Leigh syndrome

Summary

Leigh syndrome (MONDO:0009723) is a disease caused by variants in ETHE1, MTRFR, NDUFS1, and 10 other genes, with 75 cohort genes and 14 clinical trials. The dominant Reactome pathway is Respiratory electron transport (33 cohort genes). Top therapeutic interventions include mannitol, sirolimus, and vatiquinone.

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Causal genes: ETHE1 (GenCC Definitive), MTRFR (GenCC Definitive), NDUFS1 (GenCC Definitive), NDUFS4 (GenCC Definitive) (+9 more)
• Cohort genes: 75
• ClinVar variants: 3,436
• Phenotypes (HPO): 98
• Clinical trials: 14

Clinical features

Epidemiology

Prevalence records

3 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	2	Europe	Validated
Prevalence at birth	1-9 / 100 000	2.8	Europe	Validated
Annual incidence	1-9 / 100 000	1.3	Australia	Validated

Signs & symptoms

Clinical features (HPO)

98 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0002151	Increased circulating lactate concentration	Very frequent (80-99%)
HP:0002490	Increased CSF lactate	Very frequent (80-99%)
HP:0003128	Lactic acidosis	Very frequent (80-99%)
HP:0003648	Lacticaciduria	Very frequent (80-99%)
HP:0008947	Floppy infant	Very frequent (80-99%)
HP:0012379	Abnormal enzyme/coenzyme activity	Very frequent (80-99%)
HP:0100022	Abnormality of movement	Very frequent (80-99%)
HP:0000407	Sensorineural hearing impairment	Frequent (30-79%)
HP:0000587	Abnormal optic nerve morphology	Frequent (30-79%)
HP:0000602	Ophthalmoplegia	Frequent (30-79%)
HP:0000648	Optic atrophy	Frequent (30-79%)
HP:0000998	Hypertrichosis	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0001510	Growth delay	Frequent (30-79%)
HP:0001639	Hypertrophic cardiomyopathy	Frequent (30-79%)
HP:0002171	Gliosis	Frequent (30-79%)
HP:0002344	Progressive neurologic deterioration	Frequent (30-79%)
HP:0002376	Developmental regression	Frequent (30-79%)
HP:0002415	Leukodystrophy	Frequent (30-79%)
HP:0002493	Upper motor neuron dysfunction	Frequent (30-79%)
HP:0002928	Decreased activity of the pyruvate dehydrogenase complex	Frequent (30-79%)
HP:0004305	Involuntary movements	Frequent (30-79%)
HP:0006943	Diffuse spongiform leukoencephalopathy	Frequent (30-79%)
HP:0007183	Focal T2 hyperintense basal ganglia lesion	Frequent (30-79%)
HP:0008336	Complex organic aciduria	Frequent (30-79%)
HP:0008972	Decreased activity of mitochondrial respiratory chain	Frequent (30-79%)
HP:0011923	Decreased activity of mitochondrial complex I	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0012696	Abnormal thalamic MRI signal intensity	Frequent (30-79%)
HP:0012707	Elevated brain lactate level by MRS	Frequent (30-79%)
HP:0012747	Abnormal brainstem MRI signal intensity	Frequent (30-79%)
HP:0012748	Focal T2 hyperintense brainstem lesion	Frequent (30-79%)
HP:0012751	Abnormal basal ganglia MRI signal intensity	Frequent (30-79%)
HP:0031691	Severe viral infection	Frequent (30-79%)
HP:0100321	Abnormality of the dentate nucleus	Frequent (30-79%)
HP:0410263	Brain imaging abnormality	Frequent (30-79%)
HP:0000508	Ptosis	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0000924	Abnormality of the skeletal system	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001257	Spasticity	Occasional (5-29%)
HP:0001264	Spastic diplegia	Occasional (5-29%)
HP:0001266	Choreoathetosis	Occasional (5-29%)
HP:0001274	Agenesis of corpus callosum	Occasional (5-29%)
HP:0001324	Muscle weakness	Occasional (5-29%)
HP:0001332	Dystonia	Occasional (5-29%)
HP:0001399	Hepatic failure	Occasional (5-29%)
HP:0001635	Congestive heart failure	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Leigh syndrome
Mondo ID	MONDO:0009723
MeSH	D007888
OMIM	256000
Orphanet	506
DOID	DOID:3652
ICD-10-CM	G31.82
ICD-11	672871576
NCIT	C84814
SNOMED CT	29570005
UMLS	C2931891
MedGen	419518
GARD	0006877
MedDRA	10062950
NORD	1355
Is cancer (heuristic)	no

Also known as: infantile subacute necrotizing encephalopathy · Leigh disease · Leigh syndrome · Leigh syndrome spectrum · Leigh’s disease · Leigh’s necrotizing encephalopathy · LS · LSS · necrotizing encephalopathy, infantile Subacute, of Leigh · SNE · subacute necrotizing encephalopathy

Data availability: 3,436 ClinVar variants · 34 GenCC gene-disease records · 57 cell lines.

Disease family

An umbrella term covering 4 Mondo subtypes.

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › inborn mitochondrial metabolism disorder › mitochondrial oxidative phosphorylation disorder › Leigh syndrome

Related subtypes (47): mitochondrial respiratory chain complex deficiency, combined oxidative phosphorylation deficiency, myopathy, lactic acidosis, and sideroblastic anemia, optic atrophy 3, autosomal dominant optic atrophy, classic form, mitochondrial non-syndromic sensorineural hearing loss, maternally-inherited diabetes and deafness, chronic diarrhea with villous atrophy, Kearns-Sayre syndrome, Leber hereditary optic neuropathy, NARP syndrome, deafness, aminoglycoside-induced, hereditary spastic paraplegia 7, spinocerebellar ataxia type 28, leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome, spastic ataxia 3, pontocerebellar hypoplasia type 6, autosomal recessive optic atrophy, OPA7 type, acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins, congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay syndrome, spastic ataxia 4, hyperuricemia-pulmonary hypertension-renal failure-alkalosis syndrome, hereditary spastic paraplegia 55, cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome, Charcot-Marie-Tooth disease recessive intermediate D, autosomal dominant mitochondrial myopathy with exercise intolerance, Charcot-Marie-Tooth disease type 4K, hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome, hereditary spastic paraplegia 77, fatal infantile encephalocardiomyopathy, FASTKD2-related infantile mitochondrial encephalomyopathy, autosomal dominant optic atrophy and peripheral neuropathy, ataxia neuropathy spectrum, maternally-inherited mitochondrial dystonia, Perrault syndrome, hypertrophic cardiomyopathy and renal tubular disease due to mitochondrial DNA mutation, adult-onset chronic progressive external ophthalmoplegia with mitochondrial myopathy, mitochondrial DNA maintenance syndrome, coenzyme Q10 deficiency, mitochondrial DNA depletion syndrome, periodic paralysis with later-onset distal motor neuropathy, non-progressive predominantly posterior cavitating leukoencephalopathy with peripheral neuropathy, Zellweger-like syndrome without peroxisomal anomalies, maternally-inherited progressive external ophthalmoplegia, Leber plus disease, encephalopathy due to mitochondrial and peroxisomal fission defect, severe neonatal lactic acidosis due to NFS1-ISD11 complex deficiency

Subtypes (4): necrotizing encephalomyelopathy, subacute, of Leigh, adult, congenital lactic acidosis, Saguenay-Lac-Saint-Jean type, maternally-inherited Leigh syndrome, Leigh syndrome with cardiomyopathy

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

184 uncertain significance, 117 likely benign, 94 conflicting classifications of pathogenicity, 61 benign, 50 benign/likely benign, 35 pathogenic, 29 likely pathogenic, 28 pathogenic/likely pathogenic, 2 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
155894	mitochondrial DNA deletion		Pathogenic	no assertion criteria provided
1029833	NM_078470.6(COX15):c.305G>A (p.Trp102Ter)	COX15	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
156433	NM_004092.4(ECHS1):c.2T>G (p.Met1Arg)	ECHS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
156434	NM_004092.4(ECHS1):c.5C>T (p.Ala2Val)	ECHS1	Pathogenic	criteria provided, multiple submitters, no conflicts
214454	NM_017547.4(FOXRED1):c.86-1G>A	FOXRED1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2413139	NM_018060.4(IARS2):c.547_550del (p.Lys183fs)	IARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14056	NM_007103.4(NDUFV1):c.1268C>T (p.Thr423Met)	LOC126861242	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1676672	NM_017446.4(MRPL39):c.921+5G>A	MRPL39	Pathogenic/Likely pathogenic	no assertion criteria provided
1676674	NM_017446.4(MRPL39):c.589-924G>A	MRPL39	Pathogenic	criteria provided, single submitter
1594	NM_174889.5(NDUFAF2):c.139C>T (p.Arg47Ter)	NDUFAF2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1696036	NC_000005.9:g.(60241210_60368951)(60448865?)del	NDUFAF2	Pathogenic	criteria provided, single submitter
1162277	NM_024120.5(NDUFAF5):c.223-907A>C	NDUFAF5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1321429	NM_024120.5(NDUFAF5):c.604C>T (p.Gln202Ter)	NDUFAF5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1722455	NM_024120.5(NDUFAF5):c.712_715del (p.Thr238fs)	NDUFAF5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
225036	NM_024120.5(NDUFAF5):c.836T>G (p.Met279Arg)	NDUFAF5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1693584	NM_002495.4(NDUFS4):c.350+1G>A	NDUFS4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2445773	NM_002495.4(NDUFS4):c.221del (p.Thr74fs)	NDUFS4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2500769	NM_002495.4(NDUFS4):c.350+1G>T	NDUFS4	Pathogenic	criteria provided, single submitter
14057	NM_007103.4(NDUFV1):c.175C>T (p.Arg59Ter)	NDUFV1	Pathogenic	criteria provided, multiple submitters, no conflicts
14058	NM_007103.4(NDUFV1):c.1022C>T (p.Ala341Val)	NDUFV1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14059	NM_007103.4(NDUFV1):c.640G>A (p.Glu214Lys)	NDUFV1	Pathogenic	criteria provided, multiple submitters, no conflicts
214852	NM_007103.4(NDUFV1):c.365C>T (p.Pro122Leu)	NDUFV1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
160358	NM_004168.4(SDHA):c.1753C>T (p.Arg585Trp)	SDHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1182215	NM_003172.4(SURF1):c.367_368del (p.Arg123fs)	SURF1	Pathogenic	criteria provided, multiple submitters, no conflicts
12762	NM_003172.4(SURF1):c.751C>T (p.Gln251Ter)	SURF1	Pathogenic	criteria provided, multiple submitters, no conflicts
12768	NM_003172.4(SURF1):c.371G>A (p.Gly124Glu)	SURF1	Pathogenic	criteria provided, single submitter
12770	NM_003172.4(SURF1):c.845_846del (p.Ser282fs)	SURF1	Pathogenic	criteria provided, multiple submitters, no conflicts
1320126	NM_003172.4(SURF1):c.595_598del (p.Gly199fs)	SURF1	Pathogenic	criteria provided, single submitter
1320241	NM_003172.4(SURF1):c.283del (p.Glu95fs)	SURF1	Pathogenic	criteria provided, single submitter
1321366	NM_003172.4(SURF1):c.867G>A (p.Trp289Ter)	SURF1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 183 · Orphanet: 109 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
ETHE1	Definitive	Autosomal recessive	Leigh syndrome	5
MTRFR	Definitive	Autosomal recessive	Leigh syndrome	4
NDUFS1	Definitive	Autosomal recessive	Leigh syndrome	6
NDUFS4	Definitive	Autosomal recessive	Leigh syndrome	7
PDHA1	Definitive	X-linked	Leigh syndrome	8
SCO2	Definitive	Autosomal recessive	Leigh syndrome	8
SLC19A3	Definitive	Autosomal recessive	Leigh syndrome	9
SUCLA2	Definitive	Autosomal recessive	Leigh syndrome	4
SURF1	Definitive	Autosomal recessive	Leigh syndrome	9
TTC19	Definitive	Autosomal recessive	Leigh syndrome	7
EARS2	Strong	Autosomal recessive	Leigh syndrome	2
NDUFAF2	Strong	Autosomal recessive	Leigh syndrome	6
NDUFAF8	Strong	Autosomal recessive	Leigh syndrome	4
COX10	Moderate	Autosomal recessive	Leigh syndrome	4
FOXRED1	Moderate	Autosomal recessive	Leigh syndrome	7
NDUFA1	Moderate	X-linked	Leigh syndrome	6
NDUFA2	Moderate	Autosomal recessive	Leigh syndrome	5
NDUFS3	Moderate	Autosomal recessive	Leigh syndrome	5
PET100	Moderate	Autosomal recessive	Leigh syndrome	6
SDHA	Moderate	Autosomal recessive	Leigh syndrome	20
SUCLG1	Moderate	Autosomal recessive	Leigh syndrome	5
TACO1	Moderate	Autosomal recessive	Leigh syndrome	6
COX15	Supportive	Autosomal recessive	Leigh syndrome with leukodystrophy	5
NDUFA9	Supportive	Autosomal recessive	Leigh syndrome with leukodystrophy	4
BCS1L	Limited	Autosomal recessive	Leigh syndrome	16
KGD4	Limited	Autosomal recessive	Leigh syndrome
NDUFA3	Limited	Autosomal recessive	Leigh syndrome
PET117	Limited	Autosomal recessive	Leigh syndrome	4
PTCD3	Limited	Autosomal recessive	Leigh syndrome	4
UQCRQ	Limited	Autosomal recessive	Leigh syndrome	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BCS1L	Orphanet:123	Björnstad syndrome
BCS1L	Orphanet:1460	Isolated complex III deficiency
BCS1L	Orphanet:254902	Renal tubulopathy-encephalopathy-liver failure syndrome
BCS1L	Orphanet:53693	GRACILE syndrome
SDHA	Orphanet:139411	Carney triad
SDHA	Orphanet:154	Familial isolated dilated cardiomyopathy
SDHA	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
SDHA	Orphanet:3208	Isolated succinate-CoQ reductase deficiency
SDHA	Orphanet:44890	Gastrointestinal stromal tumor
SDHA	Orphanet:97286	Carney-Stratakis syndrome
SURF1	Orphanet:391351	SURF1-related Charcot-Marie-Tooth disease type 4
COX10	Orphanet:254905	Isolated cytochrome C oxidase deficiency
COX15	Orphanet:1561	Fatal infantile cytochrome C oxidase deficiency
FOXRED1	Orphanet:2609	Isolated complex I deficiency
NDUFAF2	Orphanet:2609	Isolated complex I deficiency
NDUFS1	Orphanet:2609	Isolated complex I deficiency
NDUFS3	Orphanet:2609	Isolated complex I deficiency
NDUFS4	Orphanet:2609	Isolated complex I deficiency
SCO2	Orphanet:1561	Fatal infantile cytochrome C oxidase deficiency
SCO2	Orphanet:521411	Autosomal recessive axonal Charcot-Marie-Tooth disease due to copper metabolism defect
SCO2	Orphanet:98619	Rare isolated myopia
SUCLA2	Orphanet:1933	Mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria
SUCLG1	Orphanet:17	Fatal infantile lactic acidosis with methylmalonic aciduria
SLC19A3	Orphanet:199348	Thiamine-responsive encephalopathy
SLC19A3	Orphanet:263410	Infantile spasms-psychomotor retardation-progressive brain atrophy-basal ganglia disease syndrome
SLC19A3	Orphanet:65284	Biotin-thiamine-responsive basal ganglia disease
ETHE1	Orphanet:51188	Ethylmalonic encephalopathy
TTC19	Orphanet:1460	Isolated complex III deficiency
MTRFR	Orphanet:254930	Combined oxidative phosphorylation defect type 7
MTRFR	Orphanet:320375	Autosomal recessive spastic paraplegia type 55
EARS2	Orphanet:314051	Leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome
UQCRQ	Orphanet:1460	Isolated complex III deficiency
NDUFAF8	Orphanet:2609	Isolated complex I deficiency
PET117	Orphanet:254905	Isolated cytochrome C oxidase deficiency
NDUFA1	Orphanet:2609	Isolated complex I deficiency
NDUFA2	Orphanet:85136	Cystic leukoencephalopathy without megalencephaly
PDHA1	Orphanet:79243	Pyruvate dehydrogenase E1-alpha deficiency
SCO1	Orphanet:1561	Fatal infantile cytochrome C oxidase deficiency
FBXL4	Orphanet:369897	Mitochondrial DNA depletion syndrome, encephalomyopathic form with variable craniofacial anomalies
GFM1	Orphanet:137681	Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1
LOXL3	Orphanet:250984	Autosomal recessive Stickler syndrome
HTRA2	Orphanet:2828	Young-onset Parkinson disease
HTRA2	Orphanet:505208	3-methylglutaconic aciduria type 8
LRPPRC	Orphanet:70472	Congenital lactic acidosis, Saguenay-Lac-Saint-Jean type
NDUFAF5	Orphanet:2609	Isolated complex I deficiency
TPK1	Orphanet:293955	Childhood encephalopathy due to thiamine pyrophosphokinase deficiency
SERAC1	Orphanet:352328	MEGDEL syndrome
FARS2	Orphanet:319519	Combined oxidative phosphorylation defect type 14
FARS2	Orphanet:466722	Autosomal recessive spastic paraplegia type 77
VPS13D	Orphanet:95434	Autosomal recessive cerebellar ataxia-movement disorder syndrome

Cohort genes → proteins

75 cohort genes, 74 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	75

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BCS1L	HGNC:1020	ENSG00000074582	Q9Y276	Mitochondrial chaperone BCS1	gencc,clinvar
SDHA	HGNC:10680	ENSG00000073578	P31040	Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial	gencc,clinvar
SURF1	HGNC:11474	ENSG00000148290	Q15526	Surfeit locus protein 1	gencc,clinvar
KGD4	HGNC:16631	ENSG00000134056	P82909	Alpha-ketoglutarate dehydrogenase component 4	gencc,clinvar
COX10	HGNC:2260	ENSG00000006695	Q12887	Protoheme IX farnesyltransferase, mitochondrial	gencc,clinvar
COX15	HGNC:2263	ENSG00000014919	Q7KZN9	Heme A synthase COX15	gencc,clinvar
FOXRED1	HGNC:26927	ENSG00000110074	Q96CU9	FAD-dependent oxidoreductase domain-containing protein 1	gencc,clinvar
NDUFAF2	HGNC:28086	ENSG00000164182	Q8N183	NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 2	gencc,clinvar
NDUFA9	HGNC:7693	ENSG00000139180	Q16795	NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 9, mitochondrial	gencc,clinvar
NDUFS1	HGNC:7707	ENSG00000023228	P28331	NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial	gencc,clinvar
NDUFS3	HGNC:7710	ENSG00000213619	O75489	NADH dehydrogenase [ubiquinone] iron-sulfur protein 3, mitochondrial	gencc,clinvar
NDUFS4	HGNC:7711	ENSG00000164258	O43181	NADH dehydrogenase [ubiquinone] iron-sulfur protein 4, mitochondrial	gencc,clinvar
SCO2	HGNC:10604	ENSG00000284194	O43819	Cytochrome c oxidase assembly factor SCO2	gencc
SUCLA2	HGNC:11448	ENSG00000136143	Q9P2R7	Succinate–CoA ligase [ADP-forming] subunit beta, mitochondrial	gencc
SUCLG1	HGNC:11449	ENSG00000163541	P53597	Succinate–CoA ligase [ADP/GDP-forming] subunit alpha, mitochondrial	gencc
SLC19A3	HGNC:16266	ENSG00000135917	Q9BZV2	Thiamine transporter 2	gencc
ETHE1	HGNC:23287	ENSG00000105755	O95571	Persulfide dioxygenase ETHE1, mitochondrial	gencc
TACO1	HGNC:24316	ENSG00000136463	Q9BSH4	Translational activator of cytochrome c oxidase 1	gencc
PTCD3	HGNC:24717	ENSG00000132300	Q96EY7	Small ribosomal subunit protein mS39	gencc
TTC19	HGNC:26006	ENSG00000011295	Q6DKK2	Tetratricopeptide repeat protein 19, mitochondrial	gencc
MTRFR	HGNC:26784	ENSG00000130921	Q9H3J6	Mitochondrial translation release factor in rescue	gencc
EARS2	HGNC:29419	ENSG00000103356	Q5JPH6	Nondiscriminating glutamyl-tRNA synthetase EARS2, mitochondrial	gencc
UQCRQ	HGNC:29594	ENSG00000164405	O14949	Cytochrome b-c1 complex subunit 8	gencc
NDUFAF8	HGNC:33551	ENSG00000224877	A1L188	NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 8	gencc
PET100	HGNC:40038	ENSG00000229833	P0DJ07	Protein PET100 homolog, mitochondrial	gencc
PET117	HGNC:40045	ENSG00000232838	Q6UWS5	Protein PET117 homolog, mitochondrial	gencc
NDUFA1	HGNC:7683	ENSG00000125356	O15239	NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 1	gencc
NDUFA2	HGNC:7685	ENSG00000131495	O43678	NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 2	gencc
NDUFA3	HGNC:7686	ENSG00000170906	O95167	NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 3	gencc
PDHA1	HGNC:8806	ENSG00000131828	P08559	Pyruvate dehydrogenase E1 component subunit alpha, somatic form, mitochondrial	gencc
SCO1	HGNC:10603	ENSG00000133028	O75880	Cytochrome c oxidase assembly factor SCO1	clinvar
VAV2	HGNC:12658	ENSG00000160293	P52735	Guanine nucleotide exchange factor VAV2	clinvar
FBXL4	HGNC:13601	ENSG00000112234	Q9UKA2	F-box/LRR-repeat protein 4	clinvar
GFM1	HGNC:13780	ENSG00000168827	Q96RP9	Elongation factor G, mitochondrial	clinvar
LOXL3	HGNC:13869	ENSG00000115318	P58215	Lysyl oxidase homolog 3	clinvar
MRPL39	HGNC:14027	ENSG00000154719	Q9NYK5	Large ribosomal subunit protein mL39	clinvar
HTRA2	HGNC:14348	ENSG00000115317	O43464	Serine protease HTRA2, mitochondrial	clinvar
LRPPRC	HGNC:15714	ENSG00000138095	P42704	Leucine-rich PPR motif-containing protein, mitochondrial	clinvar
NDUFAF5	HGNC:15899	ENSG00000101247	Q5TEU4	Arginine-hydroxylase NDUFAF5, mitochondrial	clinvar
TPK1	HGNC:17358	ENSG00000196511	Q9H3S4	Thiamine pyrophosphokinase 1	clinvar
UBOX5	HGNC:17777	ENSG00000185019	O94941	RING finger protein 37	clinvar
ENTPD7	HGNC:19745	ENSG00000198018	Q9NQZ7	Ectonucleoside triphosphate diphosphohydrolase 7	clinvar
SERAC1	HGNC:21061	ENSG00000122335	Q96JX3	Protein SERAC1	clinvar
FARS2	HGNC:21062	ENSG00000145982	O95363	Phenylalanine–tRNA ligase, mitochondrial	clinvar
PYROXD2	HGNC:23517	ENSG00000119943	Q8N2H3	Pyridine nucleotide-disulfide oxidoreductase domain-containing protein 2	clinvar
VPS13D	HGNC:23595	ENSG00000048707	Q5THJ4	Intermembrane lipid transfer protein VPS13D	clinvar
NDUFA12	HGNC:23987	ENSG00000184752	Q9UI09	NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 12	clinvar
COQ9	HGNC:25302	ENSG00000088682	O75208	Ubiquinone biosynthesis protein COQ9, mitochondrial	clinvar
FASTKD5	HGNC:25790	ENSG00000215251	Q7L8L6	FAST kinase domain-containing protein 5, mitochondrial	clinvar
EME2	HGNC:27289	ENSG00000197774	A4GXA9	Structure-specific endonuclease subunit EME2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BCS1L	Mitochondrial chaperone BCS1	Chaperone necessary for the incorporation of Rieske iron-sulfur protein UQCRFS1 into the mitochondrial respiratory chain complex III.
SDHA	Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial	Flavoprotein (FP) subunit of succinate dehydrogenase (SDH) that is involved in complex II of the mitochondrial electron transport chain and is responsible for transferring electrons from succinate to ubiquinone (coenzyme Q).
SURF1	Surfeit locus protein 1	Component of the MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex) complex, that regulates cytochrome c oxidase assembly.
KGD4	Alpha-ketoglutarate dehydrogenase component 4	Molecular adapter that is necessary to form a stable 2-oxoglutarate dehydrogenase enzyme complex (OGDHC).
COX10	Protoheme IX farnesyltransferase, mitochondrial	Converts protoheme IX and farnesyl diphosphate to heme O.
COX15	Heme A synthase COX15	Catalyzes the second reaction in the biosynthesis of heme A, a prosthetic group of mitochondrial cytochrome c oxidase (CcO).
FOXRED1	FAD-dependent oxidoreductase domain-containing protein 1	Required for the assembly of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I).
NDUFAF2	NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 2	Acts as a molecular chaperone for mitochondrial complex I assembly.
NDUFA9	NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 9, mitochondrial	Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed not to be involved in catalysis.
NDUFS1	NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial	Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor.
NDUFS3	NADH dehydrogenase [ubiquinone] iron-sulfur protein 3, mitochondrial	Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor.
NDUFS4	NADH dehydrogenase [ubiquinone] iron-sulfur protein 4, mitochondrial	Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed not to be involved in catalysis.
SCO2	Cytochrome c oxidase assembly factor SCO2	Copper metallochaperone essential for the synthesis and maturation of cytochrome c oxidase subunit II (MT-CO2/COX2); together with SCO1, facilitates the incorporation of copper into the Cu(A) site of MT-CO2/COX2.
SUCLA2	Succinate–CoA ligase [ADP-forming] subunit beta, mitochondrial	ATP-specific succinyl-CoA synthetase functions in the citric acid cycle (TCA), coupling the hydrolysis of succinyl-CoA to the synthesis of ATP and thus represents the only step of substrate-level phosphorylation in the TCA.
SUCLG1	Succinate–CoA ligase [ADP/GDP-forming] subunit alpha, mitochondrial	Succinyl-CoA synthetase functions in the citric acid cycle (TCA), coupling the hydrolysis of succinyl-CoA to the synthesis of either ATP or GTP and thus represents the only step of substrate-level phosphorylation in the TCA.
SLC19A3	Thiamine transporter 2	Mediates high affinity thiamine uptake, probably via a proton anti-port mechanism.
ETHE1	Persulfide dioxygenase ETHE1, mitochondrial	Sulfur dioxygenase that plays an essential role in hydrogen sulfide catabolism in the mitochondrial matrix.
TACO1	Translational activator of cytochrome c oxidase 1	Acts as a translational activator of mitochondrially-encoded cytochrome c oxidase 1.
PTCD3	Small ribosomal subunit protein mS39	Mitochondrial RNA-binding protein that has a role in mitochondrial translation.
TTC19	Tetratricopeptide repeat protein 19, mitochondrial	Required for the preservation of the structural and functional integrity of mitochondrial respiratory complex III by allowing the physiological turnover of the Rieske protein UQCRFS1.
MTRFR	Mitochondrial translation release factor in rescue	Part of a mitoribosome-associated quality control pathway that prevents aberrant translation by responding to interruptions during elongation.
EARS2	Nondiscriminating glutamyl-tRNA synthetase EARS2, mitochondrial	Non-discriminating glutamyl-tRNA synthetase that catalyzes aminoacylation of both mitochondrial tRNA(Glu) and tRNA(Gln) and participates in RNA aminoacylation for mitochondrial protein translation.
UQCRQ	Cytochrome b-c1 complex subunit 8	Component of the ubiquinol-cytochrome c oxidoreductase, a multisubunit transmembrane complex that is part of the mitochondrial electron transport chain which drives oxidative phosphorylation.
NDUFAF8	NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 8	Involved in the assembly of mitochondrial NADH:ubiquinone oxidoreductase complex (complex I, MT-ND1).
PET100	Protein PET100 homolog, mitochondrial	Plays an essential role in mitochondrial complex IV maturation and assembly.
NDUFA1	NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 1	Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed not to be involved in catalysis.
NDUFA2	NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 2	Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed not to be involved in catalysis.
NDUFA3	NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 3	Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed not to be involved in catalysis.
PDHA1	Pyruvate dehydrogenase E1 component subunit alpha, somatic form, mitochondrial	Together with PDHB forms the heterotetrameric E1 subunit of the pyruvate dehydrogenase (PDH) complex.
SCO1	Cytochrome c oxidase assembly factor SCO1	Copper metallochaperone essential for the maturation of cytochrome c oxidase subunit II (MT-CO2/COX2).
VAV2	Guanine nucleotide exchange factor VAV2	Guanine nucleotide exchange factor for the Rho family of Ras-related GTPases.
FBXL4	F-box/LRR-repeat protein 4	Substrate-recognition component of the mitochondria-localized SCF-FBXL4 ubiquitin E3 ligase complex that plays a role in the restriction of mitophagy by controlling the degradation of BNIP3 and NIX mitophagy receptors.
GFM1	Elongation factor G, mitochondrial	Mitochondrial GTPase that catalyzes the GTP-dependent ribosomal translocation step during translation elongation.
LOXL3	Lysyl oxidase homolog 3	Protein-lysine 6-oxidase that mediates the oxidation of peptidyl lysine residues to allysine in target proteins.
HTRA2	Serine protease HTRA2, mitochondrial	Serine protease that shows proteolytic activity against a non-specific substrate beta-casein.
LRPPRC	Leucine-rich PPR motif-containing protein, mitochondrial	May play a role in RNA metabolism in both nuclei and mitochondria.
NDUFAF5	Arginine-hydroxylase NDUFAF5, mitochondrial	Arginine hydroxylase that mediates hydroxylation of ‘Arg-111’ of NDUFS7 and is involved in the assembly of mitochondrial NADH:ubiquinone oxidoreductase complex (complex I, MT-ND1) at early stages.
TPK1	Thiamine pyrophosphokinase 1	Catalyzes the phosphorylation of thiamine to thiamine pyrophosphate (TPP) utilizing UTP and therefore links the biosynthesis of TPP to pyrimidines metabolism.
UBOX5	RING finger protein 37	May have a ubiquitin-protein ligase activity acting as an E3 ubiquitin-protein ligase or as a ubiquitin-ubiquitin ligase promoting elongation of ubiquitin chains on substrates.
ENTPD7	Ectonucleoside triphosphate diphosphohydrolase 7	Catalyzes the hydrolysis of nucleoside triphosphates and diphosphates in a calcium- or magnesium-dependent manner.
SERAC1	Protein SERAC1	Facilitates the transport of serine from the cytosol to the mitochondria by interacting with and stabilizing Sideroflexin-1 (SFXN1), a mitochondrial serine transporter, playing a fundamental role in the one-carbon cycle responsible for the…
FARS2	Phenylalanine–tRNA ligase, mitochondrial	Is responsible for the charging of tRNA(Phe) with phenylalanine in mitochondrial translation.
PYROXD2	Pyridine nucleotide-disulfide oxidoreductase domain-containing protein 2	Probable oxidoreductase that may play a role as regulator of mitochondrial function.
VPS13D	Intermembrane lipid transfer protein VPS13D	Mediates the transfer of lipids between membranes at organelle contact sites.
NDUFA12	NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 12	Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed not to be involved in catalysis.
COQ9	Ubiquinone biosynthesis protein COQ9, mitochondrial	Membrane-associated protein that warps the membrane surface to access and bind aromatic isoprenes with high specificity, including ubiquinone (CoQ) isoprene intermediates and presents them directly to COQ7, therefore facilitating the COQ7-…
FASTKD5	FAST kinase domain-containing protein 5, mitochondrial	Plays an important role in the processing of non-canonical mitochondrial mRNA precursors.
EME2	Structure-specific endonuclease subunit EME2	Non-catalytic subunit of the structure-specific, heterodimeric DNA endonuclease MUS81-EME2 which is involved in the maintenance of genome stability.
NDUFAF6	NADH dehydrogenase (ubiquinone) complex I, assembly factor 6	Involved in the assembly of mitochondrial NADH:ubiquinone oxidoreductase complex (complex I) at early stages.
DLAT	Dihydrolipoyllysine-residue acetyltransferase component of pyruvate dehydrogenase complex, mitochondrial	The pyruvate dehydrogenase (PDH) complex, catalyzes the overall conversion of pyruvate to acetyl-CoA and CO(2), and thereby links cytoplasmic glycolysis and the mitochondrial tricarboxylic acid (TCA) cycle.

Protein-family classification

Druggable: 19 · Difficult: 3 · Unknown: 53 · Druggable fraction: 0.25

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	13	2.1×	0.030
Other/Unknown	53	1.3×	0.030
Kinase	3	1.1×	0.870
Transporter	1	1.0×	0.870
Protease	2	1.0×	0.870
Scaffold/PPI	1	0.2×	0.999
Transcription factor	2	0.2×	0.999

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BCS1L	Other/Unknown	no		AAA+_ATPase, ATPase_AAA_core, ATPase_AAA_CS
SDHA	Other/Unknown	no		FRD_SDH_FAD_BS, FAD-dep_OxRdtase_2_FAD-bd, Succ_DH_flav_su_fwd
SURF1	Other/Unknown	no		Surf1/Shy1, Surf1/Surf4
KGD4	Other/Unknown	no		Kgd4/YMR-31
COX10	Enzyme (other)	yes	2.5.1.141	UbiA_prenyltransferase, Protohaem_IX_farnesylTrfase, Protohaem_IX_farnesylTrfase_mt
COX15	Protease	yes		COX15/CtaA_fam, Peptidase_S1_PA, HemeA_synthase_2
FOXRED1	Other/Unknown	no		FAD-dep_OxRdtase, FAD/NAD-bd_sf
NDUFAF2	Other/Unknown	no		NDUFA12, ComplexI_NDUFA12
NDUFA9	Other/Unknown	no		Epimerase_deHydtase, NAD(P)-bd_dom_sf, ComplexI_NDUFA9_subunit
NDUFS1	Other/Unknown	no		NADH_UbQ_OxRdtase_75kDa_su_CS, 2Fe-2S_ferredoxin-type, Mopterin_OxRdtase
NDUFS3	Other/Unknown	no		NADH_UbQ_OxRdtase_30kDa_su, NADH_DH_suC, NADH_UbQ_OxRdtase_CS
NDUFS4	Other/Unknown	no		NADH_UbQ_FeS_4_mit-like, NDUFS4-like_sf
SCO2	Other/Unknown	no		SCO1/SenC, Thioredoxin_domain, Synth_of_cyt-c-oxidase_Sco1/2
SUCLA2	Enzyme (other)	yes	6.2.1.5	Succ_CoA_ligase-like_bsu, SUCC_ACL_C, ATP-grasp
SUCLG1	Enzyme (other)	yes	6.2.1.4	CoA-bd, CoA_lig_alpha, SUCC_ACL_C
SLC19A3	Transporter	yes		Folate_carrier, ThTr-2, MFS_trans_sf
ETHE1	Other/Unknown	no		Metallo-B-lactamas, RibonucZ/Hydroxyglut_hydro, POD-like_MBL-fold
TACO1	Other/Unknown	no		Transcrip_reg_TACO1-like, Integrase-like_N, Transcrip_reg_TACO1-like_dom3
PTCD3	Other/Unknown	no		PPR_rpt, TPR-like_helical_dom_sf, PTCD3
TTC19	Other/Unknown	no		TPR-like_helical_dom_sf, TPR_rpt, TTC19
MTRFR	Other/Unknown	no		Pep_chain_release_fac_I, Pep_chain_release_fac_I_sf, Mito_Transl_Release_Factor
EARS2	Other/Unknown	no		Glu/Gln-tRNA-synth, aa-tRNA-synth_I_CS, Glu-tRNA-ligase_bac/mito
UQCRQ	Other/Unknown	no		Cyt_bc1_su8, Cyt_bc1_su8_sf
NDUFAF8	Other/Unknown	no		NDUFAF8
PET100	Other/Unknown	no		Pet100
PET117	Other/Unknown	no		Pet117
NDUFA1	Other/Unknown	no		NADH_Ub_cplx-1_asu_su-1
NDUFA2	Other/Unknown	no		Ribosomal_mL43/mS25/NADH_DH, NADH_Ub_cplx-1_asu_su-2, Thioredoxin-like_sf
NDUFA3	Other/Unknown	no		NDUFA3
PDHA1	Enzyme (other)	yes	1.2.1.104	DH_E1, Pyrv_DH_E1_asu_subgrp-y, THDP-binding
SCO1	Other/Unknown	no		SCO1/SenC, Synth_of_cyt-c-oxidase_Sco1/2, Thioredoxin-like_sf
VAV2	Scaffold/PPI	no		DH_dom, SH2, GDS_CDC24_CS
FBXL4	Other/Unknown	no		F-box_dom, Leu-rich_rpt_Cys-con_subtyp, LRR_dom_sf
GFM1	Other/Unknown	no		EFG_V-like, T_Tr_GTP-bd_dom, EFTu-like_2
LOXL3	Enzyme (other)	yes	1.4.3.13	SRCR, Lysyl_oxidase, Lysyl_oxidase_CS
MRPL39	Other/Unknown	no		TGS, Beta-grasp_dom_sf, TGS-like
HTRA2	Protease	yes	3.4.21.108	PDZ, Peptidase_S1C, Peptidase_S1_PA
LRPPRC	Other/Unknown	no		PPR_rpt, TPR-like_helical_dom_sf, PROP1-like_PPR_dom
NDUFAF5	Other/Unknown	no		Methyltransf_11, SAM-dependent_MTases_sf, Malonyl-ACP_OMT
TPK1	Kinase	yes	2.7.6.2	Thi_PPkinase, TPK_catalytic, Thiamin_PyroPKinase_B1-bd
UBOX5	Transcription factor	no		Znf_RING, Ubox_domain, Znf_RING/FYVE/PHD
ENTPD7	Enzyme (other)	yes	3.6.1.5	GDA1_CD39_NTPase
SERAC1	Other/Unknown	no		ARM-like, ARM-type_fold, AB_hydrolase_fold
FARS2	Enzyme (other)	yes	6.1.1.20	Phenylalanyl-tRNA_Synthase, Phe-tRNA-synth_IIc_mito, Fdx_antiC-bd
PYROXD2	Other/Unknown	no		Amino_oxidase, FAD/NAD-bd_sf
VPS13D	Other/Unknown	no		UBA-like_sf, VPS13_VAB, UBA
NDUFA12	Other/Unknown	no		NDUFA12
COQ9	Other/Unknown	no		Ubiq_biosynth_COQ9, COQ9_C, COQ9_HTH
FASTKD5	Kinase	yes		FAST_Leu-rich, FAST_2, RAP
EME2	Other/Unknown	no		ERCC4_domain, Mms4/EME1/EME2, EME1/EME2_C

Expression context

Cohort genes with no expression data: 0.

70 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	75
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	14
adrenal tissue	8
mucosa of transverse colon	7
left ventricle myocardium	7
right uterine tube	6
heart left ventricle	5
right lobe of liver	5
hindlimb stylopod muscle	5
calcaneal tendon	5
gastrocnemius	5
adipose tissue	5
primordial germ cell in gonad	5
biceps brachii	5
tibialis anterior	4
granulocyte	4
jejunal mucosa	4
endothelial cell	4
heart right ventricle	4
rectum	4
diaphragm	3

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BCS1L	279	ubiquitous	marker	body of pancreas, metanephros cortex, apex of heart
SDHA	143	ubiquitous	marker	apex of heart, heart left ventricle, mucosa of transverse colon
SURF1	183	ubiquitous	marker	apex of heart, body of pancreas, right lobe of liver
KGD4	139	ubiquitous	marker	apex of heart, heart left ventricle, hindlimb stylopod muscle
COX10	245	ubiquitous	marker	tibialis anterior, diaphragm, left ventricle myocardium
COX15	288	ubiquitous	marker	caput epididymis, corpus epididymis, cauda epididymis
FOXRED1	232	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
NDUFAF2	139	ubiquitous	marker	calcaneal tendon, lower esophagus muscularis layer, gastrocnemius
NDUFA9	295	ubiquitous	marker	apex of heart, mucosa of transverse colon, heart left ventricle
NDUFS1	142	ubiquitous	marker	corpus callosum, skeletal muscle tissue, adrenal tissue
NDUFS3	140	ubiquitous	marker	putamen, mucosa of transverse colon, apex of heart
NDUFS4	294	ubiquitous	marker	calcaneal tendon, skeletal muscle tissue of rectus abdominis, hindlimb stylopod muscle
SCO2	260	ubiquitous	yes	right uterine tube, granulocyte, mucosa of transverse colon
SUCLA2	294	ubiquitous	marker	jejunal mucosa, pons, lateral nuclear group of thalamus
SUCLG1	288	ubiquitous	marker	nephron tubule, renal glomerulus, metanephric glomerulus
SLC19A3	185	broad	marker	subcutaneous adipose tissue, adipose tissue, adipose tissue of abdominal region
ETHE1	276	ubiquitous	marker	mucosa of transverse colon, ileal mucosa, colonic mucosa
TACO1	265	ubiquitous	marker	apex of heart, mucosa of transverse colon, right lobe of liver
PTCD3	291	ubiquitous	marker	adrenal tissue, calcaneal tendon, ventricular zone
TTC19	291	ubiquitous	marker	jejunal mucosa, ileal mucosa, upper leg skin
MTRFR	250	ubiquitous	marker	thymus, oocyte, pancreatic ductal cell
EARS2	229	ubiquitous	marker	adrenal tissue, right lobe of liver, primordial germ cell in gonad
UQCRQ	295	ubiquitous	marker	apex of heart, body of tongue, cardiac ventricle
NDUFAF8	253	ubiquitous	marker	medial globus pallidus, putamen, globus pallidus
PET100	134	ubiquitous	marker	bone marrow cell, colonic epithelium, monocyte
PET117	253	ubiquitous	marker	endothelial cell, primordial germ cell in gonad, epithelial cell of pancreas
NDUFA1	294	ubiquitous	marker	left ventricle myocardium, cardiac ventricle, heart left ventricle
NDUFA2	300	ubiquitous	marker	biceps brachii, heart right ventricle, skeletal muscle tissue of biceps brachii
NDUFA3	134	ubiquitous	marker	primary visual cortex, hindlimb stylopod muscle, superior frontal gyrus
PDHA1	290	ubiquitous	marker	apex of heart, heart left ventricle, cardiac ventricle

Protein interactions among cohort

Intra-cohort edges: 251.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SDHA	6,141
GFM1	5,789
NDUFS3	5,461
DLD	5,041
PDHA1	5,038
HTRA2	4,023
NDUFA9	3,976
NDUFS1	3,899
DLAT	3,854
ECHS1	3,802

Intra-cohort edges

A	B	Sources
BCS1L	COQ9	biogrid_interaction
BCS1L	COX10	string_interaction
BCS1L	COX15	string_interaction
BCS1L	ETHE1	string_interaction
BCS1L	MT-ATP6	string_interaction
BCS1L	MTFMT	biogrid_interaction
BCS1L	MTRFR	biogrid_interaction
BCS1L	NDUFAF6	string_interaction
BCS1L	NDUFS4	string_interaction
BCS1L	SCO2	string_interaction
BCS1L	SDHA	string_interaction
BCS1L	SURF1	string_interaction
BCS1L	TACO1	string_interaction
BCS1L	TTC19	string_interaction
BCS1L	UQCRQ	string_interaction
COQ9	COX15	intact
COQ9	NDUFA9	string_interaction
COQ9	NDUFAF2	intact
COX10	COX15	string_interaction
COX10	FASTKD2	string_interaction
COX10	LRPPRC	string_interaction
COX10	MT-CO1	string_interaction
COX10	MT-CO2	string_interaction
COX10	MT-CO3	string_interaction
COX10	NDUFS1	string_interaction
COX10	PET100	string_interaction
COX10	PET117	string_interaction
COX10	SCO1	string_interaction
COX10	SCO2	string_interaction
COX10	SURF1	string_interaction
COX10	TACO1	string_interaction
COX15	HTRA2	intact
COX15	LRPPRC	string_interaction
COX15	MT-CO1	string_interaction
COX15	MT-CO2	string_interaction
COX15	MT-CO3	string_interaction
COX15	NDUFAF6	string_interaction
COX15	PET100	string_interaction
COX15	PET117	string_interaction
COX15	SCO1	string_interaction
COX15	SCO2	string_interaction
COX15	SURF1	biogrid_interaction, string_interaction
COX15	TACO1	string_interaction
DLAT	DLD	biogrid_interaction, intact, string_interaction
DLAT	LIPT1	string_interaction
DLAT	PDHA1	biogrid_interaction, string_interaction
DLAT	SDHA	string_interaction
DLD	KGD4	intact
DLD	PDHA1	biogrid_interaction, intact, string_interaction
DLD	SDHA	biogrid_interaction

Structural data

PDB: 47 · AlphaFold-only: 27 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MRPL39	Q9NYK5	85
PTCD3	Q96EY7	77
SLC19A3	Q9BZV2	19
DLD	P09622	17
HTRA2	O43464	13
DLAT	P10515	13
SCO1	O75880	10
MT-ATP6	P00846	10
MT-ATP8	P03928	10
PDHA1	P08559	9
FARS2	O95363	9
SUCLG1	P53597	8
NDUFA2	O43678	8
NDUFA9	Q16795	7
NDUFS1	P28331	7
NDUFS3	O75489	7
NDUFS4	O43181	7
TACO1	Q9BSH4	7
NDUFA1	O15239	7
NDUFA3	O95167	7
VAV2	P52735	7
NDUFA12	Q9UI09	7
MT-ND2	P03891	7
MT-ND4	C0HME5	7
MT-ND5	P03915	7
ECHS1	P30084	6
SDHA	P31040	5
UQCRQ	O14949	5
GFM1	Q96RP9	5
COQ9	O75208	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PET117	Q6UWS5	94.94
PYROXD2	Q8N2H3	91.56
LIPT1	Q9Y234	91.49
NDUFAF8	A1L188	91.12
FOXRED1	Q96CU9	90.12
EARS2	Q5JPH6	89.84
IARS2	Q9NSE4	89.77
NDUFAF6	Q330K2	87.70
PET100	P0DJ07	87.50
TMCO6	Q96DC7	87.22
BCS1L	Q9Y276	87.10
FBXL4	Q9UKA2	86.50
MTFMT	Q96DP5	86.08
NDUFAF5	Q5TEU4	85.43
COX15	Q7KZN9	85.29
ENTPD7	Q9NQZ7	84.57
LOXL3	P58215	84.11
SURF1	Q15526	82.62
TTC19	Q6DKK2	80.28
FASTKD5	Q7L8L6	79.38
NDUFAF2	Q8N183	78.98
SERAC1	Q96JX3	78.66
COX10	Q12887	77.11
FASTKD2	Q9NYY8	75.39
KGD4	P82909	74.79
UBOX5	O94941	71.33
VPS13D	Q5THJ4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 107. Enrichment computed across 85 evidence-associated genes (75 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 75 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Respiratory electron transport	33	41.9×	7e-45	BCS1L, SDHA, SURF1, NDUFAF2, NDUFA9, NDUFS1, NDUFS3, NDUFS4 (+25 more)
Aerobic respiration and respiratory electron transport	28	33.0×	1e-34	BCS1L, SDHA, SURF1, KGD4, NDUFAF2, NDUFA9, NDUFS1, NDUFS3 (+20 more)
Complex I biogenesis	23	50.8×	5e-33	FOXRED1, NDUFAF2, NDUFA9, NDUFS1, NDUFS3, NDUFS4, NDUFAF5, NDUFA12 (+15 more)
Mitochondrial protein degradation	17	25.9×	1e-18	NDUFS1, NDUFS3, HTRA2, DLD, UQCRQ, IARS2, MT-ATP6, MT-CO1 (+9 more)
Mitochondrial translation termination	17	24.9×	2e-18	KGD4, MRPL39, PTCD3, GFM2, MT-ATP6, MT-ATP8, MT-CO1, MT-CO2 (+9 more)
Complex IV assembly	10	30.4×	1e-11	SURF1, COX15, SCO1, SCO2, TACO1, PET100, PET117, MT-CO1 (+2 more)
Metabolism	29	4.5×	1e-11	BCS1L, SDHA, SURF1, KGD4, NDUFAF2, NDUFA9, NDUFS1, NDUFS3 (+21 more)
PDH complex synthesizes acetyl-CoA from PYR	3	65.3×	1e-04	DLAT, DLD, PDHA1
Complex III assembly	4	23.4×	3e-04	BCS1L, TTC19, UQCRQ, MT-CYB
Citric acid cycle (TCA cycle)	4	22.6×	3e-04	SDHA, KGD4, SUCLA2, SUCLG1
Regulation of pyruvate dehydrogenase (PDH) complex	3	28.6×	0.001	DLAT, DLD, PDHA1
FASTK family proteins regulate processing and stability of mitochondrial RNAs	2	76.1×	0.002	FASTKD5, FASTKD2
OGDH complex synthesizes succinyl-CoA from 2-OG	2	76.1×	0.002	KGD4, DLD
Formation of ATP by chemiosmotic coupling	3	22.8×	0.002	MT-ATP6, MT-ATP8, ATP5PO
Mitochondrial tRNA aminoacylation	3	20.8×	0.003	FARS2, EARS2, IARS2
Vitamin B1 (thiamin) metabolism	2	60.9×	0.003	SLC19A3, TPK1
Signaling by Retinoic Acid	3	16.3×	0.005	DLAT, DLD, PDHA1
Glycine degradation	2	43.5×	0.005	KGD4, DLD
Cristae formation	3	13.8×	0.007	MT-ATP6, MT-ATP8, ATP5PO
Translation	6	5.0×	0.007	KGD4, MRPL39, FARS2, EARS2, GFM2, IARS2
Protein lipoylation	2	27.7×	0.011	DLAT, LIPT1
Mitochondrial mRNA modification	2	27.7×	0.011	LRPPRC, FASTKD2
tRNA Aminoacylation	3	11.4×	0.011	FARS2, EARS2, IARS2
TP53 Regulates Metabolic Genes	4	6.9×	0.012	SCO2, MT-CO1, MT-CO2, MT-CO3
Mitochondrial translation initiation	4	6.8×	0.012	KGD4, MRPL39, PTCD3, MTFMT
Mitochondrial translation elongation	4	6.8×	0.012	KGD4, GFM1, MRPL39, PTCD3
Mitochondrial ribosome-associated quality control	4	6.5×	0.013	KGD4, MRPL39, PTCD3, MTRFR
Heme biosynthesis	2	20.3×	0.016	COX10, COX15
Mitochondrial short-chain enoyl-CoA hydratase deficiency 1	1	152.3×	0.024	ECHS1
Metabolism of proteins	13	2.1×	0.024	KGD4, NDUFS1, NDUFS3, MRPL39, FARS2, EARS2, LIPT1, GFM2 (+5 more)

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 79 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
proton motive force-driven mitochondrial ATP synthesis	23	76.7×	2e-36	SDHA, NDUFA9, NDUFS1, NDUFS3, NDUFS4, NDUFA12, MT-ATP6, MT-ATP8 (+15 more)
aerobic respiration	22	69.0×	9e-34	SURF1, COX10, NDUFA9, NDUFS1, NDUFS3, NDUFS4, NDUFA12, MT-CO1 (+14 more)
mitochondrial electron transport, NADH to ubiquinone	20	90.8×	1e-33	NDUFA9, NDUFS1, NDUFS3, NDUFS4, COQ9, DLD, MT-ND1, MT-ND2 (+12 more)
mitochondrial respiratory chain complex I assembly	16	83.2×	6e-26	BCS1L, FOXRED1, NDUFAF2, NDUFS1, NDUFS3, NDUFS4, NDUFAF5, NDUFAF6 (+8 more)
mitochondrial respiratory chain complex IV assembly	7	55.3×	1e-09	BCS1L, SURF1, SCO1, SCO2, TACO1, PET100, PET117
electron transport coupled proton transport	4	213.3×	2e-08	MT-CYB, MT-ND4, MT-ND5, NDUFS7
tricarboxylic acid cycle	6	38.8×	3e-07	SDHA, KGD4, SUCLA2, SUCLG1, DLAT, PDHA1
cellular respiration	6	32.8×	7e-07	NDUFS1, UQCRQ, MT-CO1, MT-CO2, MT-CO3, MT-CYB
respiratory chain complex IV assembly	3	91.4×	8e-05	SURF1, COX10, MT-CO3
pyruvate decarboxylation to acetyl-CoA	3	80.0×	1e-04	DLAT, DLD, PDHA1
response to hypoxia	7	8.5×	4e-04	MT-CO1, MT-CO2, MT-CYB, MT-ND1, MT-ND2, MT-ND4, MT-ND5
mitochondrial translation	5	11.0×	0.002	MRPL39, PTCD3, FASTKD2, GFM2, IARS2
respiratory electron transport chain	3	32.0×	0.002	SDHA, SCO2, MT-CO1
proton motive force-driven ATP synthesis	3	30.5×	0.002	MT-ATP6, MT-ATP8, ATP5PO
mitochondrial electron transport, cytochrome c to oxygen	3	29.1×	0.002	MT-CO1, MT-CO2, MT-CO3
succinate metabolic process	2	85.3×	0.003	SDHA, SUCLA2
thiamine diphosphate biosynthetic process	2	85.3×	0.003	SLC19A3, TPK1
mitochondrial translational termination	2	85.3×	0.003	MTRFR, GFM2
mitochondrial RNA processing	2	71.1×	0.004	FASTKD5, FASTKD2
regulation of mitochondrial mRNA stability	2	61.0×	0.004	FASTKD5, FASTKD2
regulation of mitochondrial translation	2	61.0×	0.004	LRPPRC, TACO1
succinyl-CoA catabolic process	2	61.0×	0.004	SUCLA2, SUCLG1
reactive oxygen species metabolic process	3	17.8×	0.006	NDUFS3, NDUFS4, MT-ND2
mitochondrial ATP synthesis coupled electron transport	2	47.4×	0.007	NDUFA12, NDUFV1
heme A biosynthetic process	2	38.8×	0.010	COX10, COX15
response to copper ion	2	38.8×	0.010	MT-CO1, MT-CYB
mitochondrial electron transport, ubiquinol to cytochrome c	2	32.8×	0.013	UQCRQ, MT-CYB
mitochondrion organization	4	7.7×	0.014	BCS1L, HTRA2, PYROXD2, VPS13D
mitochondrial respiratory chain complex III assembly	2	30.5×	0.014	BCS1L, TTC19
response to hyperoxia	2	28.4×	0.016	MT-ATP6, MT-CYB

Therapeutics

Drugs indicated for this disease

No approved or late-stage (phase ≥3) drug is indicated for this disease; the following are in earlier-phase trials only.

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Vatiquinone.

Drug target analysis

Approved (phase 4): 3 · Phase ≥3: 4 · Phased (≥1): 5 · Undrugged: 70

Druggability breadth: 44 of 85 evidence-associated genes (52%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
SDHA	LINEZOLID
LOXL3	PYRITHIONE
MT-CO2	CELECOXIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MT-CO2	6	4
LOXL3	3	4
SDHA	1	4
SUCLA2	1	3
IARS2	1	2
BCS1L	0	0
SURF1	0	0
KGD4	0	0
COX10	0	0
COX15	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
LINEZOLID	4	SDHA
PYRITHIONE	4	LOXL3
DISULFIRAM	4	LOXL3
CELECOXIB	4	MT-CO2
ROFECOXIB	4	MT-CO2
DICLOFENAC	4	MT-CO2
INDOMETHACIN	4	MT-CO2
VALDECOXIB	4	MT-CO2
CRENOLANIB	3	SUCLA2
THIRAM	2	LOXL3
PIMASERTIB	2	IARS2
TOLFENAMIC ACID	2	MT-CO2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 16.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
MT-CO2	47	Binding:41, ADMET:5, Toxicity:1
MT-CO1	19	Binding:12, Functional:4, ADMET:2, Toxicity:1
HTRA2	11	Binding:11
LOXL3	6	Binding:6
NDUFAF2	5	Binding:5
NDUFS1	5	Binding:5
NDUFS3	5	Binding:5
MT-ND1	5	Binding:5
NDUFA9	4	Binding:4
NDUFS4	4	Binding:4
NDUFA1	4	Binding:4
NDUFA2	4	Binding:4
NDUFA3	4	Binding:4
LRPPRC	4	Binding:4
NDUFA12	4	Binding:4
MT-ND2	4	Binding:4
MT-ND3	4	Binding:4
MT-ND4L	4	Binding:4
MT-ND5	4	Binding:4
MT-ND6	4	Binding:4
SDHA	3	Binding:3
FARS2	3	Binding:3
DLAT	3	Binding:3
SUCLA2	2	Binding:2
IARS2	2	Binding:2
ECHS1	2	Binding:2
COX15	1	Binding:1
SCO2	1	Binding:1
SUCLG1	1	Binding:1
PTCD3	1	Binding:1
PDHA1	1	Binding:1
GFM1	1	Binding:1
TPK1	1	Binding:1
FASTKD5	1	Binding:1
DLD	1	Binding:1
MT-ATP6	1	Binding:1
MT-ATP8	1	Binding:1
MT-CO3	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
COX10	2.5.1.141	heme o synthase
SUCLA2	6.2.1.5	succinate-CoA ligase (ADP-forming)
SUCLG1	6.2.1.4, 6.2.1.5	succinate-CoA ligase (GDP-forming), succinate-CoA ligase (ADP-forming)
PDHA1	1.2.1.104, 1.2.4.1	pyruvate dehydrogenase system, pyruvate dehydrogenase (acetyl-transferring)
LOXL3	1.4.3.13	protein-lysine 6-oxidase
HTRA2	3.4.21.108	HtrA2 peptidase
TPK1	2.7.6.2	thiamine diphosphokinase
ENTPD7	3.6.1.5	apyrase
FARS2	6.1.1.20	phenylalanine-tRNA ligase
DLAT	1.2.1.104, 2.3.1.12	pyruvate dehydrogenase system, dihydrolipoyllysine-residue acetyltransferase
DLD	1.2.1.104, 1.2.1.105, 1.4.1.27, 1.8.1.4	pyruvate dehydrogenase system, 2-oxoglutarate dehydrogenase system, glycine cleavage system, dihydrolipoyl dehydrogenase
MTFMT	2.1.2.9	methionyl-tRNA formyltransferase
IARS2	6.1.1.5	isoleucine-tRNA ligase
ECHS1	4.2.1.17	enoyl-CoA hydratase
GYG2	2.4.1.186	glycogenin glucosyltransferase
MT-CO1	7.1.1.9	cytochrome-c oxidase

Pharmacogenomics

Cohort genes with a PharmGKB record: 74; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

12 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
LINEZOLID	4	SDHA
PYRITHIONE	4	LOXL3
DISULFIRAM	4	LOXL3
CELECOXIB	4	MT-CO2
ROFECOXIB	4	MT-CO2
DICLOFENAC	4	MT-CO2
INDOMETHACIN	4	MT-CO2
VALDECOXIB	4	MT-CO2
CRENOLANIB	3	SUCLA2
THIRAM	2	LOXL3
PIMASERTIB	2	IARS2
TOLFENAMIC ACID	2	MT-CO2

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	SDHA, LOXL3, MT-CO2
B	Phased (≥1) drug, not yet approved	2	SUCLA2, IARS2
C	Druggable family + PDB, no drug	11	SUCLG1, SLC19A3, PDHA1, HTRA2, TPK1, FARS2, DLAT, DLD, ECHS1, GYG2 (+1 more)
D	Druggable family + AlphaFold only, no drug	6	COX10, COX15, ENTPD7, FASTKD5, FASTKD2, MTFMT
E	Difficult family or no structure, no drug	53	BCS1L, SURF1, KGD4, FOXRED1, NDUFAF2, NDUFA9, NDUFS1, NDUFS3, NDUFS4, SCO2 (+43 more)

Undrugged target profiles

70 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
BCS1L	0	SDHA
SCO2	1	MT-CO2
SUCLG1	1	SUCLA2
SCO1	0	MT-CO2
MT-CO1	19	MT-CO2
MT-CO3	1	MT-CO2
SURF1	0	—
KGD4	0	—
COX10	0	—
COX15	1	—
FOXRED1	0	—
NDUFAF2	5	—
NDUFA9	4	—
NDUFS1	5	—
NDUFS3	5	—
NDUFS4	4	—
SLC19A3	0	—
ETHE1	0	—
TACO1	0	—
PTCD3	1	—
TTC19	0	—
MTRFR	0	—
EARS2	0	—
UQCRQ	0	—
NDUFAF8	0	—
PET100	0	—
PET117	0	—
NDUFA1	4	—
NDUFA2	4	—
NDUFA3	4	—

Clinical trials & evidence

Clinical trials

Clinical trials: 14.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	7
PHASE2	5
PHASE2/PHASE3	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04378075	PHASE2/PHASE3	TERMINATED	A Study to Evaluate Efficacy and Safety of Vatiquinone for Treating Mitochondrial Disease in Participants With Refractory Epilepsy
NCT06843811	PHASE2	ENROLLING_BY_INVITATION	Sirolimus for Leigh Syndrome
NCT06990984	PHASE2	NOT_YET_RECRUITING	A Dose-ranging Study of TTI-0102 in Adults and Children With Leigh Syndrome Spectrum (LSS)
NCT01721733	PHASE2	COMPLETED	Safety and Efficacy Study of EPI-743 in Children With Leigh Syndrome
NCT02352896	PHASE2	COMPLETED	Long-Term Safety and Efficacy Evaluation of EPI-743 in Children With Leigh Syndrome
NCT03747328	PHASE2	WITHDRAWN	ABI-009 (Nab-sirolimus) in Patients With Genetically-confirmed Leigh or Leigh-like Syndrome
NCT02544217	PHASE1	COMPLETED	A Dose-escalating Clinical Trial With KH176
NCT01780168	Not specified	RECRUITING	The NIH MINI Study: Metabolism, Infection, and Immunity in Inborn Errors of Metabolism
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT01803906	Not specified	ENROLLING_BY_INVITATION	Tissue Sample Study for Mitochondrial Disorders
NCT03137355	Not specified	RECRUITING	The International Registry for Leigh Syndrome
NCT05554835	Not specified	RECRUITING	Global Registry and Natural History Study for Mitochondrial Disorders
NCT06967831	Not specified	RECRUITING	Drug Repurposing for Mitochondrial Disorders Using iPSCs Derived Neural Cells
NCT05277363	Not specified	WITHDRAWN	A Study of the Natural Course of SURF1 Deficiency

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
MANNITOL	4	1
SIROLIMUS	4	1
VATIQUINONE	3	3
SONLICROMANOL	3	1