Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1

Summary

Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1 (MONDO:0011451) is a disease caused by SCO2 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: SCO2 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 89

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 1
Mondo ID	MONDO:0011451
OMIM	604377
DOID	DOID:0080357
UMLS	C5399977
MedGen	1748867
GARD	0018570
Is cancer (heuristic)	no

Also known as: cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1 · cardioencephalomyopathy, fatal infantile, due to cytochrome C oxidase deficiency type 1 · CEMCOX1 · fatal infantile encephalocardiomyopathy caused by mutation in SCO2 · mitochondrial complex IV deficiency, nuclear type 2 · SCO2 fatal infantile encephalocardiomyopathy

Data availability: 89 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 1

Related subtypes (3): cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 2, 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

89 retrieved; paginated sample, class counts are floors:

31 uncertain significance, 19 conflicting classifications of pathogenicity, 11 pathogenic/likely pathogenic, 10 likely pathogenic, 8 pathogenic, 6 benign, 4 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1034155	NM_005138.3(SCO2):c.256C>T (p.Gln86Ter)	NCAPH2	Pathogenic	criteria provided, single submitter
1517419	NM_005138.3(SCO2):c.327_328del (p.His109fs)	NCAPH2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1911265	NM_005138.3(SCO2):c.481C>T (p.Gln161Ter)	NCAPH2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1913825	NM_005138.3(SCO2):c.577G>A (p.Gly193Ser)	NCAPH2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2011646	NM_005138.3(SCO2):c.45_46del (p.Gln16fs)	NCAPH2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2130639	NM_005138.3(SCO2):c.544C>T (p.Gln182Ter)	NCAPH2	Pathogenic	criteria provided, multiple submitters, no conflicts
2413129	NM_005138.3(SCO2):c.227_230del (p.Leu76fs)	NCAPH2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2722786	NM_005138.3(SCO2):c.364C>T (p.Gln122Ter)	NCAPH2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3240428	NM_005138.3(SCO2):c.135_136del (p.Glu45fs)	NCAPH2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
5678	NM_005138.3(SCO2):c.157C>T (p.Gln53Ter)	NCAPH2	Pathogenic	criteria provided, multiple submitters, no conflicts
5679	NM_005138.3(SCO2):c.674C>T (p.Ser225Phe)	NCAPH2	Pathogenic	no assertion criteria provided
5681	NM_005138.3(SCO2):c.418G>A (p.Glu140Lys)	NCAPH2	Pathogenic	criteria provided, multiple submitters, no conflicts
5682	NM_005138.3(SCO2):c.268C>T (p.Arg90Ter)	NCAPH2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
5685	NM_005138.3(SCO2):c.107G>A (p.Trp36Ter)	NCAPH2	Pathogenic	no assertion criteria provided
222816	NM_005138.3(SCO2):c.16_17insAGCATGCAGCAGTGACTCA (p.Arg6fs)	SCO2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2678604	NM_005138.3(SCO2):c.225G>A (p.Trp75Ter)	SCO2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2737058	NM_005138.3(SCO2):c.401_402del (p.Pro134fs)	SCO2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
5683	NM_005138.3(SCO2):c.179_188dup (p.Ile63fs)	SCO2	Pathogenic	no assertion criteria provided
5684	NM_005138.3(SCO2):c.398G>A (p.Cys133Tyr)	SCO2	Pathogenic	no assertion criteria provided
2678605	NM_005138.3(SCO2):c.514_515dup (p.Asp172fs)	NCAPH2	Likely pathogenic	criteria provided, single submitter
2678606	NM_005138.3(SCO2):c.609_610del (p.His203fs)	NCAPH2	Likely pathogenic	criteria provided, single submitter
2678607	NM_005138.3(SCO2):c.672_682del (p.Ser225fs)	NCAPH2	Likely pathogenic	criteria provided, single submitter
2678608	NM_005138.3(SCO2):c.233_236delinsA (p.Leu78_Arg79delinsGln)	NCAPH2	Likely pathogenic	criteria provided, single submitter
3240427	NM_005138.3(SCO2):c.120_135del (p.Gly42fs)	NCAPH2	Likely pathogenic	criteria provided, single submitter
3588120	NM_005138.3(SCO2):c.508G>T (p.Glu170Ter)	NCAPH2	Likely pathogenic	criteria provided, single submitter
800843	NM_005138.3(SCO2):c.2T>C (p.Met1Thr)	NCAPH2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3240429	NM_005138.3(SCO2):c.563del (p.Leu188fs)	SCO2	Likely pathogenic	criteria provided, single submitter
3588119	NM_005138.3(SCO2):c.738_750dup (p.Ser251delinsGlyTer)	SCO2	Likely pathogenic	criteria provided, single submitter
3588121	NM_005138.3(SCO2):c.210_229del (p.Leu71fs)	SCO2	Likely pathogenic	criteria provided, single submitter
1029942	NM_005138.3(SCO2):c.512G>A (p.Arg171Gln)	NCAPH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 3 · 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
SCO2	Definitive	Autosomal recessive	cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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

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
SCO2	HGNC:10604	ENSG00000284194	O43819	Cytochrome c oxidase assembly factor SCO2	gencc,clinvar
NCAPH2	HGNC:25071	ENSG00000025770	Q6IBW4	Condensin-2 complex subunit H2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
NCAPH2	Condensin-2 complex subunit H2	Regulatory subunit of the condensin-2 complex, a complex that seems to provide chromosomes with an additional level of organization and rigidity and in establishing mitotic chromosome architecture.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SCO2	Other/Unknown	no		SCO1/SenC, Thioredoxin_domain, Synth_of_cyt-c-oxidase_Sco1/2
NCAPH2	Other/Unknown	no		H2_N, H2_M, CNDH2_C

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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
granulocyte	1
mucosa of transverse colon	1
right uterine tube	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SCO2	260	ubiquitous	yes	right uterine tube, granulocyte, mucosa of transverse colon
NCAPH2	260	ubiquitous	marker	cerebellar hemisphere, right hemisphere of cerebellum, cerebellar cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SCO2	2,043
NCAPH2	1,561

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SCO2	O43819	1
NCAPH2	Q6IBW4	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. 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	1	114.2×	0.045	SCO2
Condensation of Prophase Chromosomes	1	78.2×	0.045	NCAPH2
TP53 Regulates Metabolic Genes	1	64.9×	0.045	SCO2
Respiratory electron transport	1	47.6×	0.045	SCO2
Aerobic respiration and respiratory electron transport	1	44.3×	0.045	SCO2
Transcriptional Regulation by TP53	1	31.0×	0.053	SCO2
RNA Polymerase II Transcription	1	11.3×	0.124	SCO2
Gene expression (Transcription)	1	8.9×	0.136	SCO2
Generic Transcription Pathway	1	7.5×	0.142	SCO2
Metabolism	1	5.8×	0.165	SCO2

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
female meiosis chromosome separation	1	4213.0×	0.003	NCAPH2
muscle system process	1	2106.5×	0.003	SCO2
mitotic sister chromatid separation	1	1685.2×	0.003	NCAPH2
meiotic chromosome condensation	1	1404.3×	0.003	NCAPH2
positive regulation of chromosome condensation	1	1053.2×	0.003	NCAPH2
positive regulation of chromosome separation	1	842.6×	0.003	NCAPH2
positive regulation of chromosome segregation	1	648.1×	0.003	NCAPH2
mitotic chromosome condensation	1	495.6×	0.004	NCAPH2
intracellular copper ion homeostasis	1	468.1×	0.004	SCO2
respiratory electron transport chain	1	421.3×	0.004	SCO2
mitochondrial respiratory chain complex IV assembly	1	312.1×	0.004	SCO2
T cell differentiation in thymus	1	205.5×	0.006	NCAPH2
eye development	1	175.5×	0.007	SCO2
response to activity	1	162.0×	0.007	SCO2
in utero embryonic development	1	36.0×	0.028	SCO2

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
SCO2	0	0
NCAPH2	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
SCO2	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	0
E	Difficult family or no structure, no drug	2	SCO2, NCAPH2

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)
SCO2	1	—
NCAPH2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.