Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 2

Summary

Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 2 (MONDO:0014051) is a disease caused by COX15 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: COX15 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 33

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 2
Mondo ID	MONDO:0014051
OMIM	615119
DOID	DOID:0080358
UMLS	C3554534
MedGen	767448
GARD	0018571
Is cancer (heuristic)	no

Also known as: cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 2 · cardioencephalomyopathy, fatal infantile, due to cytochrome C oxidase deficiency type 2 · CEMCOX2 · COX15 fatal infantile encephalocardiomyopathy · fatal infantile encephalocardiomyopathy caused by mutation in COX15 · mitochondrial complex IV deficiency, nuclear type 6

Data availability: 33 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › cardiomyopathy › familial cardiomyopathy › fatal infantile encephalocardiomyopathy › cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 2

Related subtypes (3): cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1, cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 3, cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 4

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

33 retrieved; paginated sample, class counts are floors:

9 conflicting classifications of pathogenicity, 9 likely pathogenic, 6 pathogenic/likely pathogenic, 5 uncertain significance, 2 pathogenic, 1 benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1029833	NM_078470.6(COX15):c.305G>A (p.Trp102Ter)	COX15	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1947068	NM_078470.6(COX15):c.686C>A (p.Ser229Ter)	COX15	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2791869	NM_078470.6(COX15):c.717G>A (p.Trp239Ter)	COX15	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2957504	NM_078470.6(COX15):c.457C>T (p.Arg153Ter)	COX15	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3339589	NM_078470.6(COX15):c.597G>A (p.Trp199Ter)	COX15	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
496238	NM_078470.6(COX15):c.452C>G (p.Ser151Ter)	COX15	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6175	NM_078470.6(COX15):c.649C>T (p.Arg217Trp)	COX15	Pathogenic	criteria provided, multiple submitters, no conflicts
372717	NM_003172.4(SURF1):c.758_759del (p.Thr253fs)	SURF1	Pathogenic	criteria provided, multiple submitters, no conflicts
1805607	NM_078470.6(COX15):c.839T>C (p.Phe280Ser)	COX15	Likely pathogenic	criteria provided, single submitter
2000035	NM_078470.6(COX15):c.750+1G>T	COX15	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2233034	NM_078470.6(COX15):c.750+1G>A	COX15	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2990601	NM_078470.6(COX15):c.91-1G>C	COX15	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3589777	NM_078470.6(COX15):c.755del (p.Pro252fs)	COX15	Likely pathogenic	criteria provided, single submitter
3589782	NM_078470.6(COX15):c.751-2A>T	COX15	Likely pathogenic	criteria provided, single submitter
3589807	NM_078470.6(COX15):c.319G>T (p.Glu107Ter)	COX15	Likely pathogenic	criteria provided, single submitter
3767191	NM_078470.6(COX15):c.209G>A (p.Gly70Asp)	COX15	Likely pathogenic	criteria provided, single submitter
4279626	NM_078470.6(COX15):c.834_845delinsT (p.Ala279fs)	COX15	Likely pathogenic	criteria provided, single submitter
1499491	NM_078470.6(COX15):c.287G>T (p.Gly96Val)	COX15	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1805694	NM_078470.6(COX15):c.211C>T (p.Arg71Ter)	COX15	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1933924	NM_078470.6(COX15):c.1039del (p.Ile347fs)	COX15	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214252	NM_078470.6(COX15):c.1015G>A (p.Val339Met)	COX15	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214263	NM_078470.6(COX15):c.929C>G (p.Pro310Arg)	COX15	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2495167	NM_078470.6(COX15):c.469C>T (p.Arg157Cys)	COX15	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
280009	NM_078470.6(COX15):c.396-3C>G	COX15	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
40258	NM_078470.6(COX15):c.1030T>C (p.Ser344Pro)	COX15	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
522748	NM_078470.6(COX15):c.532C>T (p.Arg178Cys)	COX15	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1354045	NM_078470.6(COX15):c.679C>G (p.Leu227Val)	COX15	Uncertain significance	criteria provided, multiple submitters, no conflicts
298420	NM_078470.6(COX15):c.131G>A (p.Ser44Asn)	COX15	Uncertain significance	criteria provided, multiple submitters, no conflicts
298424	NM_004376.7(COX15):c.-84G>A	COX15	Uncertain significance	criteria provided, multiple submitters, no conflicts
4057289	NM_078470.6(COX15):c.1019T>C (p.Leu340Pro)	COX15	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 2 · 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
COX15	Definitive	Autosomal recessive	cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 2	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
COX15	Orphanet:1561	Fatal infantile cytochrome C oxidase deficiency
SURF1	Orphanet:391351	SURF1-related Charcot-Marie-Tooth disease type 4

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
COX15	HGNC:2263	ENSG00000014919	Q7KZN9	Heme A synthase COX15	gencc,clinvar
SURF1	HGNC:11474	ENSG00000148290	Q15526	Surfeit locus protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
COX15	Heme A synthase COX15	Catalyzes the second reaction in the biosynthesis of heme A, a prosthetic group of mitochondrial cytochrome c oxidase (CcO).
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.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Protease	1	18.3×	0.108
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
COX15	Protease	yes		COX15/CtaA_fam, Peptidase_S1_PA, HemeA_synthase_2
SURF1	Other/Unknown	no		Surf1/Shy1, Surf1/Surf4

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
caput epididymis	1
cauda epididymis	1
corpus epididymis	1
apex of heart	1
body of pancreas	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
COX15	288	ubiquitous	marker	caput epididymis, corpus epididymis, cauda epididymis
SURF1	183	ubiquitous	marker	apex of heart, body of pancreas, right lobe of liver

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COX15	2,345
SURF1	1,721

Intra-cohort edges

A	B	Sources
COX15	SURF1	biogrid_interaction, string_interaction

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
COX15	Q7KZN9	85.29
SURF1	Q15526	82.62

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Complex IV assembly	2	228.4×	9e-05	COX15, SURF1
Heme biosynthesis	1	380.7×	0.007	COX15
Respiratory electron transport	1	47.6×	0.028	SURF1
Aerobic respiration and respiratory electron transport	1	44.3×	0.028	SURF1
Metabolism	1	5.8×	0.165	SURF1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cytochrome complex assembly	1	4213.0×	0.001	COX15
respiratory chain complex IV assembly	1	1203.7×	0.002	SURF1
heme A biosynthetic process	1	766.0×	0.003	COX15
mitochondrial respiratory chain complex IV assembly	1	312.1×	0.004	SURF1
heme biosynthetic process	1	300.9×	0.004	COX15
aerobic respiration	1	123.9×	0.008	SURF1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
COX15	0	0
SURF1	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
COX15	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	1	COX15
E	Difficult family or no structure, no drug	1	SURF1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
COX15	1	—
SURF1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.