, hereditary sensory and autonomic, type II; Pseudohypoaldosteronism, type IIC AD, AR
XK 314850 Mcleod syndrome XL
YARS1 603623 intermediate type C Charcot-Marie-Tooth AD

Differential diagnosis

The differential diagnosis of muscular dystrophy-related disorders – depending on the major symptoms in the initial case – includes the following diseases:

  • Emery-Dreifuss Muscular Dystrophy
  • Metabolic Myopathies
  • Spinal Muscular Atrophy
  • Congenital Myopathies
  • Dystrophinopathies.

Testing strategy

CENTOGENE offers an advanced, fast and cost-effective strategy to test large NGS panels and diagnose complex phenotypes based on PCR-free whole genome sequencing and NGS technology. This approach offers an unparalleled advantage by reducing amplification/capture biases and providing sequencing of the entire gene with more uniform coverage.

To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for muscular dystrophy using NGS Panel Genomic targeted towards this specific phenotype:

Step 1: Whole genome sequencing from a single filter card. The sequencing covers the entire gene (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the Muscular dystrophy panel. Copy Number Variants analysis derived from NGS data is also included.

Step 2: If no mutation is identified after analysis of the Muscular dystrophy panel, we further recommend continuing the bioinformatics analysis of the data using whole genome sequencing to cover those genes which are either implicated in an overlapping phenotype or could be involved in a similar pathway but are not strongly clinically implicated based on the current information in literature.

Referral reasons

The following individuals are candidates for muscular dystrophy testing:

  • Individuals with a family history of muscular dystrophy and presentation of the most common symptoms
  • Individuals without a positive family history of muscular dystrophy, but with symptoms resembling the disease
  • Individuals with a negative but suspected family history of muscular dystrophy, in order to perform proper genetic counseling.

Test utility

Sequencing, deletion/duplication of the muscular dystrophy panel genes should be performed in all individuals suspected of having muscular dystrophy and suspected phenotypes. In parallel, other genes reported to be related with this clinical phenotype should also be analyzed for the presence of mutations, due to the overlap in many clinical features caused by those particular genes.

Confirmation of a clinical diagnosis through genetic testing can allow for genetic counseling and may direct medical management. Genetic counseling can provide a patient and/or family with the natural history of the muscular dystrophy and related disorders identify at-risk family members, provide disease risks as well as appropriate referral for patient support and/or resources.