X-linked nonsyndromic hearing loss

Summary

X-linked nonsyndromic hearing loss (MONDO:0019586) is a disease (an umbrella term covering 6 Mondo subtypes) with 4 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide)
• Umbrella term: 6 Mondo subtypes
• Cohort genes: 4
• ClinVar variants: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	X-linked nonsyndromic hearing loss
Mondo ID	MONDO:0019586
Orphanet	90625
DOID	DOID:0050566
UMLS	C5680192
MedGen	1825990
GARD	0016790
Is cancer (heuristic)	no

Also known as: nonsyndromic deafness, X-linked · nonsyndromic genetic deafness, X-linked · X-linked deafness · X-linked isolated neurosensory deafness type DFN · X-linked isolated neurosensory hearing loss type DFN · X-linked isolated sensorineural deafness type DFN · X-linked isolated sensorineural hearing loss type DFN · X-linked non-syndromic neurosensory deafness type DFN · X-linked non-syndromic neurosensory hearing loss type DFN · X-linked non-syndromic sensorineural deafness type DFN · X-linked non-syndromic sensorineural hearing loss type DFN · X-linked nonsyndromic deafness · X-linked nonsyndromic genetic deafness

Data availability: 1 ClinVar variant · 3 GenCC gene-disease records · 2 cell lines.

Disease family

An umbrella term covering 6 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › auditory system disorder › hearing disorder › hearing loss disorder › nonsyndromic genetic hearing loss › X-linked nonsyndromic hearing loss

Related subtypes (5): prelingual non-syndromic genetic hearing loss, postlingual non-syndromic genetic hearing loss, autosomal dominant nonsyndromic hearing loss, hearing loss, autosomal recessive, nonsyndromic deafness, Y-linked

Subtypes (6): hearing loss, X-linked 3, hearing loss, X-linked 4, X-linked hereditary sensory and autonomic neuropathy with hearing loss, hearing loss, X-linked 6, X-linked mixed hearing loss with perilymphatic gusher, hearing loss, X-linked 1

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

1 retrieved; paginated sample, class counts are floors:

1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3387797	NM_000307.5(POU3F4):c.782C>A (p.Ser261Ter)	POU3F4	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 27 · Orphanet: 12 · 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
PRPS1	Definitive	X-linked	hearing loss, X-linked 1	17
SMPX	Definitive	X-linked	nonsyndromic genetic hearing loss	6
COL4A6	Strong	X-linked	hearing loss, X-linked 6	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SMPX	Orphanet:700163	SMPX-related distal myopathy
SMPX	Orphanet:90625	Rare X-linked non-syndromic sensorineural deafness type DFN
COL4A6	Orphanet:1018	X-linked Alport syndrome-diffuse leiomyomatosis
COL4A6	Orphanet:90625	Rare X-linked non-syndromic sensorineural deafness type DFN
PRPS1	Orphanet:1187	Lethal ataxia with deafness and optic atrophy
PRPS1	Orphanet:411536	Mild phosphoribosylpyrophosphate synthetase superactivity
PRPS1	Orphanet:411543	Severe phosphoribosylpyrophosphate synthetase superactivity
PRPS1	Orphanet:423479	X-linked intellectual disability-limb spasticity-retinal dystrophy-arginine vasopressin deficiency
PRPS1	Orphanet:90625	Rare X-linked non-syndromic sensorineural deafness type DFN
PRPS1	Orphanet:99014	X-linked Charcot-Marie-Tooth disease type 5
POU3F4	Orphanet:1435	Xq21 microdeletion syndrome
POU3F4	Orphanet:90641	Rare mitochondrial non-syndromic sensorineural deafness

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SMPX	HGNC:11122	ENSG00000091482	Q9UHP9	Small muscular protein	gencc
COL4A6	HGNC:2208	ENSG00000197565	Q14031	Collagen alpha-6(IV) chain	gencc
PRPS1	HGNC:9462	ENSG00000147224	P60891	Ribose-phosphate pyrophosphokinase 1	gencc
POU3F4	HGNC:9217	ENSG00000196767	P49335	POU domain, class 3, transcription factor 4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SMPX	Small muscular protein	Plays a role in the regulatory network through which muscle cells coordinate their structural and functional states during growth, adaptation, and repair.
COL4A6	Collagen alpha-6(IV) chain	Type IV collagen is the major structural component of glomerular basement membranes (GBM), forming a ‘chicken-wire’ meshwork together with laminins, proteoglycans and entactin/nidogen.
PRPS1	Ribose-phosphate pyrophosphokinase 1	Catalyzes the synthesis of phosphoribosylpyrophosphate (PRPP) that is essential for nucleotide synthesis.
POU3F4	POU domain, class 3, transcription factor 4	Probable transcription factor which exert its primary action widely during early neural development and in a very limited set of neurons in the mature brain.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.25

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
Kinase	1	6.9×	0.410
Transcription factor	1	2.1×	0.605
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SMPX	Other/Unknown	no		Chisel
COL4A6	Other/Unknown	no		Collagen_IV_NC, Collagen, CTDL_fold
PRPS1	Kinase	yes	2.7.6.1	PRTase_dom, PRib_PP_synth_CS, Rib-P_diPkinase
POU3F4	Transcription factor	no		POU_dom, HD, Homeodomain-like_sf

Expression context

Cohort genes with no expression data: 0.

3 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ventricular zone	2
biceps brachii	1
heart right ventricle	1
skeletal muscle tissue of biceps brachii	1
lower esophagus	1
lower esophagus muscularis layer	1
mucosa of stomach	1
islet of Langerhans	1
sural nerve	1
ganglionic eminence	1
nucleus accumbens	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SMPX	186	broad	marker	heart right ventricle, biceps brachii, skeletal muscle tissue of biceps brachii
COL4A6	197	broad	marker	mucosa of stomach, lower esophagus muscularis layer, lower esophagus
PRPS1	291	ubiquitous	marker	islet of Langerhans, ventricular zone, sural nerve
POU3F4	54	broad	yes	ganglionic eminence, ventricular zone, nucleus accumbens

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COL4A6	1,535
POU3F4	1,132
SMPX	1,066
PRPS1	881

Intra-cohort edges

A	B	Sources
COL4A6	SMPX	string_interaction
POU3F4	SMPX	string_interaction

Structural data

PDB: 1 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PRPS1	P60891	27

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SMPX	Q9UHP9	67.55
POU3F4	P49335	64.25
COL4A6	Q14031	48.27

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 17. Enrichment computed across 4 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
5-Phosphoribose 1-diphosphate biosynthesis	1	1903.3×	0.009	PRPS1
Anchoring fibril formation	1	380.7×	0.011	COL4A6
Fibronectin matrix formation	1	285.5×	0.011	COL4A6
Crosslinking of collagen fibrils	1	285.5×	0.011	COL4A6
Attachment of bacteria to epithelial cells	1	248.3×	0.011	COL4A6
Attenuation phase	1	203.9×	0.011	COL4A6
Laminin interactions	1	190.3×	0.011	COL4A6
HSF1 activation	1	190.3×	0.011	COL4A6
HSF1-dependent transactivation	1	158.6×	0.012	COL4A6
Collagen chain trimerization	1	129.8×	0.013	COL4A6
Assembly of collagen fibrils and other multimeric structures	1	100.2×	0.015	COL4A6
Collagen degradation	1	87.8×	0.015	COL4A6
Collagen biosynthesis and modifying enzymes	1	85.2×	0.015	COL4A6
Non-integrin membrane-ECM interactions	1	77.2×	0.015	COL4A6
ECM proteoglycans	1	75.1×	0.015	COL4A6
Regulation of HSF1-mediated heat shock response	1	69.6×	0.015	COL4A6
Integrin cell surface interactions	1	67.2×	0.015	COL4A6

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
hypoxanthine biosynthetic process	1	4213.0×	0.003	PRPS1
pyrimidine nucleotide biosynthetic process	1	2106.5×	0.003	PRPS1
urate biosynthetic process	1	2106.5×	0.003	PRPS1
ribonucleoside monophosphate biosynthetic process	1	1053.2×	0.004	PRPS1
5-phosphoribose 1-diphosphate biosynthetic process	1	842.6×	0.004	PRPS1
purine nucleobase metabolic process	1	601.9×	0.004	PRPS1
negative regulation of mesenchymal cell apoptotic process	1	601.9×	0.004	POU3F4
purine nucleotide biosynthetic process	1	324.1×	0.006	PRPS1
collagen-activated tyrosine kinase receptor signaling pathway	1	324.1×	0.006	COL4A6
striated muscle contraction	1	210.7×	0.009	SMPX
cochlea morphogenesis	1	145.3×	0.011	POU3F4
cellular response to amino acid stimulus	1	76.6×	0.019	COL4A6
collagen fibril organization	1	56.2×	0.024	COL4A6
sensory perception of sound	1	25.2×	0.050	POU3F4
brain development	1	19.9×	0.059	POU3F4
nervous system development	1	11.5×	0.095	PRPS1
cell adhesion	1	9.4×	0.109	COL4A6
regulation of transcription by RNA polymerase II	1	2.9×	0.302	POU3F4

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 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
SMPX	0	0
COL4A6	0	0
PRPS1	0	0
POU3F4	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
PRPS1	10	Binding:10

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PRPS1	2.7.6.1	ribose-phosphate diphosphokinase

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	1	PRPS1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	SMPX, COL4A6, POU3F4

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SMPX	0	—
COL4A6	0	—
PRPS1	10	—
POU3F4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.