TABLE 3.
Pathogenic Mitochondrial DNA Variants of Undetermined Clinical Relevance in the 11,424 Exomes Analyzed
| Subject | Age, yr /sex | mtDNA variant | Gene | No. ref reads | No. alt reads | Het (%) | Reported associated disease 9 | Subject phenotype/ investigations |
|---|---|---|---|---|---|---|---|---|
| 12 | 77/F | m.3243A>G | MT‐TL1 | 0 | 17 | 98 | MELAS/LS/DMDF/MIDD/SNHL/CPEO/MM/FSGS/ASD/cardiac + multi‐organ dysfunction |
IBM diagnosed 2012 Onset of symptoms aged 40 yr with grasp and proximal lower limb weakness Muscle biopsy; endomysial inflammatory cell infiltrate with invasion of non‐necrotic muscle fibers, fibers with rimmed vacuoles, ragged red and COX negative fibers |
| 13 | NA | m.3243A>G | MT‐TL1 | 10 | 4 | 29 | MELAS/LS/DMDF/MIDD/SNHL/CPEO/MM/FSGS/ASD/Cardiac and multi‐organ dysfunction | Adult subject with brain calcifications, no family history |
| 14 | 3/f | m.3260A>G | MT‐TL1 | 7 | 16 | 68 | MMC/MELAS |
Hypotonia since birth, severe intellectual disability, stereotyped hand movements, choreic movements, dystonic postures, anarthria MRI; thin corpus callosum with delayed myelination Confirmed heterozygous VAMP2 mutation |
| 15 | NA | m.3271T>C | MT‐TL1 | 51 | 20 | 30 | MELAS/DM | MSA; pathologically confirmed |
| 16 | NA | m.7497G>A | MT‐TS1 | 32 | 26 | 45 | MM/EXIT | MSA; pathologically confirmed |
| 17 | NA | m.8344A>G | MT‐TK | 54 | 107 | 65 | MERRF; Other ‐ LS/depressive mood disorder/Leukoencephalopathy/HCM | MSA; pathologically confirmed |
| 18 | NA | m.8851T>C | MT‐ATP6 | 22 | 5 | 21 | BSN/LS | Unaffected subject |
| 19 | NA | m.8993T>G | MT‐ATP6 | 20 | 28 | 58 | NARP/Leigh Disease/MILS/Other | PD |
| 20 | NA | m.9176T>C | MT‐ATP6 | 17 | 15 | 47 | FBSN/Leigh disease | Unaffected subject |
| 21 | NA | m.9185T>C | MT‐ATP6 | 16 | 5 | 25 | Leigh disease/Ataxia syndromes/NARP‐like disease | Extrapyramidal disorder |
| 22 | NA | m.11778G>A | MT‐ND4 | 4 | 11 | 73 | LHON/progressive dystonia | PD |
| 23 | 21/m | m.13513G>A | MT‐ND5 | 69 | 27 | 28 | Leigh disease/MELAS/LHON‐MELAS overlap syndrome | Cyclic vomiting syndrome |
ASD = autistic spectrum disorder; BSN = bilateral striatal necrosis; CPEO = chronic progressive external ophthalmoplegia; DM = diabetes mellitus; DMDF = diabetes deafness; EXIT = exercise intolerance; FBSN = familial bilateral striatal necrosis; FSGS = focal segmental glomerulosclerosis; HCM = hypertrophic cardiomyopathy; Het = heteroplasmy; IBM = inclusion body myositis; LHON = Leber hereditary optic neuropathy; LDYT = LHON and dystonia; LS = Leigh syndrome; MELAS = mitochondrial encephalomyopathy with lactic acidosis and stroke‐like episodes; MERRF = Myoclonic epilepsy with ragged‐red fibers; MIDD = Maternally inherited diabetes and deafness; MILS = maternally inherited Leigh syndrome; MM = mitochondrial myopathy; MMC = maternal myopathy and cardiomyopathy; MSA = multi‐system atrophy; mtDNA = mitochondrial DNA; NA = not available; NARP = neurogenic muscle weakness, ataxia, and retinitis pigmentosa; No. = number; PD = Parkinson's disease; SNHL = sensorineural hearing loss.