Autosomal recessive nonsyndromic hearing loss 28

Summary

Autosomal recessive nonsyndromic hearing loss 28 (MONDO:0012355) is a disease caused by TRIOBP (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: TRIOBP (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 138

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive nonsyndromic hearing loss 28
Mondo ID	MONDO:0012355
MeSH	C565218
OMIM	609823
DOID	DOID:0110486
NCIT	C129023
UMLS	C1853276
MedGen	342839
GARD	0022617
Is cancer (heuristic)	no

Also known as: autosomal recessive deafness 28 · autosomal recessive nonsyndromic deafness 28 · autosomal recessive nonsyndromic deafness caused by mutation in TRIOBP · autosomal recessive nonsyndromic deafness type 28 · autosomal recessive nonsyndromic hearing loss 28 · deafness, autosomal recessive 28 · deafness, autosomal recessive type 28 · DFNB28 · TRIOBP autosomal recessive nonsyndromic deafness

Data availability: 138 ClinVar variants · 3 GenCC gene-disease records · 2 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › hearing loss, autosomal recessive › autosomal recessive nonsyndromic hearing loss 28

Related subtypes (101): autosomal recessive nonsyndromic hearing loss 5, autosomal recessive nonsyndromic hearing loss 1A, autosomal recessive nonsyndromic hearing loss 2, autosomal recessive nonsyndromic hearing loss 3, autosomal recessive nonsyndromic hearing loss 4, autosomal recessive nonsyndromic hearing loss 6, autosomal recessive nonsyndromic hearing loss 7, autosomal recessive nonsyndromic hearing loss 9, autosomal recessive nonsyndromic hearing loss 8, autosomal recessive nonsyndromic hearing loss 12, autosomal recessive nonsyndromic hearing loss 15, autosomal recessive nonsyndromic hearing loss 18A, autosomal recessive nonsyndromic hearing loss 17, autosomal recessive nonsyndromic hearing loss 13, autosomal recessive nonsyndromic hearing loss 21, autosomal recessive nonsyndromic hearing loss 14, autosomal recessive nonsyndromic hearing loss 16, autosomal recessive nonsyndromic hearing loss 20, autosomal recessive nonsyndromic hearing loss 26, autosomal recessive nonsyndromic hearing loss 27, autosomal recessive nonsyndromic hearing loss 22, autosomal recessive nonsyndromic hearing loss 31, autosomal recessive nonsyndromic hearing loss 30, autosomal recessive nonsyndromic hearing loss 33, autosomal recessive nonsyndromic hearing loss 37, autosomal recessive nonsyndromic hearing loss 38, autosomal recessive nonsyndromic hearing loss 40, autosomal recessive nonsyndromic hearing loss 39, autosomal recessive nonsyndromic hearing loss 35, autosomal recessive nonsyndromic hearing loss 32, autosomal recessive nonsyndromic hearing loss 36, autosomal recessive nonsyndromic hearing loss 48, autosomal recessive nonsyndromic hearing loss 23, autosomal recessive nonsyndromic hearing loss 42, autosomal recessive nonsyndromic hearing loss 46, autosomal recessive nonsyndromic hearing loss 53, autosomal recessive nonsyndromic hearing loss 51, autosomal recessive nonsyndromic hearing loss 47, autosomal recessive nonsyndromic hearing loss 55, autosomal recessive nonsyndromic hearing loss 62, autosomal recessive nonsyndromic hearing loss 49, autosomal recessive nonsyndromic hearing loss 44, autosomal recessive nonsyndromic hearing loss 66, autosomal recessive nonsyndromic hearing loss 59, autosomal recessive nonsyndromic hearing loss 65, autosomal recessive nonsyndromic hearing loss 67, autosomal recessive nonsyndromic hearing loss 68, autosomal recessive nonsyndromic hearing loss 24, autosomal recessive nonsyndromic hearing loss 63, autosomal recessive nonsyndromic hearing loss 45, autosomal recessive nonsyndromic hearing loss 1B, autosomal recessive nonsyndromic hearing loss 71, autosomal recessive nonsyndromic hearing loss 77, autosomal recessive nonsyndromic hearing loss 25, autosomal recessive nonsyndromic hearing loss 79, autosomal recessive nonsyndromic hearing loss 84A, autosomal recessive nonsyndromic hearing loss 85, autosomal recessive nonsyndromic hearing loss 91, autosomal recessive nonsyndromic hearing loss 83, autosomal recessive nonsyndromic hearing loss 74, autosomal recessive nonsyndromic hearing loss 61, autosomal recessive nonsyndromic hearing loss 89, autosomal recessive nonsyndromic hearing loss 29, autosomal recessive nonsyndromic hearing loss 96, autosomal recessive nonsyndromic hearing loss 86, autosomal recessive nonsyndromic hearing loss 98, autosomal recessive nonsyndromic hearing loss 93, autosomal recessive nonsyndromic hearing loss 70, autosomal recessive nonsyndromic hearing loss 84B, autosomal recessive nonsyndromic hearing loss 18B, autosomal recessive nonsyndromic hearing loss 88, autosomal recessive nonsyndromic hearing loss 76, autosomal recessive nonsyndromic hearing loss 101, autosomal recessive nonsyndromic hearing loss 102, autosomal recessive nonsyndromic hearing loss 103, autosomal recessive nonsyndromic hearing loss 104, autosomal recessive nonsyndromic hearing loss 97, hearing loss, autosomal recessive 111, hearing loss, autosomal recessive 118, with cochlear aplasia, hearing loss, autosomal recessive 119, hearing loss, autosomal recessive 117, hearing loss, autosomal recessive 112, hearing loss, autosomal recessive 113, hearing loss, autosomal recessive 100, hearing loss, autosomal recessive 94, hearing loss, autosomal recessive 114, hearing loss, autosomal recessive 115, hearing loss, autosomal recessive 99, hearing loss, autosomal recessive 106, hearing loss, autosomal recessive 107, hearing loss, autosomal recessive 108, hearing loss, autosomal recessive 57, hearing loss, autosomal recessive 109, hearing loss, autosomal recessive 116, hearing loss, autosomal recessive 110, hearing loss, autosomal recessive 120, hearing loss, autosomal recessive 121, hearing loss, autosomal recessive 122, hearing loss, autosomal recessive 123, autosomal recessive nonsyndromic hearing loss 124, hearing loss, autosomal recessive 125

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

138 retrieved; paginated sample, class counts are floors:

37 uncertain significance, 32 pathogenic, 16 likely pathogenic, 16 benign, 14 conflicting classifications of pathogenicity, 13 benign/likely benign, 8 pathogenic/likely pathogenic, 2 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
449111	NM_007118.4(TRIO):c.3232C>T (p.Arg1078Trp)	TRIO	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1034395	NM_001039141.3(TRIOBP):c.3232dup (p.Arg1078fs)	TRIOBP	Pathogenic	criteria provided, multiple submitters, no conflicts
1174531	NM_001039141.3(TRIOBP):c.3214dup (p.Arg1072fs)	TRIOBP	Pathogenic	criteria provided, multiple submitters, no conflicts
1185086	NM_001039141.3(TRIOBP):c.1342C>T (p.Arg448Ter)	TRIOBP	Pathogenic	criteria provided, multiple submitters, no conflicts
1185656	NM_001039141.3(TRIOBP):c.3672_3673del (p.Arg1225fs)	TRIOBP	Pathogenic	no assertion criteria provided
1325235	NM_001039141.3(TRIOBP):c.2176C>T (p.Arg726Ter)	TRIOBP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1490	NM_001039141.3(TRIOBP):c.1039C>T (p.Arg347Ter)	TRIOBP	Pathogenic	criteria provided, multiple submitters, no conflicts
1491	NM_001039141.3(TRIOBP):c.1741C>T (p.Gln581Ter)	TRIOBP	Pathogenic	criteria provided, single submitter
1492	NM_001039141.3(TRIOBP):c.889C>T (p.Gln297Ter)	TRIOBP	Pathogenic	no assertion criteria provided
1493	NM_001039141.3(TRIOBP):c.2362C>T (p.Arg788Ter)	TRIOBP	Pathogenic	criteria provided, single submitter
1494	NM_001039141.3(TRIOBP):c.3202C>T (p.Arg1068Ter)	TRIOBP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1495	NM_001039141.3(TRIOBP):c.3349C>T (p.Arg1117Ter)	TRIOBP	Pathogenic	criteria provided, multiple submitters, no conflicts
1496	NM_001039141.3(TRIOBP):c.3202_3203del (p.Asp1069fs)	TRIOBP	Pathogenic	no assertion criteria provided
1511999	NM_001039141.3(TRIOBP):c.5184+1G>A	TRIOBP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1897803	NM_001039141.3(TRIOBP):c.4320_4321del (p.His1440fs)	TRIOBP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2445671	NM_001039141.3(TRIOBP):c.1783C>T (p.Arg595Ter)	TRIOBP	Pathogenic	criteria provided, multiple submitters, no conflicts
2445672	NM_001039141.3(TRIOBP):c.1861C>T (p.Arg621Ter)	TRIOBP	Pathogenic	criteria provided, single submitter
2445673	NM_001039141.3(TRIOBP):c.2581C>T (p.Arg861Ter)	TRIOBP	Pathogenic	criteria provided, multiple submitters, no conflicts
3255083	NM_001039141.3(TRIOBP):c.2758C>T (p.Arg920Ter)	TRIOBP	Pathogenic	criteria provided, multiple submitters, no conflicts
3382233	NM_001039141.3(TRIOBP):c.2355_2356del (p.Arg785fs)	TRIOBP	Pathogenic	criteria provided, single submitter
3601943	NM_001039141.3(TRIOBP):c.1006C>T (p.Gln336Ter)	TRIOBP	Pathogenic	criteria provided, single submitter
3601944	NM_001039141.3(TRIOBP):c.1101_1105del (p.Phe368fs)	TRIOBP	Pathogenic	criteria provided, single submitter
3601945	NM_001039141.3(TRIOBP):c.1104del (p.Pro369fs)	TRIOBP	Pathogenic	criteria provided, single submitter
3601946	NM_001039141.3(TRIOBP):c.1150C>T (p.Gln384Ter)	TRIOBP	Pathogenic	criteria provided, single submitter
3601947	NM_001039141.3(TRIOBP):c.1489C>T (p.Arg497Ter)	TRIOBP	Pathogenic	criteria provided, single submitter
3601948	NM_001039141.3(TRIOBP):c.2147_2148dup (p.Gln717fs)	TRIOBP	Pathogenic	criteria provided, single submitter
3601949	NM_001039141.3(TRIOBP):c.2220del (p.Gln740fs)	TRIOBP	Pathogenic	criteria provided, single submitter
3601951	NM_001039141.3(TRIOBP):c.2986dup (p.Tyr996fs)	TRIOBP	Pathogenic	criteria provided, single submitter
3601953	NM_001039141.3(TRIOBP):c.3011del (p.Leu1004fs)	TRIOBP	Pathogenic	criteria provided, single submitter
3601954	NM_001039141.3(TRIOBP):c.3100C>T (p.Gln1034Ter)	TRIOBP	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 4 · 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
TRIOBP	Definitive	Autosomal recessive	hearing loss, autosomal recessive	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TRIOBP	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
TRIO	Orphanet:476126	Micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome
ESPN	Orphanet:231169	Usher syndrome type 1
ESPN	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TRIOBP	HGNC:17009	ENSG00000100106	Q9H2D6	TRIO and F-actin-binding protein	gencc,clinvar
TRIO	HGNC:12303	ENSG00000038382	O75962	Triple functional domain protein	clinvar
ESPN	HGNC:13281	ENSG00000187017	B1AK53	Espin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TRIOBP	TRIO and F-actin-binding protein	Regulates actin cytoskeletal organization, cell spreading and cell contraction by directly binding and stabilizing filamentous F-actin and prevents its depolymerization.
TRIO	Triple functional domain protein	Guanine nucleotide exchange factor (GEF) for RHOA and RAC1 GTPases.
ESPN	Espin	Multifunctional actin-bundling protein.

Protein-family classification

Druggable: 1 · Difficult: 2 · Unknown: 0 · Druggable fraction: 0.33

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	2	11.5×	0.019
Kinase	1	9.2×	0.104

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TRIOBP	Scaffold/PPI	no		PH_domain, PH-like_dom_sf, M-RIP_PH
TRIO	Kinase	yes		DH_dom, Prot_kinase_dom, CRAL-TRIO_dom
ESPN	Scaffold/PPI	no		Ankyrin_rpt, WH2_dom, Ankyrin_rpt-contain_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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	1
cervix squamous epithelium	1
lower lobe of lung	1
cortical plate	1
stromal cell of endometrium	1
sural nerve	1
left testis	1
right testis	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TRIOBP	289	ubiquitous	marker	lower lobe of lung, cervix squamous epithelium, apex of heart
TRIO	279	ubiquitous	marker	sural nerve, cortical plate, stromal cell of endometrium
ESPN	184	broad	marker	right testis, left testis, right uterine tube

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TRIO	2,892
ESPN	1,702
TRIOBP	1,355

Intra-cohort edges

A	B	Sources
ESPN	TRIOBP	string_interaction

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TRIO	O75962	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ESPN	B1AK53	68.76
TRIOBP	Q9H2D6	40.77

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Sensory processing of sound by outer hair cells of the cochlea	2	135.9×	7e-04	TRIOBP, ESPN
Sensory processing of sound by inner hair cells of the cochlea	2	108.8×	7e-04	TRIOBP, ESPN
DCC mediated attractive signaling	1	237.9×	0.018	TRIO
RHOJ GTPase cycle	1	66.8×	0.036	TRIO
NRAGE signals death through JNK	1	61.4×	0.036	TRIO
RHOG GTPase cycle	1	49.4×	0.036	TRIO
G alpha (12/13) signalling events	1	45.9×	0.036	TRIO
RAC2 GTPase cycle	1	42.3×	0.036	TRIO
RAC3 GTPase cycle	1	39.6×	0.036	TRIO
RHOA GTPase cycle	1	24.9×	0.048	TRIO
CDC42 GTPase cycle	1	24.1×	0.048	TRIO
RAC1 GTPase cycle	1	20.4×	0.051	TRIO
G alpha (q) signalling events	1	19.1×	0.051	TRIO

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
microvillar actin bundle assembly	1	5617.3×	0.002	ESPN
sensory perception of sound	2	67.3×	0.002	TRIOBP, ESPN
actin modification	1	1872.4×	0.002	TRIOBP
cell surface receptor protein tyrosine phosphatase signaling pathway	1	702.2×	0.005	TRIO
auditory receptor cell stereocilium organization	1	280.9×	0.009	TRIOBP
barbed-end actin filament capping	1	267.5×	0.009	TRIOBP
postsynaptic modulation of chemical synaptic transmission	1	224.7×	0.009	TRIO
actin filament bundle assembly	1	151.8×	0.012	ESPN
positive regulation of substrate adhesion-dependent cell spreading	1	124.8×	0.012	TRIOBP
negative regulation of fat cell differentiation	1	104.0×	0.013	TRIO
neuron projection morphogenesis	1	92.1×	0.014	TRIO
regulation of small GTPase mediated signal transduction	1	48.0×	0.024	TRIO
axon guidance	1	30.2×	0.035	TRIO
cell division	1	15.4×	0.064	TRIOBP

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TRIOBP	0	0
TRIO	0	0
ESPN	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
TRIO	2	Binding:2

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	TRIO
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	TRIOBP, ESPN

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TRIOBP	0	—
TRIO	2	—
ESPN	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.