Encephalopathy-hypertrophic cardiomyopathy-renal tubular disease syndrome

Summary

Encephalopathy-hypertrophic cardiomyopathy-renal tubular disease syndrome (MONDO:0013840) is a disease caused by COQ9 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: COQ9 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 58

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

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

Identifiers

Disease identifiers

Field	Value
Canonical name	encephalopathy-hypertrophic cardiomyopathy-renal tubular disease syndrome
Mondo ID	MONDO:0013840
OMIM	614654
Orphanet	319678
DOID	DOID:0070242
UMLS	C3553374
MedGen	766288
GARD	0017470
Is cancer (heuristic)	no

Also known as: coenzyme Q10 deficiency, primary, 5 · coenzyme Q10 deficiency, primary, type 5 · COQ10D5

Data availability: 58 ClinVar variants · 2 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 › coenzyme Q10 deficiency › encephalopathy-hypertrophic cardiomyopathy-renal tubular disease 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, neonatal encephalomyopathy-cardiomyopathy-respiratory distress 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

58 retrieved; paginated sample, class counts are floors:

21 uncertain significance, 10 pathogenic, 10 conflicting classifications of pathogenicity, 7 benign/likely benign, 5 benign, 3 likely pathogenic, 2 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1027680	NM_020312.4(COQ9):c.73G>A (p.Val25Met)	COQ9	Pathogenic	no assertion criteria provided
192296	NM_020312.4(COQ9):c.521+1del	COQ9	Pathogenic	criteria provided, single submitter
1924901	NM_020312.4(COQ9):c.197_198del (p.Gln66fs)	COQ9	Pathogenic	criteria provided, multiple submitters, no conflicts
1931230	NM_020312.4(COQ9):c.679_680del (p.Met227fs)	COQ9	Pathogenic	criteria provided, multiple submitters, no conflicts
1937704	NM_020312.4(COQ9):c.202dup (p.Ala68fs)	COQ9	Pathogenic	criteria provided, single submitter
2637678	NM_020312.4(COQ9):c.157C>T (p.Gln53Ter)	COQ9	Pathogenic	criteria provided, single submitter
2910403	NM_020312.4(COQ9):c.711+3G>C	COQ9	Pathogenic	criteria provided, multiple submitters, no conflicts
3382518	NM_020312.4(COQ9):c.262G>T (p.Glu88Ter)	COQ9	Pathogenic	criteria provided, single submitter
431	NM_020312.4(COQ9):c.730C>T (p.Arg244Ter)	COQ9	Pathogenic	criteria provided, multiple submitters, no conflicts
3902374	NM_020312.4(COQ9):c.55C>T (p.Gln19Ter)	LOC112469007	Pathogenic	criteria provided, multiple submitters, no conflicts
1324161	NM_020312.4(COQ9):c.74-2A>G	COQ9	Likely pathogenic	criteria provided, single submitter
1324162	NM_020312.4(COQ9):c.522-1G>A	COQ9	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3769405	NM_020312.4(COQ9):c.242+2T>G	COQ9	Likely pathogenic	criteria provided, single submitter
1369063	NM_020312.4(COQ9):c.37G>A (p.Ala13Thr)	COQ9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
136992	NM_020312.4(COQ9):c.74-13G>A	COQ9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214241	NM_020312.4(COQ9):c.184C>T (p.His62Tyr)	COQ9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214243	NM_020312.4(COQ9):c.835G>A (p.Asp279Asn)	COQ9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214245	NM_020312.4(COQ9):c.362T>C (p.Ile121Thr)	COQ9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214248	NM_020312.4(COQ9):c.323T>G (p.Leu108Arg)	COQ9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
320007	NM_020312.4(COQ9):c.315G>A (p.Thr105=)	COQ9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
884775	NM_020312.4(COQ9):c.378+9A>G	COQ9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
884776	NM_020312.4(COQ9):c.379-9C>T	COQ9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
887925	NM_020312.4(COQ9):c.71C>T (p.Pro24Leu)	COQ9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1032073	NM_020312.4(COQ9):c.449T>C (p.Val150Ala)	COQ9	Uncertain significance	criteria provided, single submitter
1413988	NM_020312.4(COQ9):c.466C>T (p.Arg156Trp)	COQ9	Uncertain significance	criteria provided, multiple submitters, no conflicts
320002	NM_020312.4(COQ9):c.-25C>G	COQ9	Uncertain significance	criteria provided, single submitter
320006	NM_020312.4(COQ9):c.305G>A (p.Arg102His)	COQ9	Uncertain significance	criteria provided, multiple submitters, no conflicts
320009	NM_020312.4(COQ9):c.404C>T (p.Ala135Val)	COQ9	Uncertain significance	criteria provided, single submitter
320010	NM_020312.4(COQ9):c.812G>A (p.Arg271His)	COQ9	Uncertain significance	criteria provided, single submitter
320011	NM_020312.4(COQ9):c.*74G>A	COQ9	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · Orphanet: 1 · 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
COQ9	Definitive	Autosomal recessive	encephalopathy-hypertrophic cardiomyopathy-renal tubular disease syndrome	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
COQ9	Orphanet:319678	Encephalopathy-hypertrophic cardiomyopathy-renal tubular disease syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
COQ9	HGNC:25302	ENSG00000088682	O75208	Ubiquinone biosynthesis protein COQ9, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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-…

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
COQ9	Other/Unknown	no		Ubiq_biosynth_COQ9, COQ9_C, COQ9_HTH

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	1
hindlimb stylopod muscle	1
metanephros cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
COQ9	203	ubiquitous	marker	apex of heart, hindlimb stylopod muscle, metanephros cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COQ9	1,992

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
COQ9	O75208	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 evidence-associated genes (1 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 1 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	878.5×	0.001	COQ9

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
ubiquinone biosynthetic process	1	936.2×	0.002	COQ9
mitochondrial electron transport, NADH to ubiquinone	1	358.6×	0.003	COQ9

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
COQ9	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	COQ9

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
COQ9	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.