Table 1.
Summary of clinical features of patients with mtDNA or/and nDNA variants.
| Patient | Gender | Gene | Inheritance pattern | Variant | Zygosity | Origin | Age of onset (years) | Lactate (mmol/L) | MRI | Clinical features | ACMG | Evidence | Final clinical diagnosis | Novel mutation |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| nDNA | ||||||||||||||
| n6 | F | HIBCH | AR | c.1118A > G (p.N373S); c.810-4A > G | com.het | parental | 10.2 | 8.57 | Normal | Psychological and behavioral disorder | VUS/VUS | PM2 + PP3/PM2 + PP3 | Behavioral abnormality | Y/Y |
| n10 | M | PANK2 | AR | c.1355A > G (p.D452G) | hom | parental | 1 | 3.38 | Basal ganglia involvement | DD, ataxia, retinitis pigmentosa | VUS | PS1 + PP4 | Pantothenate kinase-associated neurodegeneration | N |
| n14 | F | AARS2 | AR | c.2682 + 5G > A; c.331G > C (p.A111P) | com.het | parental | 1 | 2.9 | Normal | Seizure, myoclonus, developmental delay, ataxia | VUS/VUS | PM2 + PP3/PM2 + PP3 | Epileptic encephalopathy | N/N |
| n22 | F | GFM1 | AR | c.2167 T > C (p.C723R); c.539delG (p.G180Afs*11) | com.het | parental | 7 | 5.83 | Basal ganglia involvement | Muscle weakness, dystonia | VUS/P | PM2 + PM3 + PP4/PVS1 + PS1 + PM2 | Leigh syndrome | Y/N |
| n26 | M | AIFM1 | XLR | c.1084A > C (p.K362Q) | hem | maternal | at birth | 9.39 | Thin corpus callosum | DD, hypertonia, microcephaly | VUS | PM2 + PP2 | GDD | Y |
| n33 | F | HSD17B10 | XLD | c.628C > G (p.P210A) | het | de novo | at birth | 10.22 | Normal | DD | LP | PS2 + PM2 + PP3 | HSD10 mitochondrial disease | Y |
| n20 | M | CARS2 | AR | c.323 T > G (p.F108C); c.1036C > T (p.R346W) | com.het | parental | 2 | 2.74 | Cortical atrophy | Seizure, psychological and behavioral disorder | VUS/VUS | PM2 + PP3/PM2 + PP3 | Epileptic encephalopathy | Y/Y |
| n54 | M | HIBCH | AR | c.958A > G (p.K320E); c.439-2A > G | com.het | parental | 1.5 | 6.3 | Basal ganglia involvement | Developmental regression, myoclonus, feeding difficulties | VUS/LP | PM2_P + PP3/ PVS1_M + PM3 + PP3 | 3-hydroxyisobutryl-CoA hydrolase deficiency | Y/Y |
| n59 | F | POLG | AR | c.2890C > T (p.R964C); c.2584G > A (p.A862T) | com.het | parental | 13 | 2.74 | Cortical abnormalities | Seizure, tremer, liver disorder | VUS/VUS | PM3 + PM2_P + PP3/ PM3 + PM2_P + PP3 | Alpers syndrome | N/N |
| n62 | M | COQ4 | AR | c.550 T > C (p.W184R); c.743 T > C (p.L248P) | com.het | parental | 2 | 3.31 | Basal ganglia involvement | DD, hypertonia, feeding difficulties | VUS/VUS | PM3 + PM2_P_PP3/PM2_P + PP3 | Primary coenzyme Q10 deficiency | Y/Y |
| n89 | F | OPA3 | AR | c.123C > G (p.I41M) | hom | parental | 1 | 1.23 | Cerebellar atrophy | DD, seizure, ataxia | VUS | PM2_P + PP3 | DD, seizure, ataxia | N |
| n98 | F | GTPBP3 | AR | c.187C > T (p.R63*); c.776A > G (p.N259S) | com.het | parental | at birth | 6.94 | Bilateral thalamus and left cortical involvement | DD, seizure | P/VUS | PVS1 + PM2.PP3/PM2 + PM3 + PP3 | Combined oxidative phosphorylation deficiency 23 | N/N |
| n108 | F | PDHA1 | XLD | c.901C > G(p.R301G) | het | de novo | 0.5 | 3 | Basal ganglia involvement | Muscle weakness | P | PS3 + PM2_P + PP3 + PP1_S | Pyruvate dehydrogenase E1-alpha deficiency | Y |
| n111 | M | WARS2 | AR | c.751 T > C (p.F251L) | hom | parental | 1 | 4.68 | Na | DD, seizure, tic disorder, ataxia, liver disorder | VUS | PM2_P + PP3 | NEMMLAS | Y |
| n115 | M | LIPT1 | AR | c.302G > A (p.S101N); c.316G > A (p.V106I) | com.het | parental | 4.6 | 1.5 | Involvement of brainstem and thalamus | DD, gastrointestinal disorder | VUS/VUS | PM2_P + PP3/ PM2_P + PP3 | Lipoyltransferase 1 deficiency | Y |
| n116 | M | ACAD9 | AR | c.1693-1G > A; c.1237G > A (p.E413K) | com.het | parental | 0.3 | 1.9 | Normal | Cardiovascular disorder, respiratory distress | VUS/LP | PVS1_M + PM2_P/PS3 + PM3 + PM2_P + PP3 | Mitochondrial complex I deficiency | Y |
| n126 | F | PDHB | AR | c.97-3C > G | hom | parental | 2 | 8.67 | White matter abnormalities | Ptosis, DD, seizure | VUS | PM2_P + PP3 | Pyruvate dehydrogenase E1-beta deficiency | Y |
| n129 | F | DNM1L | AD | c.1207C > T (p.R403C) | het | de novo | 4.4 | 3.3 | Involvement of brainstem and thalamus | Seizure, seizure status, coma | P | PS3 + PS2_M + PM2_P + PP1_M + PP3 | Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1 | N |
| n130 | M | NAXE | AR | c.473G > C (p.C158S); c.490C > A (p.P164T) | com.het | parental | 2 | Na | White matter abnormalities | DD, seizure | VUS/VUS | PM2_P + PP3/ PM2_P + PP3 | Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy | Y |
| n155 | M | POLG | AR | c.2890C > T (p.R964C); c.2584G > A (p.A862T) | com.het | parental | 5 | Na | Cortical abnormalities | Seizure, muscle weakness, headache | VUS/VUS | PM3 + PM2_P + PP3/ PM3 + PM2_P + PP3 | Alpers syndrome | Y |
| n167 | M | GTPBP3 | AR | c.413C > T (p.A138V); c.509_510delAG (p.E170Gfs*42) | com. het | parental | at birth | 26 | Na | respiratory failure | VUS/LP | PM3 + PM2_P + PP3/ PVS1 + PM2_P | Combined oxidative phosphorylation deficiency 23 | Y |
| n179 | M | ETFDH | AR | c.886G > T (p.G296C); c.1773_1774delAT (p.C592*) | com.het | parental | 0.5 | 2 | Normal | Muscle weakness, gastrointestinal disorder, impaired vision | VUS/VUS | PM2_P + PP3/ PVS1_M + PM2_P | Multiple acyl-CoA dehydrogenase deficiency |
N/ N |
| n180 | M | NDUFAF5 | AR | c.752 T > G (p.M251R); c.155A > C (p.K52T) | com.het | parental | 0.6 | 4.61 | White matter abnormalities | Developmental regression | LP/LP | PM3_S + PM2_P + PP3/ PM3_S + PM2_P + PP3 | Cavitating Leukoencephalopathy | N |
| 2n4 | M | ETFDH | AR | c.250G > A (p.A84T); c.2 T > G (p.M1?) | com.het | parental | 0.5 | Na | Na | Muscle weakness, liver disorder, gastrointestinal disorder | LP/VUS | PS3 + PM2 + PP3 + PPM2 + PP3 | Combined oxidative phosphorylation deficiency 23 | N/N |
| 2n5 | M | TWNK | AD | c.1421G > C (p.W474S) | het | maternal | at birth | 5 | Na | Ptosis | LP | PM2_P + PP3 + PM5 + PM6 | Congenital myasthenic syndrome | Y |
| CHRNB1 | AD | c.1394 T > C (p.M465T) | het | maternal | VUS | - | Y | |||||||
| mtDNA | ||||||||||||||
| m1 | M | MT-TL1 | maternal | m.3243A > G (71.2%) | 71.20% | maternal (23.6%) | 14 | Na | Occipital cortex involvement with calcification | Seizure, headache, vomiting | P | PM2 + PP3-B + PS5 + PS2 + PS3 | MELAS | N |
| m3 | F | MT-TL1 | maternal | m.3243A > G | 66.20% | maternal (24.0%) | 6.3 | 6.47 | Cortical and basal ganglia involvement | Seizure, headache, vomiting | P | PM2 + PP3-B + PS5 + PS2 + PS3 | MELAS | N |
| m4 | F | MT-TL1 | maternal | m.3243A > G | 71.70% | maternal (24.4%) | 4.7 | 9.33 | Cortical, basal ganglia and thalamus involvement | Seizure, behavioral disorder | P | PM2 + PP3-B + PS5 + PS2 + PS3 | MELAS | N |
| m6 | F | MT-ND3 | maternal | m.10197G > A | 99.60% | de novo | 0.5 | 3.5 | Basal ganglia, thalamus and brainstem involvement | Developmental regression, seizure | LP | PP3-B + PP4 + PM9 + PM8 | Leigh syndrome | N |
| m8 | M | MT-TL1 | maternal | m.3243A > G | 66.10% | maternal (24.4%) | 1 | 6.5 | Basal ganglia involvement | Seizure, ID, diabetes | P | PM2 + PP3-B + PS5 + PS2 + PS3 | Leigh syndrome | N |
| m9 | M | MT-ATP6 | maternal | m.9176 T > C | 99.50% | maternal (88.2%) | 8 | 4.49 | Basal ganglia and brainstem involvement | Ptosis, muscle weakness, dysuria, tachycardia, tachypnea | P | PP3-A1 + PP3-B + PS1 + PM5 + PM9 + PM10 + PP4 | Leigh syndrome | N |
| m10 | M | MT-TL1 | maternal | m.3243A > G | 72.40% | de novo | 12.6 | 7.33 | Cortical abnormalities | Seizure | P | PM2 + PP3-B + PS5 + PS2 + PS3 | MELAS | N |
| m12 | M | MT-TL1 | maternal | m.3243A > G | 74.20% | maternal (10.2%) | 8.7 | 4.73 | Cortical abnormalities | Headache, vomiting, impaired vision | P | PM2 + PP3-B + PS5 + PS2 + PS3 | MELAS | N |
| m13 | M | MT-ND1 | maternal | m.3761C > A | 81.40% | 0% | 0.6 | 5.31 | Ventriculomegaly | West syndrome | LP | PM2 + PM9 | West syndrome | N |
| m14 | M | mtDNA (tissue) | maternal | m.10947-15362del | / | Na | 11 | 3.68 | Na | Ptosis, growth restriction, skeletal muscle biopsy showing ragged red fibers | P | PM2 + PVS1 + PP4 | KSS | Y |
| m16 | F | MT-TL1 | maternal | m.3243A > G | 66.40% | de novo | 8 | 6.69 | Basal ganglia involvement | Developmental delay | P | PM2 + PP3-B + PS5 + PS2 + PS3 | Leigh syndrome | N |
| m17 | M | MT-CO2, MT-ATP6 | maternal | m.7929G > A; m.9035 T > C | 13.9%, 99.5% | de novo, de novo | 1 | 3.3 | Basal ganglia and brainstem involvement | Muscle weakness, hearing loss | VUS/LP | PM2 + PM9/PM2 + PM9 + PP4 | Leigh syndrome | Y |
| m19 | M | MT-ATP6 | maternal | m.9176 T > C | 99.80% | maternal (99.2%) | 7 | 2.07 | Abnormal signal foci around the midbrain aqueduct | ptosis, dysuria | P | PP3-A1 + PP3-B + PS1 + PM5 + PM9 + PM10 + PP4 | Leigh syndrome | N |
| mn6 | M | MT-ATP6 | maternal | m.8993 T > C | 99.50% | maternal (10.0%) | 1.7 | 3.3 | Basal ganglia involvement | muscle weakness, easy fatigability | P | PM2 + PP3-B + PS3 + PM5 + PS2 | Leigh syndrome | N |
| mn9 | M | MT-ND4 | maternal | m.11778G > A | 99.40% | maternal (99.4%) | 0.6 | 3 | Normal | Vision loss | P | PP3-A1 + PP3-B + PS1 + PS3 | LHON | N |
| mtDNA + nDNA | ||||||||||||||
| mn1 | F | MT-ND6 | maternal | m.14453A > G | 69.10% | de novo | 4.9 | 6.2 | Cortical and basal ganglia involvement | Seizure | P | PM2 + PP3-B + PS4_M + PS2 | MD | N |
| POLG | AD/AR | c.3643 + 1G > A | het | paternal | VUS | PM2_P + PVS1_M | Y | |||||||
| mn2 | M | MT-ND5 | maternal | m.13327A > G | 60.60% | maternal (53.3%) | at birth | 4.13 | Ventriculomegaly | DD, seizure, microcephalus | VUS | BS1 + BS4 | EIEE | Y |
| RARS2 | AR |
c.1210A > G (p.M404V); c.622C > T (p.Q208*) |
com. het | parental | VUS/LP | PM2_P + PP3-B2(+ PP4) / PM2_P + PVS1(+ PP4) | Y/Y | |||||||
| mn3 | M | MT-TL1 | maternal | m.3243A > G | 32.40% | de novo | 2 | 1.67 | Normal | Developmental regression, seizure, hearing loss | P | PM2 + PP3-B + PS5 + PS2 + PS3 | MD | N |
| NARS2 | AR | c.1253G > A (p.R418H); c.141 + 2 T > G | com. het | parental | VUS/LP | PM2_P + PP3/ PVS1 + PM2_P | N/Y | |||||||
| mn4 | F | MT-CO2 | maternal | m.7979G > A | 9.60% | de novo | at birth | 6.52 | Basal ganglia and brainstem involvement, ventriculomegaly | Muscle weakness, growth restriction | VUS | PM2 + BP4 | Leigh syndrome | Y |
| NDUFS1 | AR | c.1222C > T(p.R408C); c.61 + 3_61 + 6delGAGT | com.het | parental | VUS/VUS | PM3_S + PM2_P + PP3/ PM2_P + PP3 | N/Y | |||||||
| mn5 | M | MT-CYB | maternal | m.15272A > G | 17.80% | de novo | 1.9 | 6.81 | Hippocampus involvement | Development regression, seizure, dysarthria | VUS | PP3-B | Epileptic encephalopathy | N |
| SMARCA2 | AD | c.1399C > T (p.R467W) | het | de novo | LP | PS2 + PM2_P + PP3 | Y | |||||||
| mn6 | F | CHRNA4 | AD | c.988G > A (p.V330M) | het | paternal | 2.1 | 1.31 | Normal | seizure | VUS | PM2_P + PP3 | Epilepsy | Y |
| MT-CO3 | maternal | m.9984G > A | 16% | de novo | VUS | PP7 + PS6 | N | |||||||
F, female; M, male; Na, not available; hom. homozygote; het, heterozygote; com. het. compound heterozygote; hem, hemizygote; DD, development delay; ID, intellectual disorder; NEMMLAS, neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures; GDD, global developmental delay; MELAS, mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes; LHON, Leber's hereditary optic neuropathy; MD, mitochondrial disease; EIEE, early onset epileptic encephalopathy; KSS, Kearns-Sayre syndrome; ACMG, American College of Medical Genetics and Genomics; P, pathogenic; LP, likely pathogenic; VUS, variant of uncertain significance.
Family history: n111, father had seizure; 2n5, mother, mother's sister, father, two father's sisters, and grandmother have ptosis; m8, mother had diabetes.