Table 2.
Nuclear gene testing in a proband with suspected mitochondrial disease.
| Clinical indication/disorder | Phenotype/appropriate referral reasons | Gene(s)—for gene panels, genes based on PanelApp gene content are listeda | Function | Possible further testing, especially mtDNA |
|---|---|---|---|---|
| Single gene tests | ||||
|
POLG-related disorders (AR, rarely AD) Common variant testing may be prioritised (refer to the main text for further details) |
Highly variable from Alpers syndrome to PEO Epilepsy, neuropathy, ataxia, suspected mtDNA maintenance disorder, sodium valproate toxicity |
POLG | Catalytic subunit of DNA polymerase gamma, required for replication of mtDNA |
Nuclear gene panels as appropriate Refer to phenotypes in Table 1 for appropriate mtDNA testing |
| Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) (AR) |
Progressive gastrointestinal dysmotility, PEO, leukoencephalopathy, demyelinating peripheral neuropathy, distal weakness Elevated plasma levels of thymidine/deoxyuridine Reduced TP activity |
TYMP | Thymidine phosphorylase (TP), catalyses phosphorylation of thymidine/deoxyuridine to thymine/uracil |
m.3243A>G (MT-TL1) POLG Mitochondrial DNA maintenance disorder gene panel |
| Thiamine metabolism dysfunction syndrome-2 (also known as biotin-responsive basal ganglia disease) (AR) |
Childhood-onset encephalopathy Strong clinical suspicion |
SLC19A3 | Thiamine transporter |
Nuclear gene panels as appropriate Refer to phenotypes in Table 1 for appropriate mtDNA testing |
|
Mitochondrial complex V deficiency nuclear type 2 (AR) Common variant testing may be prioritised (refer to the main text for further details) |
Neonatal mitochondrial encephalo-cardiomyopathy Strong clinical suspicion, particularly of Roma population origin Complex V deficiency |
TMEM70 | Mitochondrial membrane protein involved in the biogenesis of mitochondrial ATP synthase |
Nuclear gene panels as appropriate Refer to phenotypes in Table 1 for appropriate mtDNA testing |
| Nuclear gene panels | ||||
| Mitochondrial liver disease, including transient infantile liver failure (AR) |
Liver disease Infantile acute liver failure Transient infantile liver failure Liver disease with suspected mitochondrial dysfunction |
BCS1L | OXPHOS assembly factor | mtDNA replication and maintenance |
| DGUOK, MPV17, POLG, TWNK | mtDNA replication and maintenance | |||
| TRMU | tRNA modification | |||
| Mitochondrial DNA maintenance disorder (AR, AD) |
MtDNA depletion syndromes, PEO with multiple mtDNA deletions Evidence of mtDNA depletion or multiple mtDNA deletions Strong clinical suspicion |
AFG3L2, SPG7 | Mitochondrial protein quality control |
mtDNA copy number analysis Large-scale mtDNA rearrangements |
| ABAT, DGUOK, DNA2, MGME1, MPV17, POLG, POLG2, RNASEH1, RRM2B, SLC25A4, SUCLA2, SUCLG1, TK2, TOP3A, TWNK, TYMP | mtDNA replication and maintenance | |||
| MFN2, OPA1 | Mitochondrial dynamics | |||
| DNM2, FBXL4 | Other | |||
| Mitochondrial disorder with complex I deficiency (AR, rarely X-linked) |
Mainly neonatal/childhood-onset Leigh syndrome, neurological disorder or cardiomyopathy Biochemical evidence of complex I deficiency |
NDUFA1, NDUFA10, NDUFA11, NDUFA2, NDUFA6, NDUFA9, NDUFB11, NDUFB3, NDUFB8, NDUFS1, NDUFS2, NDUFS3, NDUFS4, NDUFS6, NDUFS7, NDUFS8, NDUFV1, NDUFV2 | OXPHOS Complex I subunits and accessory subunits |
Whole mtDNA sequencing Comprehensive mitochondrial disorder nuclear gene panel |
| ACAD9, FOXRED1, NDUFAF1, NDUFAF2, NDUFAF3, NDUFAF4, NDUFAF5, NDUFAF6, NDUFAF8, NUBPL, TMEM126B | OXPHOS Complex I assembly factors | |||
| Mitochondrial disorder with complex II deficiency (AR, rarely AD) |
Leukoencephalopathy, Leigh syndromeb Biochemical evidence of complex II deficiency |
SDHA, SDHD | OXPHOS Complex II subunits | Comprehensive mitochondrial disorder nuclear gene panel |
| SDHAF1 | OXPHOS Complex II assembly factors | |||
| Mitochondrial disorder with complex III deficiency (AR) |
Variable including Leigh syndrome, neurological disorder, liver disease, renal tubular acidosis Biochemical evidence of complex III deficiency |
CYC1, UQCRB | OXPHOS Complex III subunits |
Whole mtDNA sequencing Comprehensive mitochondrial disorder nuclear gene panel |
| BCS1L, LYRM7, TTC19, UQCC2 | OXPHOS Complex III assembly factors and chaperones | |||
| Mitochondrial disorder with complex IV deficiency (AR) |
Mainly Leigh syndrome, cardiomyopathy. Biochemical evidence of complex IV deficiency |
COX6A1, COX6B1, COX7B | OXPHOS Complex IV subunits |
Whole mtDNA sequencing Comprehensive mitochondrial disorder nuclear gene panel |
| COA6, COA7, COX10, COX14, COX15, COX20, NDUFA4, PET100, SURF1 | OXPHOS Complex IV assembly factors and chaperones | |||
| FASTKD2, LRPPRC | RNA processing/modification and transcriptional regulation | |||
| APOPT1, SCO1, SCO2, TACO1 | Other | |||
| Mitochondrial disorder with complex V deficiency (AR) |
Mainly Leigh syndrome, cardiomyopathy Biochemical evidence of complex V deficiency |
ATP5F1D | OXPHOS Complex V subunits |
Whole mtDNA sequencing Comprehensive mitochondrial disorder nuclear gene panel |
| ATPAF2, TMEM70 | OXPHOS Complex V assembly factors and chaperones | |||
| Pyruvate dehydrogenase (PDH) deficiency (X-linked, AR, rarely AD) |
Variable including Leigh syndrome, neurological disorder, dysgenesis of the corpus callosum Strong clinical suspicion Biochemical evidence of PDH deficiency |
DLAT, DLD, PDHA1, PDHB, PDHX | Core subunits of the PDH complex | Comprehensive mitochondrial disorder nuclear gene panel |
| PDP1 | PDH regulation | |||
| BOLA3, GLRX5, IBA57, ISCA1, ISCA2, NFU1 | Iron-sulfur (Fe-S) biosynthesisd | |||
| LIAS, LIPT1, LIPT2, TPK1 | Cofactor biosynthesisd | |||
| SLC19A2, SLC19A3, SLC25A19, SLC25A26 | Transporters required for cofactor metabolismd | |||
| ECHS1, FBXL4, HIBCH, LONP1 | Other/unknownd | |||
| Comprehensive mitochondrial disorder nuclear gene panelc (AR, AD, X-linked) |
Highly variable Strong clinical suspicion of mitochondrial disease (where a nuclear defect is suspected and/or mtDNA variants have been excluded) Biochemical evidence of combined respiratory chain enzyme deficiency |
All genes listed in panels above | ||
| AIFM1, CLPB, CLPP, DNAJC19, GFER, HSPD1, HTRA2, MIPEP, PMPCA, PMPCB, SACS | Protein processing | |||
| ELAC2, GTPBP3, HSD17B10, MTFMT, MTO1, MTPAP, PNPT1, PUS1, TRIT1, TRMT10C, TRMT5, TRNT1 | RNA processing/modification | |||
| AARS2, CARS2, DARS2, EARS2, FARS2, GARS1, HARS2, IARS2, KARS1, LARS2, MARS2, NARS2, PARS2, QRSL1, RARS2, SARS2, VARS2, WARS2, YARS2 | Mitochondrial aminoacyl tRNA synthetases | |||
| MRPS2, MRPS22, MRPS34, MRPL3, MRPL44 | Mitochondrial ribosome components | |||
| MTRFR, GFM1, GFM2, RMND1, TSFM, TUFM | Translation | |||
| AGK, ATAD3A, C19orf70, DNM1L, GDAP1, MFF, MSTO1, OPA3, PNPLA8, SERAC1, SLC25A46, TAZ | Mitochondrial membrane and dynamics | |||
| FDX2, FDXR, FLAD1, HCCS, HLCS, ISCU, MECR, NADK2, NAXE, PDSS1, PDSS2 | Cofactors | |||
| ABCB7, SLC25A1, SLC25A12, SLC25A3, SLC25A32, SLC25A38, SLC25A42, TIMM50, TIMM8A | Carriers, transporters, protein import | |||
| COQ2, COQ4, COQ6, COQ7, COQ8A, COQ8B, COQ9 | Coenzyme Q10 biosynthesis | |||
| ACO2, CA5A, FH, MDH2, MPC1, PC, PPA2 | PDC and TCA cycle | |||
| ETFDH | Fatty acid β-oxidation | |||
| BTD | Biotin synthesis | |||
| ANO10, APTX, C1QBP, CHCHD10, ETHE1, MICU1, RTN4IP1, SFXN4 | Other | |||
Single nuclear gene and panel tests for routine diagnostic referrals of patients with suspected primary mitochondrial disease, including guidance on appropriate referrals and information on minimal appropriate gene content of panels.
AR autosomal recessive, AD autosomal dominant, PEO progressive external ophthalmoplegia.
aPanelApp: https://nhsgms-panelapp.genomicsengland.co.uk/ and https://panelapp.genomicsengland.co.uk/panels/. PanelApp ‘green’ genes are listed, from the NHS Genomic Medicine Service Signed Off Panels Resource as of 5 November 2022 (these are versions 1.2 for all panels except version 1.17 for the Comprehensive mitochondrial disorder nuclear gene panel, which is termed ‘possible mitochondrial disorder—nuclear genes’ on PanelApp). Laboratories may wish to include additional genes in these panels, such ‘amber’ genes with moderate/limited evidence of gene-disease association and candidate genes based on known biological function but with no reported disease association to date. Content of nuclear gene panels requires regular updates as new evidence of gene-disease associations is identified. Users can refer to the PanelApp website for updates and for gene content of the latest signed-off versions for UK diagnostic use.
bMono-allelic dominant SDHx variants are associated with predisposition to cancer (pheochromocytoma and paraganglioma) and are reviewed in [90]. Complex II associated genes that are currently listed in OMIM with mitochondrial-related disease association include SDHA, SDHD and SDHAF1.
cGene-agnostic WES or WGS is an appropriate alternative testing strategy, if available, particularly for urgent paediatric referrals where samples from a parent–child trio can be obtained and/or for referrals where mitochondrial disease is one of several possible differential diagnoses.
dThese genes also function in pathways unrelated to pyruvate dehydrogenase.