Autosomal dominant nonsyndromic hearing loss 28

Summary

Autosomal dominant nonsyndromic hearing loss 28 (MONDO:0012083) is a disease caused by GRHL2 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: GRHL2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 15

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal dominant nonsyndromic hearing loss 28
Mondo ID	MONDO:0012083
MeSH	C563890
OMIM	608641
DOID	DOID:0110557
UMLS	C1837640
MedGen	324846
GARD	0018124
Is cancer (heuristic)	no

Also known as: autosomal dominant deafness 28 · autosomal dominant nonsyndromic deafness 28 · autosomal dominant nonsyndromic deafness caused by mutation in GRHL2 · autosomal dominant nonsyndromic deafness type 28 · deafness, autosomal dominant 28 · deafness, autosomal dominant type 28 · DFNA28 · GRHL2 autosomal dominant nonsyndromic deafness

Data availability: 15 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 28

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 5, 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 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

15 retrieved; paginated sample, class counts are floors:

4 uncertain significance, 4 likely pathogenic, 3 benign, 3 pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2195	NM_024915.4(GRHL2):c.1609dup (p.Arg537fs)	GRHL2	Pathogenic	no assertion criteria provided
4528931	NM_024915.4(GRHL2):c.284+2039_678+217del	GRHL2	Pathogenic	criteria provided, single submitter
92126	NM_024915.4(GRHL2):c.1258-1G>A	GRHL2	Pathogenic	no assertion criteria provided
3600504	NM_024915.4(GRHL2):c.1099-1G>A	GRHL2	Likely pathogenic	criteria provided, single submitter
3601162	NM_024915.4(GRHL2):c.1318C>T (p.Gln440Ter)	GRHL2	Likely pathogenic	criteria provided, single submitter
3601163	NM_024915.4(GRHL2):c.1698+1G>A	GRHL2	Likely pathogenic	criteria provided, single submitter
4813842	NM_024915.4(GRHL2):c.310C>T (p.Gln104Ter)	GRHL2	Likely pathogenic	criteria provided, single submitter
178378	NM_024915.4(GRHL2):c.548G>A (p.Arg183Gln)	GRHL2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3731507	NM_024915.4(GRHL2):c.558C>G (p.Ile186Met)	GRHL2	Uncertain significance	criteria provided, single submitter
46216	NM_024915.4(GRHL2):c.1723G>A (p.Val575Met)	GRHL2	Uncertain significance	criteria provided, multiple submitters, no conflicts
517614	NM_024915.4(GRHL2):c.1081G>A (p.Val361Met)	GRHL2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1260503	NM_024915.4(GRHL2):c.*41G>A	GRHL2	Benign	criteria provided, multiple submitters, no conflicts
261793	NM_024915.4(GRHL2):c.1764-19C>T	GRHL2	Benign	criteria provided, multiple submitters, no conflicts
46214	NM_024915.4(GRHL2):c.1098+9C>T	GRHL2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
508097	NM_024915.4(GRHL2):c.-24C>G	GRHL2	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · 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
GRHL2	Definitive	Autosomal dominant	nonsyndromic genetic hearing loss	14

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GRHL2	Orphanet:423454	Nail and teeth abnormalities-marginal palmoplantar keratoderma-oral hyperpigmentation syndrome
GRHL2	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
GRHL2	Orphanet:98973	Posterior polymorphous corneal dystrophy

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
GRHL2	HGNC:2799	ENSG00000083307	Q6ISB3	Grainyhead-like protein 2 homolog	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GRHL2	Grainyhead-like protein 2 homolog	Transcription factor playing an important role in primary neurulation and in epithelial development.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GRHL2	Transcription factor	no		CP2, TF_CP2-like, GRHL1/CP2_C

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
buccal mucosa cell	1
cervix squamous epithelium	1
oviduct epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GRHL2	200	broad	marker	buccal mucosa cell, oviduct epithelium, cervix squamous epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GRHL2	1,365

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GRHL2	Q6ISB3	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

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
epithelium migration	1	16852.0×	0.001	GRHL2
epithelial cell morphogenesis involved in placental branching	1	5617.3×	0.002	GRHL2
anterior neural tube closure	1	4213.0×	0.002	GRHL2
lung lobe morphogenesis	1	2106.5×	0.002	GRHL2
cardiac ventricle morphogenesis	1	1872.4×	0.002	GRHL2
lung epithelial cell differentiation	1	1872.4×	0.002	GRHL2
cell junction assembly	1	1685.2×	0.002	GRHL2
epithelial cell morphogenesis	1	936.2×	0.003	GRHL2
face development	1	802.5×	0.003	GRHL2
embryonic cranial skeleton morphogenesis	1	581.1×	0.004	GRHL2
neural tube development	1	526.6×	0.004	GRHL2
camera-type eye development	1	358.6×	0.005	GRHL2
bicellular tight junction assembly	1	330.4×	0.005	GRHL2
embryonic digit morphogenesis	1	300.9×	0.005	GRHL2
keratinocyte differentiation	1	247.8×	0.006	GRHL2
neural tube closure	1	187.2×	0.007	GRHL2
multicellular organism growth	1	137.0×	0.009	GRHL2
brain development	1	79.5×	0.015	GRHL2
cell adhesion	1	37.5×	0.030	GRHL2
positive regulation of transcription by RNA polymerase II	1	14.9×	0.071	GRHL2
regulation of transcription by RNA polymerase II	1	11.7×	0.086	GRHL2

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
GRHL2	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	GRHL2

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)
GRHL2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.