Autosomal dominant nonsyndromic hearing loss 5

Summary

Autosomal dominant nonsyndromic hearing loss 5 (MONDO:0010973) is a disease caused by GSDME (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: GSDME (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 93

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal dominant nonsyndromic hearing loss 5
Mondo ID	MONDO:0010973
MeSH	C563410
OMIM	600994
DOID	DOID:0110575
UMLS	C1832932
MedGen	331398
GARD	0018102
Is cancer (heuristic)	no

Also known as: autosomal dominant deafness 5 · autosomal dominant nonsyndromic deafness 5 · autosomal dominant nonsyndromic deafness caused by mutation in GSDME · autosomal dominant nonsyndromic deafness type 5 · deafness, autosomal dominant 5 · deafness, autosomal dominant type 5 · DFNA5 · GSDME autosomal dominant nonsyndromic deafness

Data availability: 93 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › autosomal dominant nonsyndromic hearing loss › autosomal dominant nonsyndromic hearing loss 5

Related subtypes (75): autosomal dominant nonsyndromic hearing loss 1, autosomal dominant nonsyndromic hearing loss 2A, autosomal dominant nonsyndromic hearing loss 4A, autosomal dominant nonsyndromic hearing loss 6, autosomal dominant nonsyndromic hearing loss 10, autosomal dominant nonsyndromic hearing loss 11, autosomal dominant nonsyndromic hearing loss 9, autosomal dominant nonsyndromic hearing loss 7, autosomal dominant nonsyndromic hearing loss 12, autosomal dominant nonsyndromic hearing loss 3A, autosomal dominant nonsyndromic hearing loss 13, autosomal dominant nonsyndromic hearing loss 15, autosomal dominant nonsyndromic hearing loss 17, autosomal dominant nonsyndromic hearing loss 16, autosomal dominant nonsyndromic hearing loss 20, autosomal dominant nonsyndromic hearing loss 23, autosomal dominant nonsyndromic hearing loss 25, autosomal dominant nonsyndromic hearing loss 18, autosomal dominant nonsyndromic hearing loss 24, autosomal dominant nonsyndromic hearing loss 22, autosomal dominant nonsyndromic hearing loss 30, autosomal dominant nonsyndromic hearing loss 36, autosomal dominant nonsyndromic hearing loss 21, autosomal dominant nonsyndromic hearing loss 44, autosomal dominant nonsyndromic hearing loss 48, autosomal dominant nonsyndromic hearing loss 41, autosomal dominant nonsyndromic hearing loss 49, autosomal dominant nonsyndromic hearing loss 43, autosomal dominant nonsyndromic hearing loss 28, autosomal dominant nonsyndromic hearing loss 31, autosomal dominant nonsyndromic hearing loss 47, autosomal dominant auditory neuropathy 1, autosomal dominant nonsyndromic hearing loss 53, autosomal dominant nonsyndromic hearing loss 27, autosomal dominant nonsyndromic hearing loss 59, autosomal dominant nonsyndromic hearing loss 3B, autosomal dominant nonsyndromic hearing loss 2B, autosomal dominant nonsyndromic hearing loss 50, autosomal dominant nonsyndromic hearing loss 51, autosomal dominant nonsyndromic hearing loss 64, autosomal dominant nonsyndromic hearing loss 33, autosomal dominant nonsyndromic hearing loss 4B, autosomal dominant nonsyndromic hearing loss 56, autosomal dominant nonsyndromic hearing loss 54, autosomal dominant nonsyndromic hearing loss 58, autosomal dominant nonsyndromic hearing loss 65, autosomal dominant nonsyndromic hearing loss 67, autosomal dominant nonsyndromic hearing loss 40, autosomal dominant nonsyndromic hearing loss 69, autosomal dominant nonsyndromic hearing loss 68, autosomal dominant nonsyndromic hearing loss 70, autosomal dominant nonsyndromic hearing loss 66, hearing loss, autosomal dominant 74, hearing loss, autosomal dominant 77, hearing loss, autosomal dominant 81, hearing loss, autosomal dominant 82, hearing loss, autosomal dominant 83, hearing loss, autosomal dominant 84, hearing loss, autosomal dominant 80, hearing loss, autosomal dominant 37, hearing loss, autosomal dominant 75, hearing loss, autosomal dominant 76, hearing loss, autosomal dominant 71, hearing loss, autosomal dominant 72, hearing loss, autosomal dominant 73, hearing loss, autosomal dominant 34, with or without inflammation, hearing loss, autosomal dominant 78, hearing loss, autosomal dominant 79, hearing loss, autosomal dominant 85, hearing loss, autosomal dominant 86, hearing loss, autosomal dominant 87, hearing loss, autosomal dominant 88, hearing loss, autosomal dominant 89, hearing loss, autosomal dominant 90, autosomal dominant nonsyndromic hearing loss 91

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

93 retrieved; paginated sample, class counts are floors:

32 uncertain significance, 20 conflicting classifications of pathogenicity, 20 benign, 8 benign/likely benign, 7 likely benign, 5 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
179997	NM_001127453.2(GSDME):c.991-21TTC[2]	GSDME	Pathogenic	criteria provided, multiple submitters, no conflicts
2090	NG_011593.1:g.55397_56585delins59701_59837invGCCCA	GSDME	Pathogenic	no assertion criteria provided
2092	NM_004403.3(GSDME):c.991-6C>G	GSDME	Pathogenic	no assertion criteria provided
2093	NM_004403.3(GSDME):c.1183+4A>G	GSDME	Pathogenic	no assertion criteria provided
2498199	NM_001127453.2(GSDME):c.1089_1113dup (p.Pro372fs)	GSDME	Pathogenic	no assertion criteria provided
1298356	NM_001127453.2(GSDME):c.1102C>G (p.Gln368Glu)	GSDME	Likely pathogenic	criteria provided, single submitter
1030791	NM_001127453.2(GSDME):c.212-1G>A	GSDME	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1327394	NM_001127453.2(GSDME):c.314dup (p.Ser106fs)	GSDME	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1676322	NM_001127453.2(GSDME):c.781C>T (p.Arg261Ter)	GSDME	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
178332	NM_001127453.2(GSDME):c.1122C>T (p.Pro374=)	GSDME	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
178333	NM_001127453.2(GSDME):c.658G>A (p.Gly220Ser)	GSDME	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
179118	NM_001127453.2(GSDME):c.991T>C (p.Cys331Arg)	GSDME	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
225338	NM_001127453.2(GSDME):c.1193_1196dup (p.Ser399delinsArgTer)	GSDME	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
227286	NM_001127453.2(GSDME):c.934G>A (p.Asp312Asn)	GSDME	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
228558	NM_001127453.2(GSDME):c.712C>T (p.Arg238Ter)	GSDME	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2470839	NM_001127453.2(GSDME):c.1454T>G (p.Leu485Arg)	GSDME	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
359841	NM_001127453.2(GSDME):c.1179C>T (p.Leu393=)	GSDME	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
359847	NM_001127453.2(GSDME):c.766G>A (p.Asp256Asn)	GSDME	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
359850	NM_001127453.2(GSDME):c.611A>T (p.Asp204Val)	GSDME	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
359851	NM_001127453.2(GSDME):c.584C>T (p.Ala195Val)	GSDME	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
359855	NM_001127453.2(GSDME):c.480G>C (p.Gln160His)	GSDME	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
359857	NM_001127453.2(GSDME):c.325G>A (p.Val109Ile)	GSDME	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
517175	NM_001127453.2(GSDME):c.1208T>C (p.Leu403Pro)	GSDME	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
811160	NM_001127453.2(GSDME):c.1183+5G>A	GSDME	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
908399	NM_001127453.2(GSDME):c.577-12T>G	GSDME	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
911450	NM_001127453.2(GSDME):c.75G>T (p.Leu25=)	GSDME	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2431826	NM_001127453.2(GSDME):c.868del (p.Leu290fs)	GSDME	Uncertain significance	criteria provided, single submitter
2440748	NM_001127453.2(GSDME):c.725G>A (p.Gly242Asp)	GSDME	Uncertain significance	criteria provided, single submitter
2440749	NM_001127453.2(GSDME):c.1441C>A (p.Leu481Ile)	GSDME	Uncertain significance	criteria provided, single submitter
359820	NM_001127453.2(GSDME):c.*583T>G	GSDME	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
GSDME	Strong	Autosomal dominant	autosomal dominant nonsyndromic hearing loss 5	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GSDME	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA

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
GSDME	HGNC:2810	ENSG00000105928	O60443	Gasdermin-E	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GSDME	Gasdermin-E	Precursor of a pore-forming protein that converts non-inflammatory apoptosis to pyroptosis.

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)
GSDME	Other/Unknown	no		Gasdermin_pore, Gasdermin_PUB, GSDME

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
germinal epithelium of ovary	1
jejunal mucosa	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GSDME	259	ubiquitous	marker	germinal epithelium of ovary, jejunal mucosa, stromal cell of endometrium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GSDME	794

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GSDME	O60443	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
Release of apoptotic factors from the mitochondria	1	1631.4×	0.002	GSDME
Regulation of TLR by endogenous ligand	1	496.5×	0.003	GSDME
Pyroptosis	1	423.0×	0.003	GSDME
Defective pyroptosis	1	156.4×	0.006	GSDME

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
positive regulation of immune response to tumor cell	1	8426.0×	1e-03	GSDME
pyroptotic cell death	1	5617.3×	1e-03	GSDME
programmed cell death	1	1296.3×	0.002	GSDME
inner ear auditory receptor cell differentiation	1	1203.7×	0.002	GSDME
pyroptotic inflammatory response	1	510.7×	0.004	GSDME
positive regulation of intrinsic apoptotic signaling pathway	1	481.5×	0.004	GSDME
cellular response to virus	1	200.6×	0.008	GSDME
cellular response to tumor necrosis factor	1	163.6×	0.008	GSDME
sensory perception of sound	1	100.9×	0.012	GSDME
positive regulation of MAPK cascade	1	80.6×	0.014	GSDME
negative regulation of cell population proliferation	1	42.1×	0.024	GSDME

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
GSDME	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	GSDME

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)
GSDME	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.