Deafness-encephaloneuropathy-obesity-valvulopathy syndrome

Summary

Deafness-encephaloneuropathy-obesity-valvulopathy syndrome (MONDO:0013837) is a disease caused by PDSS1 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PDSS1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 116

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	deafness-encephaloneuropathy-obesity-valvulopathy syndrome
Mondo ID	MONDO:0013837
OMIM	614651
Orphanet	254898
DOID	DOID:0070239
UMLS	C3553354
MedGen	766268
GARD	0017230
Is cancer (heuristic)	no

Also known as: coenzyme Q10 deficiency, primary, 2 · coenzyme Q10 deficiency, primary, type 2 · COQ10D2 · hearing loss-encephaloneuropathy-obesity-valvulopathy syndrome

Data availability: 116 ClinVar variants · 5 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 › deafness-encephaloneuropathy-obesity-valvulopathy syndrome

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

116 retrieved; paginated sample, class counts are floors:

63 uncertain significance, 20 conflicting classifications of pathogenicity, 10 benign, 7 likely pathogenic, 6 benign/likely benign, 5 pathogenic, 4 likely benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1033282	NM_014317.5(PDSS1):c.1164_1165del (p.Ile388fs)	PDSS1	Pathogenic	criteria provided, single submitter
2499453	NM_014317.5(PDSS1):c.735G>T (p.Gln245His)	PDSS1	Pathogenic	no assertion criteria provided
2499454	NM_014317.5(PDSS1):c.716T>G (p.Val239Gly)	PDSS1	Pathogenic	no assertion criteria provided
3237	NM_014317.5(PDSS1):c.924T>G (p.Asp308Glu)	PDSS1	Pathogenic	no assertion criteria provided
375348	NM_014317.5(PDSS1):c.1108A>C (p.Ser370Arg)	PDSS1	Pathogenic	no assertion criteria provided
1878854	NM_014317.5(PDSS1):c.18G>A (p.Trp6Ter)	PDSS1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2499451	NM_014317.5(PDSS1):c.661C>T (p.Arg221Ter)	PDSS1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2500794	NM_014317.5(PDSS1):c.173_174insA (p.Ile58_Asn59insTer)	PDSS1	Likely pathogenic	criteria provided, single submitter
3594203	NM_014317.5(PDSS1):c.52dup (p.Ala18fs)	PDSS1	Likely pathogenic	criteria provided, single submitter
3594270	NM_014317.5(PDSS1):c.436C>T (p.Arg146Ter)	PDSS1	Likely pathogenic	criteria provided, single submitter
3767224	NM_014317.5(PDSS1):c.668G>T (p.Gly223Val)	PDSS1	Likely pathogenic	criteria provided, single submitter
4081585	NM_014317.5(PDSS1):c.709_710insCA (p.Asp237fs)	PDSS1	Likely pathogenic	criteria provided, single submitter
138683	NM_014317.5(PDSS1):c.589A>G (p.Lys197Glu)	PDSS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1450186	NM_014317.5(PDSS1):c.1162A>G (p.Ile388Val)	PDSS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1462868	NM_014317.5(PDSS1):c.337G>T (p.Glu113Ter)	PDSS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1624909	NM_014317.5(PDSS1):c.1157A>G (p.Glu386Gly)	PDSS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214977	NM_014317.5(PDSS1):c.1108-7C>G	PDSS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214986	NM_014317.5(PDSS1):c.686C>G (p.Ser229Cys)	PDSS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2183692	NM_014317.5(PDSS1):c.582A>G (p.Thr194=)	PDSS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2972004	NM_014317.5(PDSS1):c.294C>A (p.Leu98=)	PDSS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2977320	NM_014317.5(PDSS1):c.291A>G (p.Lys97=)	PDSS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
299691	NM_014317.5(PDSS1):c.51G>A (p.Ala17=)	PDSS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
299692	NM_014317.5(PDSS1):c.83G>T (p.Arg28Leu)	PDSS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
299695	NM_014317.5(PDSS1):c.130-10G>T	PDSS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
299696	NM_014317.5(PDSS1):c.163-12T>C	PDSS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
299697	NM_014317.5(PDSS1):c.243C>T (p.Thr81=)	PDSS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3023165	NM_014317.5(PDSS1):c.129+9G>A	PDSS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
383622	NM_014317.5(PDSS1):c.218G>A (p.Arg73His)	PDSS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
4753952	NM_014317.5(PDSS1):c.581_582del (p.Thr194fs)	PDSS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
509560	NM_014317.5(PDSS1):c.467+9T>G	PDSS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
PDSS1	Strong	Autosomal recessive	deafness-encephaloneuropathy-obesity-valvulopathy syndrome	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PDSS1	Orphanet:254898	Deafness-encephaloneuropathy-obesity-valvulopathy syndrome

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
PDSS1	HGNC:17759	ENSG00000148459	Q5T2R2	All trans-polyprenyl-diphosphate synthase PDSS1	gencc,clinvar
ABI1	HGNC:11320	ENSG00000136754	Q8IZP0	Abl interactor 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PDSS1	All trans-polyprenyl-diphosphate synthase PDSS1	Heterotetrameric enzyme that catalyzes the condensation of farnesyl diphosphate (FPP), which acts as a primer, and isopentenyl diphosphate (IPP) to produce prenyl diphosphates of varying chain lengths and participates in the determination…
ABI1	Abl interactor 1	May act in negative regulation of cell growth and transformation by interacting with nonreceptor tyrosine kinases ABL1 and/or ABL2.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · 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
Scaffold/PPI	1	8.6×	0.160
Enzyme (other)	1	6.0×	0.160

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PDSS1	Enzyme (other)	yes	2.5.1.91	Polyprenyl_synt, Isoprenoid_synthase_dom_sf, Polyprenyl_synt_CS
ABI1	Scaffold/PPI	no		T_SNARE_dom, SH3_domain, Abl-interactor_HHR_dom

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
jejunal mucosa	1
mucosa of transverse colon	1
rectum	1
amniotic fluid	1
epithelium of nasopharynx	1
palpebral conjunctiva	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PDSS1	242	ubiquitous	marker	mucosa of transverse colon, rectum, jejunal mucosa
ABI1	295	ubiquitous	marker	epithelium of nasopharynx, amniotic fluid, palpebral conjunctiva

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ABI1	1,929
PDSS1	1,811

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ABI1	Q8IZP0	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PDSS1	Q5T2R2	78.45

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 24. 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×	0.029	PDSS1
Parasite infection	1	173.0×	0.029	ABI1
Leishmania phagocytosis	1	173.0×	0.029	ABI1
RHO GTPases Activate WASPs and WAVEs	1	158.6×	0.029	ABI1
Fcgamma receptor (FCGR) dependent phagocytosis	1	139.3×	0.029	ABI1
Signaling by VEGF	1	109.8×	0.029	ABI1
FCGR3A-mediated phagocytosis	1	93.6×	0.029	ABI1
Regulation of actin dynamics for phagocytic cup formation	1	92.1×	0.029	ABI1
Leishmania infection	1	81.6×	0.029	ABI1
Parasitic Infection Pathways	1	81.6×	0.029	ABI1
VEGFA-VEGFR2 Pathway	1	69.6×	0.031	ABI1
RAC2 GTPase cycle	1	63.4×	0.031	ABI1
RAC3 GTPase cycle	1	59.5×	0.031	ABI1
RHO GTPase Effectors	1	34.0×	0.049	ABI1
RAC1 GTPase cycle	1	30.5×	0.049	ABI1
RHO GTPase cycle	1	30.1×	0.049	ABI1
Signaling by Receptor Tyrosine Kinases	1	25.8×	0.054	ABI1
Signaling by Rho GTPases	1	17.1×	0.074	ABI1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	16.7×	0.074	ABI1
Innate Immune System	1	12.8×	0.090	ABI1
Infectious disease	1	12.4×	0.090	ABI1
Disease	1	6.5×	0.155	ABI1
Immune System	1	6.5×	0.155	ABI1
Signal Transduction	1	5.1×	0.187	ABI1

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
cell projection morphogenesis	1	1404.3×	0.004	ABI1
lamellipodium morphogenesis	1	1203.7×	0.004	ABI1
positive regulation of protein tyrosine kinase activity	1	1053.2×	0.004	ABI1
isoprenoid biosynthetic process	1	842.6×	0.004	PDSS1
ubiquinone biosynthetic process	1	468.1×	0.005	PDSS1
actin polymerization or depolymerization	1	383.0×	0.005	ABI1
megakaryocyte development	1	351.1×	0.005	ABI1
dendrite morphogenesis	1	216.1×	0.007	ABI1
somitogenesis	1	187.2×	0.007	ABI1
cell surface receptor protein tyrosine kinase signaling pathway	1	86.9×	0.014	ABI1
neuron migration	1	66.9×	0.016	ABI1
negative regulation of cell population proliferation	1	21.1×	0.047	ABI1

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
PDSS1	0	0
ABI1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PDSS1	2.5.1.91	all-trans-decaprenyl-diphosphate synthase

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	PDSS1
E	Difficult family or no structure, no drug	1	ABI1

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)
PDSS1	0	—
ABI1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.