Leigh syndrome with cardiomyopathy

Summary

Leigh syndrome with cardiomyopathy (MONDO:0019083) is a disease with 4 cohort genes. The dominant Reactome pathway is Respiratory electron transport (4 cohort genes).

At a glance

• Cohort genes: 4

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Leigh syndrome with cardiomyopathy
Mondo ID	MONDO:0019083
Orphanet	70474
ICD-11	583594497
GARD	0016685
Is cancer (heuristic)	no

Also known as: cardiomyopathy with hypotonia due to cytochrome C oxidase deficiency · cardiomyopathy with myopathy due to COX deficiency · Leigh disease with myopathy

Data availability: 4 GenCC gene-disease records.

Disease family

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 › Leigh syndrome with cardiomyopathy

Related subtypes (3): necrotizing encephalomyelopathy, subacute, of Leigh, adult, congenital lactic acidosis, Saguenay-Lac-Saint-Jean type, maternally-inherited Leigh syndrome

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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 28 · Orphanet: 4 · 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
SURF1	Definitive	Autosomal recessive	Leigh syndrome	9
NDUFAF3	Supportive	Autosomal recessive	Leigh syndrome with cardiomyopathy	5
NDUFB8	Supportive	Autosomal recessive	Leigh syndrome with cardiomyopathy	5
NDUFS2	Supportive	Autosomal recessive	Leigh syndrome with leukodystrophy	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SURF1	Orphanet:391351	SURF1-related Charcot-Marie-Tooth disease type 4
NDUFAF3	Orphanet:2609	Isolated complex I deficiency
NDUFS2	Orphanet:104	Leber hereditary optic neuropathy
NDUFS2	Orphanet:2609	Isolated complex I deficiency

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SURF1	HGNC:11474	ENSG00000148290	Q15526	Surfeit locus protein 1	gencc
NDUFAF3	HGNC:29918	ENSG00000178057	Q9BU61	NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 3	gencc
NDUFB8	HGNC:7703	ENSG00000166136	O95169	NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 8, mitochondrial	gencc
NDUFS2	HGNC:7708	ENSG00000158864	O75306	NADH dehydrogenase [ubiquinone] iron-sulfur protein 2, mitochondrial	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
NDUFAF3	NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 3	Essential factor for the assembly of mitochondrial NADH:ubiquinone oxidoreductase complex (complex I).
NDUFB8	NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 8, mitochondrial	Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed not to be involved in catalysis.
NDUFS2	NADH dehydrogenase [ubiquinone] iron-sulfur protein 2, 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.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 4 · Druggable fraction: 0.0

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
Other/Unknown	4	1.8×	0.097

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SURF1	Other/Unknown	no		Surf1/Shy1, Surf1/Surf4
NDUFAF3	Other/Unknown	no		NDUFAF3/AAMDC, NDUF3, MTH938-like_sf
NDUFB8	Other/Unknown	no		NDUFB8, Ndufb8_metazoa
NDUFS2	Other/Unknown	no		NADH_Q_OxRdtase_suD, NADH_UbQ_OxRdtase_49kDa_CS, NDH1_su_D/H

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	3
body of pancreas	1
right lobe of liver	1
left testis	1
right testis	1
Brodmann (1909) area 23	1
endothelial cell	1
lateral nuclear group of thalamus	1
gastrocnemius	1
heart left ventricle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SURF1	183	ubiquitous	marker	apex of heart, body of pancreas, right lobe of liver
NDUFAF3	280	ubiquitous	marker	left testis, right testis, apex of heart
NDUFB8	305	ubiquitous	marker	endothelial cell, lateral nuclear group of thalamus, Brodmann (1909) area 23
NDUFS2	292	ubiquitous	marker	apex of heart, gastrocnemius, heart left ventricle

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NDUFS2	4,412
NDUFB8	3,366
SURF1	1,721
NDUFAF3	1,332

Intra-cohort edges

A	B	Sources
NDUFAF3	NDUFS2	biogrid_interaction, string_interaction

Structural data

PDB: 2 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NDUFS2	O75306	8
NDUFB8	O95169	7

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SURF1	Q15526	82.62
NDUFAF3	Q9BU61	79.02

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 4 evidence-associated genes (4 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 4 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	4	95.2×	5e-08	SURF1, NDUFAF3, NDUFB8, NDUFS2
Aerobic respiration and respiratory electron transport	4	88.5×	5e-08	SURF1, NDUFAF3, NDUFB8, NDUFS2
Complex I biogenesis	3	124.1×	2e-06	NDUFAF3, NDUFB8, NDUFS2
Metabolism	4	11.6×	1e-04	SURF1, NDUFAF3, NDUFB8, NDUFS2
Complex IV assembly	1	57.1×	0.024	SURF1
Protein localization	1	47.6×	0.024	NDUFB8
Mitochondrial protein import	1	42.0×	0.024	NDUFB8

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
aerobic respiration	3	185.9×	3e-06	SURF1, NDUFB8, NDUFS2
mitochondrial respiratory chain complex I assembly	2	205.5×	2e-04	NDUFAF3, NDUFS2
mitochondrial electron transport, NADH to ubiquinone	2	179.3×	2e-04	NDUFB8, NDUFS2
proton motive force-driven mitochondrial ATP synthesis	2	131.7×	2e-04	NDUFB8, NDUFS2
cellular response to oxygen levels	1	1053.2×	0.002	NDUFS2
gliogenesis	1	702.2×	0.003	NDUFS2
respiratory chain complex IV assembly	1	601.9×	0.003	SURF1
mitochondrial ATP synthesis coupled electron transport	1	468.1×	0.003	NDUFS2
neural precursor cell proliferation	1	168.5×	0.007	NDUFS2
mitochondrial respiratory chain complex IV assembly	1	156.0×	0.007	SURF1
neurogenesis	1	52.0×	0.019	NDUFS2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 4

Druggability breadth: 3 of 4 evidence-associated genes (75%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SURF1	0	0
NDUFAF3	0	0
NDUFB8	0	0
NDUFS2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
NDUFS2	11	Binding:10, Functional:1
NDUFB8	5	Binding:5
NDUFAF3	4	Binding:4

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	SURF1, NDUFAF3, NDUFB8, NDUFS2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SURF1	0	—
NDUFAF3	4	—
NDUFB8	5	—
NDUFS2	11	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.