Neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome

Summary

Neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome (MONDO:0014562) is a disease caused by COQ4 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: COQ4 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 277

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		11	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome
Mondo ID	MONDO:0014562
OMIM	616276
Orphanet	457185
DOID	DOID:0070244
UMLS	C5568562
MedGen	1799985
GARD	0017796
Is cancer (heuristic)	no

Also known as: coenzyme Q10 deficiency, primary, 7 · coenzyme Q10 deficiency, primary, type 7 · COQ10D7 · COQ4-related neonatal encephalomyopathy

Data availability: 277 ClinVar variants · 3 GenCC gene-disease records · 3 cell lines.

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 › coenzyme Q10 deficiency › neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome

Related subtypes (8): coenzyme Q10 deficiency, primary, 1, autosomal recessive ataxia due to ubiquinone deficiency, familial steroid-resistant nephrotic syndrome with sensorineural deafness, deafness-encephaloneuropathy-obesity-valvulopathy syndrome, coenzyme Q10 deficiency, primary, 3, encephalopathy-hypertrophic cardiomyopathy-renal tubular disease syndrome, primary coenzyme Q10 deficiency 8, coenzyme q10 deficiency, primary, 9

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

277 retrieved; paginated sample, class counts are floors:

128 likely benign, 88 uncertain significance, 19 pathogenic, 15 conflicting classifications of pathogenicity, 11 likely pathogenic, 6 pathogenic/likely pathogenic, 5 benign/likely benign, 5 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
431013	NM_016035.4(COQ4):c.[23_33delTCCTCCGTCGG];[331G>T;356C>T]		Pathogenic	no assertion criteria provided
1368452	NM_016035.5(COQ4):c.385dup (p.Arg129fs)	COQ4	Pathogenic	criteria provided, single submitter
1388291	NM_016035.5(COQ4):c.301G>T (p.Glu101Ter)	COQ4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1455564	NM_016035.5(COQ4):c.19_20del (p.Pro7fs)	COQ4	Pathogenic	criteria provided, single submitter
1685665	NM_016035.5(COQ4):c.202G>A (p.Asp68Asn)	COQ4	Pathogenic	criteria provided, single submitter
189199	NM_016035.5(COQ4):c.433C>G (p.Arg145Gly)	COQ4	Pathogenic	no assertion criteria provided
189200	NM_016035.5(COQ4):c.421C>T (p.Arg141Ter)	COQ4	Pathogenic	criteria provided, single submitter
189201	NM_016035.5(COQ4):c.718C>T (p.Arg240Cys)	COQ4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
189202	NM_016035.5(COQ4):c.155T>C (p.Leu52Ser)	COQ4	Pathogenic	no assertion criteria provided
189203	NM_016035.5(COQ4):c.518CCA[1] (p.Thr174del)	COQ4	Pathogenic	no assertion criteria provided
2099803	NM_016035.5(COQ4):c.223G>T (p.Glu75Ter)	COQ4	Pathogenic	criteria provided, single submitter
2102003	NM_016035.5(COQ4):c.662G>A (p.Trp221Ter)	COQ4	Pathogenic	criteria provided, single submitter
2158634	NM_016035.5(COQ4):c.613C>T (p.Arg205Ter)	COQ4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
267347	NM_016035.5(COQ4):c.202G>C (p.Asp68His)	COQ4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
280320	NM_016035.5(COQ4):c.23_33del (p.Val8fs)	COQ4	Pathogenic	criteria provided, multiple submitters, no conflicts
2894348	NM_016035.5(COQ4):c.142C>T (p.Gln48Ter)	COQ4	Pathogenic	criteria provided, single submitter
3017586	NM_016035.5(COQ4):c.130_137del (p.Thr44fs)	COQ4	Pathogenic	criteria provided, single submitter
3700679	NM_016035.5(COQ4):c.626+1G>C	COQ4	Pathogenic	criteria provided, single submitter
379740	NM_016035.5(COQ4):c.402+1G>C	COQ4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
476179	NM_016035.5(COQ4):c.370G>A (p.Gly124Ser)	COQ4	Pathogenic	criteria provided, multiple submitters, no conflicts
476186	NM_016035.5(COQ4):c.67dup (p.Ala23fs)	COQ4	Pathogenic	criteria provided, single submitter
638639	NM_016035.5(COQ4):c.371G>T (p.Gly124Val)	COQ4	Pathogenic	criteria provided, single submitter
660116	NM_016035.5(COQ4):c.402+1G>A	COQ4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
915899	NM_016035.5(COQ4):c.305G>A (p.Arg102His)	COQ4	Pathogenic	criteria provided, single submitter
662282	NC_000009.12:g.(?127612384)(128566997_?)del	LOC102723566	Pathogenic	criteria provided, single submitter
1029574	NM_016035.5(COQ4):c.2T>C (p.Met1Thr)	COQ4	Likely pathogenic	criteria provided, single submitter
1679218	NM_016035.5(COQ4):c.540del (p.Ile180fs)	COQ4	Likely pathogenic	criteria provided, single submitter
2101637	NM_016035.5(COQ4):c.70+1G>A	COQ4	Likely pathogenic	criteria provided, single submitter
2897600	NM_016035.5(COQ4):c.299+1G>A	COQ4	Likely pathogenic	criteria provided, single submitter
3596460	NM_016035.5(COQ4):c.627-1G>A	COQ4	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · 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
COQ4	Strong	Autosomal recessive	neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
COQ4	Orphanet:457185	Neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome
ABCA2	Orphanet:88616	Autosomal recessive non-syndromic intellectual disability

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
COQ4	HGNC:19693	ENSG00000167113	Q9Y3A0	Ubiquinone biosynthesis protein COQ4 homolog, mitochondrial	gencc,clinvar
ABCA2	HGNC:32	ENSG00000107331	Q9BZC7	ATP-binding cassette sub-family A member 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
COQ4	Ubiquinone biosynthesis protein COQ4 homolog, mitochondrial	Lyase that catalyzes the C1-decarboxylation of 4-hydroxy-3-methoxy-5-(all-trans-decaprenyl)benzoic acid into 2-methoxy-6-(all-trans-decaprenyl)phenol during ubiquinone biosynthesis.
ABCA2	ATP-binding cassette sub-family A member 2	Probable lipid transporter that modulates cholesterol sequestration in the late endosome/lysosome by regulating the intracellular sphingolipid metabolism, in turn participates in cholesterol homeostasis.

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
Transporter	1	38.9×	0.051
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
COQ4	Other/Unknown	no		Coq4, Coq4_euk
ABCA2	Transporter	yes		ABC_transporter-like_ATP-bd, AAA+_ATPase, ABC2_TM

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
adenohypophysis	1
olfactory segment of nasal mucosa	1
right uterine tube	1
C1 segment of cervical spinal cord	1
right hemisphere of cerebellum	1
spinal cord	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
COQ4	254	ubiquitous	marker	right uterine tube, olfactory segment of nasal mucosa, adenohypophysis
ABCA2	234	ubiquitous	marker	C1 segment of cervical spinal cord, spinal cord, right hemisphere of cerebellum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ABCA2	1,678
COQ4	953

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
COQ4	Q9Y3A0	88.56
ABCA2	Q9BZC7	71.46

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
Ubiquinol biosynthesis	1	439.2×	0.007	COQ4
ABC transporters in lipid homeostasis	1	300.5×	0.007	ABCA2
ABC-family protein mediated transport	1	60.7×	0.022	ABCA2
Transport of small molecules	1	12.6×	0.078	ABCA2

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
negative regulation of intracellular cholesterol transport	1	8426.0×	9e-04	ABCA2
negative regulation of phospholipid biosynthetic process	1	8426.0×	9e-04	ABCA2
negative regulation of sphingolipid biosynthetic process	1	8426.0×	9e-04	ABCA2
regulation of protein localization to cell periphery	1	8426.0×	9e-04	ABCA2
negative regulation of steroid metabolic process	1	4213.0×	9e-04	ABCA2
ceramide translocation	1	4213.0×	9e-04	ABCA2
regulation of post-translational protein modification	1	4213.0×	9e-04	ABCA2
negative regulation of receptor-mediated endocytosis involved in cholesterol transport	1	4213.0×	9e-04	ABCA2
positive regulation of low-density lipoprotein particle receptor catabolic process	1	2808.7×	0.001	ABCA2
ganglioside metabolic process	1	2106.5×	0.001	ABCA2
regulation of intracellular cholesterol transport	1	2106.5×	0.001	ABCA2
sphingomyelin metabolic process	1	1685.2×	0.001	ABCA2
positive regulation of amyloid precursor protein biosynthetic process	1	1685.2×	0.001	ABCA2
intracellular sphingolipid homeostasis	1	1685.2×	0.001	ABCA2
negative regulation of cholesterol efflux	1	1404.3×	0.001	ABCA2
glycosphingolipid metabolic process	1	1203.7×	0.001	ABCA2
regulation of steroid metabolic process	1	1203.7×	0.001	ABCA2
central nervous system myelin formation	1	1203.7×	0.001	ABCA2
response to cholesterol	1	842.6×	0.002	ABCA2
positive regulation of amyloid precursor protein catabolic process	1	842.6×	0.002	ABCA2
regulation of protein localization to cell surface	1	842.6×	0.002	ABCA2
sphingosine biosynthetic process	1	526.6×	0.003	ABCA2
ubiquinone biosynthetic process	1	468.1×	0.003	COQ4
positive regulation of amyloid-beta formation	1	443.5×	0.003	ABCA2
response to steroid hormone	1	421.3×	0.003	ABCA2
lipid transport	1	131.7×	0.009	ABCA2
locomotory behavior	1	89.6×	0.013	ABCA2
transport across blood-brain barrier	1	89.6×	0.013	ABCA2
transmembrane transport	1	84.3×	0.013	ABCA2
cholesterol homeostasis	1	78.0×	0.014	ABCA2

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
COQ4	0	0
ABCA2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	ABCA2
E	Difficult family or no structure, no drug	1	COQ4

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)
COQ4	0	—
ABCA2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.