DIAPH1-related sensorineural hearing loss-thrombocytopenia syndrome

Summary

DIAPH1-related sensorineural hearing loss-thrombocytopenia syndrome (MONDO:0044635) is a disease caused by DIAPH1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: DIAPH1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 1
• Phenotypes (HPO): 6

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		8	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

6 HPO clinical features (Orphanet curated; top 6 by frequency):

HPO ID	Term	Frequency
HP:0000408	Progressive sensorineural hearing impairment	Very frequent (80-99%)
HP:0001873	Thrombocytopenia	Very frequent (80-99%)
HP:0011877	Increased mean platelet volume	Very frequent (80-99%)
HP:0001875	Decreased total neutrophil count	Frequent (30-79%)
HP:0001891	Iron deficiency anemia	Frequent (30-79%)
HP:0006285	Enamel hypomineralization	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	DIAPH1-related sensorineural hearing loss-thrombocytopenia syndrome
Mondo ID	MONDO:0044635
Orphanet	494444
UMLS	C5567465
MedGen	1798888
GARD	0017904
Is cancer (heuristic)	no

Also known as: DIAPH1-related sensorineural hearing loss-thrombocytopenia syndrome

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

Disease family

Classification path: disease › human disease › disease by body system or component › hematologic disorder › blood platelet disease › thrombocytopenia › inherited thrombocytopenia › syndromic constitutional thrombocytopenia › DIAPH1-related sensorineural hearing loss-thrombocytopenia syndrome

Related subtypes (11): Jacobsen syndrome, platelet storage pool deficiency, Stormorken syndrome, thrombocytopenia-absent radius syndrome, radio-ulnar synostosis-amegakaryocytic thrombocytopenia syndrome, GNE myopathy, macrothrombocytopenia-lymphedema-developmental delay-facial dysmorphism-camptodactyly syndrome, thrombocytopenia 6, macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss, marcothrombocytopenia with mitral valve insufficiency, ACTB-associated syndromic thrombocytopenia

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 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
844136	NM_005219.5(DIAPH1):c.1963C>G (p.Pro655Ala)	DIAPH1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · 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
DIAPH1	Definitive	Autosomal dominant	DIAPH1-related sensorineural hearing loss-thrombocytopenia syndrome	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DIAPH1	Orphanet:2573	Moyamoya disease
DIAPH1	Orphanet:477814	Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome
DIAPH1	Orphanet:494444	DIAPH1-related sensorineural hearing loss-thrombocytopenia 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
DIAPH1	HGNC:2876	ENSG00000131504	O60610	Protein diaphanous homolog 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DIAPH1	Protein diaphanous homolog 1	Actin nucleation and elongation factor required for the assembly of F-actin structures, such as actin cables and stress fibers.

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)
DIAPH1	Other/Unknown	no		Drf_DAD, FH3_dom, GTPase-bd

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
granulocyte	1
leukocyte	1
lower esophagus mucosa	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DIAPH1	291	ubiquitous	marker	granulocyte, lower esophagus mucosa, leukocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DIAPH1	2,316

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DIAPH1	O60610	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. 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
Regulation of MITF-M dependent genes involved in invasion	1	2855.0×	0.003	DIAPH1
ERBB2 Regulates Cell Motility	1	713.8×	0.006	DIAPH1
RHOF GTPase cycle	1	259.6×	0.010	DIAPH1
RHOD GTPase cycle	1	203.9×	0.010	DIAPH1
RHOB GTPase cycle	1	154.3×	0.010	DIAPH1
RHOC GTPase cycle	1	146.4×	0.010	DIAPH1
RHO GTPases Activate Formins	1	77.7×	0.015	DIAPH1
RHOA GTPase cycle	1	74.6×	0.015	DIAPH1
Neutrophil degranulation	1	23.1×	0.043	DIAPH1

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
cellular response to histamine	1	2808.7×	0.003	DIAPH1
regulation of microtubule-based process	1	1872.4×	0.003	DIAPH1
protein localization to microtubule	1	1296.3×	0.003	DIAPH1
regulation of release of sequestered calcium ion into cytosol	1	936.2×	0.003	DIAPH1
regulation of cytoskeleton organization	1	648.1×	0.003	DIAPH1
actin filament polymerization	1	481.5×	0.003	DIAPH1
cytoskeleton organization	1	132.7×	0.010	DIAPH1
regulation of cell shape	1	123.0×	0.010	DIAPH1
sensory perception of sound	1	100.9×	0.011	DIAPH1
actin cytoskeleton organization	1	79.1×	0.013	DIAPH1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DIAPH1	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
DIAPH1	3	Binding:3

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	DIAPH1

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)
DIAPH1	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.