Inherited neuromuscular disorders, not detectable with whole exome sequencing techniques
Inherited neuromuscular disorders are a heterogenous group of disorders affecting peripheral nervous system and muscle tissue and are caused by nuclear or mitochondrial genome abnormality.
Genetic testing play an important role in the diagnosis and management of inherited neuromuscular disorders and has supplanted the muscle biopsy in many conditions as a non-invasive and accurate diagnostic tool.
Different techniques of genetic testing are available with different indications based on the most probable clinical diagnosis based on the patient’s phenotype.
In this article we will review gene-disease correlation in both nuclear and mitochondrial genome in genetic disorders that are not detectable with whole exome sequencing techniques; including repeat expansion disorders, deletion/duplication associated disorders and mitochondrial DNA associated disorders.
Inherited neuromuscular disorders associated with repeat expansion
| AR | Kennedy disease |
| ATN1 | Dentatorubral-pallidoluysian atrophy |
| ATXN1 | Spinocerebellar ataxia type 1 |
| ATXN10 | Spinocerebellar ataxia type 10 |
| ATXN2 | Spinocerebellar ataxia type 2 |
| ATXN3 | Machado-Joseph disease |
| ATXN7 | Spinocerebellar ataxia type 7 |
| ATXN8 | Spinocerebellar ataxia type 8 |
| ATXN8OS | Spinocerebellar ataxia type 8 |
| BEAN1 | Spinocerebellar ataxia type 31 |
| C9orf72 | Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 |
| CACNA1A | Spinocerebellar ataxia type 6 |
| CNBP | Myotonic dystrophy type 2 (proximal myotonic myopathy) |
| DAB1 | Spinocerebellar ataxia type 37 |
| DMPK | Congenital myotonic dystrophy
Myotonic dystrophy type 1 |
| FXN | Friedreich ataxia with retained reflexes
Friedreich ataxia |
| LRP12 | Oculopharyngodistal myopathy 1 |
| NOP56 | Spinocerebellar ataxia type 36 |
| NOTCH2NLC | Oculopharyngodistal myopathy 3
Neuronal intranuclear inclusion disease |
| NUTM2B-AS1 | Oculopharyngeal myopathy with leukoencephalopathy 1 |
| PABPN1 | Oculopharyngeal muscular dystrophy |
| PPP2R2B | Spinocerebellar ataxia type 12 |
| RFC1 | Cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome |
| TBP | Spinocerebellar ataxia type 17 |
Inherited neuromuscular disorders associated with deletion/duplication
| DMD (deletion) | Intermediate Duchenne muscular dystrophy
Becker muscular dystrophy Duchenne muscular dystrophy Familial isolated dilated cardiomyopathy Symptomatic DMD female carriers |
| PMP22 (deletion) | Hereditary neuropathy with liability to pressure palsies |
| SMN1 (deletion) | Spinal muscular atrophy type 1 (Werdnig-Hoffman)
Spinal muscular atrophy type 2 (intermediate) Spinal muscular atrophy type 3 (Kugelberg-Welander) Spinal muscular atrophy type 4, adult form |
| D4Z4 contraction | Facioscapulohumeral muscular dystrophy type 1 |
| PMP22 (duplication) | Charcot-Marie-Tooth disease type 1A |
Inherited neuromuscular disorders associated with mitochondrial DNA mutation or deletion
| MT-ATP6 (mtDNA mutation) | Familial isolated hypertrophic cardiomyopathy
Isolated ATP synthase deficiency Mitochondrial DNA-associated Leigh syndrome MT-ATP6-related mitochondrial spastic paraplegia NARP syndrome Periodic paralysis with later-onset distal motor neuropathy |
| MT-ATP8 (mtDNA mutation) | Isolated ATP synthase deficiency
Periodic paralysis with later-onset distal motor neuropathy |
| MT-CO1 (mtDNA mutation) | Genetic recurrent myoglobinuria
Isolated cytochrome C oxidase deficiency MELAS |
| MT-CO2 (mtDNA mutation) | Isolated cytochrome C oxidase deficiency
MELAS |
| MT-CO3 (mtDNA mutation) | Genetic recurrent myoglobinuria
Isolated cytochrome C oxidase deficiency MELAS |
| MT-CYB (mtDNA mutation) | Isolated complex III deficiency |
| MT-ND1 (mtDNA mutation) | Isolated complex I deficiency
MELAS Mitochondrial DNA-associated Leigh syndrome |
| MT-ND2 (mtDNA mutation) | Isolated complex I deficiency
Mitochondrial DNA-associated Leigh syndrome |
| MT-ND3 (mtDNA mutation) | Isolated complex I deficiency
Leber plus disease Mitochondrial DNA-associated Leigh syndrome |
| MT-ND4 (mtDNA mutation) | Leber plus disease
MELAS Mitochondrial DNA-associated Leigh syndrome |
| MT-ND5 (mtDNA mutation) | MELAS
MERRF Mitochondrial DNA-associated Leigh syndrome |
| MT-ND6 (mtDNA mutation) | Leber plus disease
MELAS Mitochondrial DNA-associated Leigh syndrome |
| MT-RNR1 (mtDNA mutation) | MERRF |
| MT-TE (mtDNA mutation) | Mitochondrial myopathy with reversible cytochrome C oxidase deficiency
Myopathy and diabetes mellitus |
| MT-TF (mtDNA mutation) | MELAS
MERRF |
| MT-TH (mtDNA mutation) | Familial isolated hypertrophic cardiomyopathy
MELAS MERRF |
| MT-TI (mtDNA mutation) | Familial isolated hypertrophic cardiomyopathy |
| MT-TK (mtDNA mutation) | MERRF
Mitochondrial DNA-associated Leigh syndrome |
| MT-TL1 (mtDNA mutation) | MELAS
MERRF Mitochondrial DNA-associated Leigh syndrome |
| MT-TP (mtDNA mutation) | MERRF |
| MT-TQ (mtDNA mutation) | MELAS
MERRF |
| MT-TS1 (mtDNA mutation) | MELAS
MERRF |
| MT-TS2 (mtDNA mutation) | MELAS
MERRF |
| MT-TT (mtDNA mutation) | Lethal infantile mitochondrial myopathy |
| MT-TV (mtDNA mutation) | Mitochondrial DNA-associated Leigh syndrome |
| MT-TW (mtDNA mutation) | MELAS
Mitochondrial DNA-associated Leigh syndrome |
| MT-ATP8 (mtDNA deletion) | Kearns-Sayre syndrome |
| MT-TL1 (mtDNA deletion) | Kearns-Sayre syndrome
Mitochondrial DNA-related progressive external ophthalmoplegia |
| MT-TL2 (mtDNA deletion) | Mitochondrial DNA-related progressive external ophthalmoplegia |
| MT-TN (mtDNA deletion) | Mitochondrial DNA-related progressive external ophthalmoplegia |
| MT-TS1 (mtDNA deletion) | Mitochondrial DNA-related progressive external ophthalmoplegia |