Table 2 Nuclear gene testing in a proband with suspected mitochondrial disease.

From: Genetic testing for mitochondrial disease: the United Kingdom best practice guidelines

Clinical indication/disorder	Phenotype/appropriate referral reasons	Gene(s)—for gene panels, genes based on PanelApp gene content are listed^a	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 syndrome^b Biochemical evidence of complex II deficiency	SDHA, SDHD	OXPHOS Complex II subunits	Comprehensive mitochondrial disorder nuclear gene panel
		SDHAF1	OXPHOS Complex II assembly factors	Comprehensive mitochondrial disorder nuclear gene panel
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
Mitochondrial disorder with complex III deficiency (AR)		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
Mitochondrial disorder with complex V deficiency (AR)		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) biosynthesis^d
		LIAS, LIPT1, LIPT2, TPK1	Cofactor biosynthesis^d
		SLC19A2, SLC19A3, SLC25A19, SLC25A26	Transporters required for cofactor metabolism^d
		ECHS1, FBXL4, HIBCH, LONP1	Other/unknown^d
Comprehensive mitochondrial disorder nuclear gene panel^c (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.

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Table 2 Nuclear gene testing in a proband with suspected mitochondrial disease.

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