Table 1.
Summary of cases diagnosed via RNA-seq. AE: aberrant expression, AS: aberrant splicing, MAE: mono-allelic expression, Var: intronic variant detected via RNA-seq. Variant coordinates and further details are provided in Additional file 1: Table S1
| Index | Patient ID | Sex | Age range of onset | Primary symptoms | Genetic diagnosis | Variant RNA level | Variant class | RNA defects |
|---|---|---|---|---|---|---|---|---|
| 1 | R62943 | F | Prenatal | Neurodevelopmental delay, 3-MGA | C19orf70 | c.143del | Frameshift | AE, AS |
| NM_205767.1 | c.29+272G>C | Intronic | ||||||
| 2 | R98254 | F | Infant | Leigh syndrome, basal ganglia abnormality MRI, neurodevelopmental delay, intellectual disability, seizures, encephalopathy, brainstem abnormality MRI, complex I and IV defects | MRPL38 | c.770C>G | Missense | AE |
| NM_032478.3 | c.-174_-148del | 5′UTR deletion | ||||||
| 3 | R86287 | M | Infant | Hypotonia, cardiomyopathy, white matter abnormality MRI, elevated lactate, complex I and IV defects | DARS2 | c.492+2T>C | Splice donor | AS |
| NM_018122.4 | c.228-12C>G; c.228-20T>C | Intronic multi-nucleotide variant (MNV) | ||||||
| 4 | R89912 | M | Infant | Leigh syndrome, basal ganglia abnormality MRI, neurodevelopmental delay, speech delay, intellectual disability, encephalopathy, hypotonia, nystagmus, brainstem abnormality MRI, elevated lactate, metabolic acidosis, complex I defect | NFU1 | c.362T>C | Missense | AE, MAE |
| NM_001002755.2 | c.485-2588_545+1655del | Deletion | ||||||
| 5 | R19100 | M | Child | Myopathic facies, exercise intolerance, muscle weakness, motor, growth, speech and neurodevelopmental delay, intellectual disability, microcephaly, hypotonia, cardiomyopathy, dysmorphic features, ragged red fibers, elevated lactate | SLC25A4 | c.598G>A | Splice region | AE |
| NM_001151.3 | c.598G>A | Splice region | ||||||
| 6 | R15264 | F | Infant | Muscle weakness, myopathy, muscular dystrophy, hypotonia | TIMMDC1 | c.596+2146A>G | Intronic | AE, AS, Var |
| NM_016589.3 | c.596+2146A>G | Intronic | ||||||
| 7 | R36605 | M | Infant | Acute liver failure, hypotension of the muscles, hypertension of the limbs, intermittent deficiency of motor function of the pupil, delayed light reaction and nystagmus | TWNK | c.1302C>G | Synonymous | AE, AS |
| NM_001163812.1 | c.1302C>G | Synonymous | ||||||
| 8 | R61100 | F | Infant | Encephalopathy, respiratory distress | NAXE | c.292-12C>G | Intron | AE, AS |
| NM_144772.2 | c.292-12C>G | Intron | ||||||
| 9 | R77611 | F | Infant | Recurrent acute liver failure | DLD | c.685G>T | Missense | AE, MAE |
| NM_000108.3 | ||||||||
| 10 | R16472 | M | Child | Motor developmental delay, neurodevelopmental delay, respiratory distress, brainstem abnormality MRI, white matter abnormality MRI, leukoencephalopathy, elevated lactate, complex IV defect | MRPS25 | c.329+75G>A | Intronic | AE, AS, Var |
| NM_022497.4 | c.329+75G>A | Intronic | ||||||
| 11 | R51757 | M | Infant | Motor developmental delay, neurodevelopmental delay, seizures, feeding difficulties, elevated lactate, complex I defect | NDUFA10 | c.-99_-75del | 5′UTR | AE |
| NM_004544.3 | c.-99_-75del | 5′UTR | ||||||
| 12 | R80346 | F | Birth | MDDS, seizures, encephalopathy, hypotonia, died as neonate, elevated lactate, complex III, IV and V defects | LIG3 | c.86G>A | Stop | AE, Var |
| NM_002311.4 | c.1611+208G>A | Intronic | ||||||
| 13 | R20754 | M | Neonatal | Nystagmus, hearing impairment, white matter abnormality MRI | UFM1 | c.-273_-271del | Promoter | AE |
| NM_016617.2 | c.-273_-271del | Promoter | ||||||
| 14 | R25473 | F | Adult | Usher syndrome, immune abnormality, neutropenia, abnormality retina, cataract, visual impairment, hearing impairment | PEX1 | c.1842del | Frameshift | AE, Var |
| NM_000466.2 | c.1240-1551A>G | Intronic | ||||||
| 15 | R28774 | M | Infant | Myopathy, neurodevelopmental delay, hypotonia, movement disorder, failure to thrive, feeding difficulties, died as a young child due to recurrent respiratory infections, complex I defect | TIMMDC1 | c.596+2146A>G | Intronic | AE, AS, Var |
| NM_016589.3 | c.596+2146A>G | Intronic | ||||||
| 16 | R96820 | F | Neonatal | Muscle weakness, neurodevelopmental delay, hypotonia, microcephaly, cardiomyopathy, hearing impairment, elevated lactate, metabolic acidosis, complex IV defect | CLPP | c.661G>A | Splice region | AE, AS |
| NM_006012.2 | c.661G>A | Splice region | ||||||
| 17 | R21147 | M | Infant | Neurodevelopmental delay, feeding difficulties, elevated lactate, complex I defect | NDUFA10 | c.-99_-75del | 5′UTR | AE |
| NM_004544.3 | c.-99_-75del | 5′UTR | ||||||
| 18 | R64921 | M | Child | Ophthalmoplegia, speech delay, developmental regression, ataxia, abnormality retina, visual impairment, complex I defect | MCOLN1 | c.681-19A>C | Intronic | AE, AS |
| NM_020533.2 | c.832C>T | Stop | ||||||
| 19 | R52016 | M | Infant | Died as infant, basal ganglia abnormality MRI, neurodevelopmental delay, encephalopathy, hypotonia, myoclonus, nystagmus, abnormality eye movement, neuropathy, brainstem abnormality MRI, elevated lactate, complex I defect | TIMMDC1 | c.596+2146A>G | Intronic | AE, AS, Var |
| NM_016589.3 | c.596+2146A>G | Intronic | ||||||
| 20 | R46723 | F | Infant | Basal ganglia abnormality MRI, encephalopathy, brainstem abnormality MRI, complex I defect | NDUFAF5 | c.2T>C | Start loss | AE, AS, Var |
| NM_024120.4 | c.223-907A>C | Intronic | ||||||
| 21 | R58859 | M | Adult | Ophthalmoplegia, myopathic facies, myalgia, diabetes, arrhythmias | TAZ | c.348C>T | Synonymous | AS |
| NM_181313 | c.348C>T | Synonymous | ||||||
| 22 | R80184 | M | Prenatal | Muscle weakness, myopathy, neurodevelopmental delay, intellectual disability, seizures, hypotonia, dystonia, spasticity, microcephaly, growth delay, failure to thrive, respiratory distress, cataract, abnormality eye movement, delayed myelination, hypoplasia of the corpus callosum, lack of insular opercularization, died as a young child from pneumonia, elevated lactate, complex I and I/III defects | ALDH18A1 | c.1982C>A | Stop | AE, MAE |
| NM_001017423.1 | c.1858C>T | Missense | ||||||
| 23 | R59185 | F | Child | Basal ganglia abnormality MRI, ophthalmoplegia, ataxia, growth delay, arrhythmias, optic atrophy, visual impairment, neuropathy, white matter abnormality MRI, elevated lactate | NDUFS4 | c.466_469dup | Frameshift | AE |
| NM_002495.2 | c.466_469dup | Frameshift | ||||||
| 24 | R63087 | M | Child | Basal ganglia abnormality MRI, muscle weakness, myopathy, rhabdomyolysis, neurodevelopmental delay, seizures, infection related deterioration, elevated lactate | SLC25A42 | c.380+2T>A | Splice donor | AS |
| NM_178526.4 | c.380+2T>A | Splice donor | ||||||
| 25 | R44456 | F | Infant | MADD, respiratory distress, dysmorphic features | MRPL44 | c.179+3A>G | Splice region | AE, AS |
| NM_022915.3 | c.179+3A>G | Splice region | ||||||
| 26 | R33391 | F | Infant | Failure to thrive, elevated lactate, complex I defect | NDUFAF5 | c.605dup | Frameshift | AS, Var |
| NM_024120.4 | c.223-907A>C | Intronic | ||||||
| 27 | R66696 | M | Young child | Muscle weakness, myopathy, rhabdomyolysis, infection related deterioration, died as child, complex I, III and IV defects | LPIN1 | c.2550-865_2667-34del | Deletion | AS |
| NM_001261427.1 | c.2550-865_2667-34del | Deletion | ||||||
| 28 | R24289 | M | Young child | Hypotonia, developmental delay, hearing impairment, white matter abnormality on MRI, lactic acidemia, hyperlactacidemia, proteinuria, glycosuria | RRM2B | c.328C>T | Missense | AE, MAE |
| NM_015713.4 | c.? | Intergenic | ||||||
| 29 | R98349 | F | Infant | Clotting defect, lactic acidosis | DLD | c.685G>T | Missense | AS |
| NM_000108.5 | c.1046+5G>T | Splice region | ||||||
| 30 | R91273 | F | Adult | MADD during pregnancy | ETFDH | c.687_688del | Frameshift | AE |
| NM_004453.3 | - | |||||||
| 31 | R60537 | M | Neonatal | Congenital disorder of glycosylation, seizures, cognitive impairment, nose abnormalities, large fleshy ears, abnormal isoelectric focusing of serum transferrin | ATP6AP1 | c.291-135C>T | Intronic | AE, Var |
| NM_00183.4 | c.291-135C>T | Intronic | ||||||
| 32 | R70961 | M | Young child | Leigh syndrome, optic atrophy, parkinsonism, status epilepticus, developmental regression, abnormal thalamic size, lactic acidosis, urinary glycosaminoglycan excretion | PTCD3 | c.1519-1G>C | Splice acceptor | AS |
| NM_017952 | c.1918C>G | Missense |