Autosomal recessive nonsyndromic hearing loss 35

Summary

Autosomal recessive nonsyndromic hearing loss 35 (MONDO:0012060) is a disease caused by ESRRB (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: ESRRB (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 92

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive nonsyndromic hearing loss 35
Mondo ID	MONDO:0012060
MeSH	C563908
OMIM	608565
DOID	DOID:0110493
UMLS	C1837857
MedGen	324897
GARD	0022609
Is cancer (heuristic)	no

Also known as: autosomal recessive deafness 35 · autosomal recessive nonsyndromic deafness 35 · autosomal recessive nonsyndromic deafness caused by mutation in ESRRB · autosomal recessive nonsyndromic deafness type 35 · autosomal recessive nonsyndromic hearing loss 35 · deafness, autosomal recessive 35 · deafness, autosomal recessive type 35 · DFNB35 · ESRRB autosomal recessive nonsyndromic deafness

Data availability: 92 ClinVar variants · 4 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 recessive disease › hearing loss, autosomal recessive › autosomal recessive nonsyndromic hearing loss 35

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 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 28, 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

92 retrieved; paginated sample, class counts are floors:

53 uncertain significance, 20 conflicting classifications of pathogenicity, 8 pathogenic, 6 benign, 3 benign/likely benign, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1174538	NM_001379180.1(ESRRB):c.562G>A (p.Gly188Arg)	ESRRB	Pathogenic	no assertion criteria provided
3775555	NM_001379180.1(ESRRB):c.661C>T (p.Gln221Ter)	ESRRB	Pathogenic	criteria provided, single submitter
402254	NM_001379180.1(ESRRB):c.608G>A (p.Arg203His)	ESRRB	Pathogenic	no assertion criteria provided
402255	NM_001379180.1(ESRRB):c.850G>A (p.Gly284Ser)	ESRRB	Pathogenic	no assertion criteria provided
4689316	NM_001379180.1(ESRRB):c.1335_1336del (p.Phe446fs)	ESRRB	Pathogenic	criteria provided, single submitter
7498	NM_001379180.1(ESRRB):c.1081_1087dup (p.Val363fs)	ESRRB	Pathogenic	no assertion criteria provided
7499	NM_001379180.1(ESRRB):c.392C>T (p.Ala131Val)	ESRRB	Pathogenic	no assertion criteria provided
7500	NM_001379180.1(ESRRB):c.1087G>T (p.Val363Leu)	ESRRB	Pathogenic	no assertion criteria provided
1028247	NM_001379180.1(ESRRB):c.*1451C>G	ESRRB	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3601086	NM_001379180.1(ESRRB):c.834G>C (p.Trp278Cys)	ESRRB	Likely pathogenic	criteria provided, single submitter
1313365	NM_001379180.1(ESRRB):c.1360G>C (p.Val454Leu)	ESRRB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
163420	NM_001379180.1(ESRRB):c.765G>A (p.Glu255=)	ESRRB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
163421	NM_001379180.1(ESRRB):c.1120+8C>T	ESRRB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
163424	NM_001379180.1(ESRRB):c.*1517C>T	ESRRB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
163425	NM_001379180.1(ESRRB):c.*1546C>T	ESRRB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
178342	NM_001379180.1(ESRRB):c.206C>T (p.Ala69Val)	ESRRB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
178343	NM_001379180.1(ESRRB):c.1176C>T (p.His392=)	ESRRB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
179615	NM_001379180.1(ESRRB):c.689-10G>A	ESRRB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
225349	NM_001379180.1(ESRRB):c.1207C>T (p.Arg403Cys)	ESRRB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
228675	NM_001379180.1(ESRRB):c.952G>A (p.Asp318Asn)	ESRRB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
314481	NM_001379180.1(ESRRB):c.177G>A (p.Ser59=)	ESRRB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
314485	NM_001379180.1(ESRRB):c.577+15C>T	ESRRB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
314488	NM_001379180.1(ESRRB):c.*1527C>T	ESRRB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
314489	NM_001379180.1(ESRRB):c.*2287G>A	ESRRB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3389400	NM_001379180.1(ESRRB):c.938C>T (p.Ser313Leu)	ESRRB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3601085	NM_001379180.1(ESRRB):c.518G>A (p.Arg173His)	ESRRB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
44997	NM_001379180.1(ESRRB):c.*1474T>C	ESRRB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
44999	NM_001379180.1(ESRRB):c.*1535G>A	ESRRB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
869463	NM_001379180.1(ESRRB):c.583C>T (p.Arg195Cys)	ESRRB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
884543	NM_001379180.1(ESRRB):c.*1556T>C	ESRRB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
ESRRB	Definitive	Autosomal recessive	nonsyndromic genetic hearing loss	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ESRRB	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB

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
ESRRB	HGNC:3473	ENSG00000119715	O95718	Steroid hormone receptor ERR2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ESRRB	Steroid hormone receptor ERR2	Transcription factor that binds a canonical ESRRB recognition (ERRE) sequence 5’TCAAGGTCA-3’ localized on promoter and enhancer of targets genes regulating their expression or their transcription activity.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Nuclear receptor	1	385.9×	0.003

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ESRRB	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt

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
adult mammalian kidney	1
male germ line stem cell (sensu Vertebrata) in testis	1
metanephros cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ESRRB	131	tissue_specific	marker	metanephros cortex, male germ line stem cell (sensu Vertebrata) in testis, adult mammalian kidney

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ESRRB	1,965

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ESRRB	O95718	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Nuclear Receptor transcription pathway	1	200.3×	0.005	ESRRB

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
morula formation	1	5617.3×	0.003	ESRRB
cell dedifferentiation	1	2808.7×	0.003	ESRRB
stem cell division	1	1872.4×	0.003	ESRRB
regulation of stem cell division	1	1404.3×	0.003	ESRRB
negative regulation of stem cell differentiation	1	842.6×	0.004	ESRRB
stem cell population maintenance	1	421.3×	0.005	ESRRB
inner ear development	1	374.5×	0.005	ESRRB
photoreceptor cell maintenance	1	358.6×	0.005	ESRRB
positive regulation of stem cell population maintenance	1	343.9×	0.005	ESRRB
somatic stem cell population maintenance	1	247.8×	0.006	ESRRB
cell population proliferation	1	102.8×	0.013	ESRRB
regulation of DNA-templated transcription	1	31.6×	0.040	ESRRB
positive regulation of DNA-templated transcription	1	27.9×	0.041	ESRRB
positive regulation of transcription by RNA polymerase II	1	14.9×	0.072	ESRRB
regulation of transcription by RNA polymerase II	1	11.7×	0.086	ESRRB

Therapeutics

Drug target analysis

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

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

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
ESRRB	ESTRADIOL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ESRRB	2	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ESTRADIOL	4	ESRRB
GENISTEIN	2	ESRRB

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
ESRRB	27	Binding:19, Functional:8

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

2 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.

Compound	Max phase	Cohort target (bioactivity)
ESTRADIOL	4	ESRRB
GENISTEIN	2	ESRRB

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ESRRB
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.