Hearing loss, autosomal recessive 106

Summary

Hearing loss, autosomal recessive 106 (MONDO:0033198) is a disease caused by EPS8L2 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: EPS8L2 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 29

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hearing loss, autosomal recessive 106
Mondo ID	MONDO:0033198
OMIM	617637
DOID	DOID:0080261
UMLS	C4539954
MedGen	1627111
GARD	0022656
Is cancer (heuristic)	no

Also known as: autosomal recessive nonsyndromic deafness 106 · deafness autosomal recessive 106 · deafness, autosomal recessive 106 · DFNB106

Data availability: 29 ClinVar variants · 2 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 › hearing loss, autosomal recessive 106

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 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 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

29 retrieved; paginated sample, class counts are floors:

11 pathogenic, 7 uncertain significance, 6 likely pathogenic, 4 benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1334120	NM_022772.4(EPS8L2):c.148_149insGGACA (p.Ser50fs)	EPS8L2	Pathogenic	criteria provided, single submitter
1334121	NM_022772.4(EPS8L2):c.1430dup (p.Val478fs)	EPS8L2	Pathogenic	criteria provided, multiple submitters, no conflicts
3601078	NM_022772.4(EPS8L2):c.1197G>A (p.Trp399Ter)	EPS8L2	Pathogenic	criteria provided, single submitter
3601081	NM_022772.4(EPS8L2):c.961dup (p.Ile321fs)	EPS8L2	Pathogenic	criteria provided, single submitter
3601082	NM_022772.4(EPS8L2):c.996del (p.Lys333fs)	EPS8L2	Pathogenic	criteria provided, single submitter
4077394	NM_022772.4(EPS8L2):c.818_827dup (p.Ala279fs)	EPS8L2	Pathogenic	criteria provided, single submitter
4293253	NM_022772.4(EPS8L2):c.1176G>A (p.Trp392Ter)	EPS8L2	Pathogenic	criteria provided, single submitter
433529	NM_022772.4(EPS8L2):c.1014del (p.Ser339fs)	EPS8L2	Pathogenic	criteria provided, single submitter
433530	NM_022772.4(EPS8L2):c.738del (p.Val247fs)	EPS8L2	Pathogenic	no assertion criteria provided
4531328	NM_022772.4(EPS8L2):c.1412dup (p.Asp473fs)	EPS8L2	Pathogenic	criteria provided, multiple submitters, no conflicts
4814128	NM_022772.4(EPS8L2):c.1623delinsAT (p.Pro542fs)	EPS8L2	Pathogenic	criteria provided, single submitter
3601079	NM_022772.4(EPS8L2):c.1317dup (p.Leu440fs)	EPS8L2	Likely pathogenic	criteria provided, single submitter
3601080	NM_022772.4(EPS8L2):c.357_361dup (p.Gln121fs)	EPS8L2	Likely pathogenic	criteria provided, single submitter
3779620	NM_022772.4(EPS8L2):c.883A>T (p.Lys295Ter)	EPS8L2	Likely pathogenic	criteria provided, single submitter
4077395	NM_022772.4(EPS8L2):c.1878C>A (p.Tyr626Ter)	EPS8L2	Likely pathogenic	criteria provided, single submitter
4077396	NM_022772.4(EPS8L2):c.767C>G (p.Thr256Arg)	EPS8L2	Likely pathogenic	criteria provided, single submitter
4687936	NM_022772.4(EPS8L2):c.1412del (p.Pro471fs)	EPS8L2	Likely pathogenic	criteria provided, single submitter
1028775	NM_022772.4(EPS8L2):c.206C>T (p.Thr69Met)	EPS8L2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1028776	NM_022772.4(EPS8L2):c.779A>G (p.Asn260Ser)	EPS8L2	Uncertain significance	criteria provided, single submitter
1489788	NM_022772.4(EPS8L2):c.1584G>C (p.Trp528Cys)	EPS8L2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2664027	NM_022772.4(EPS8L2):c.460C>T (p.His154Tyr)	EPS8L2	Uncertain significance	no assertion criteria provided
3064378	NM_022772.4(EPS8L2):c.163C>T (p.Gln55Ter)	EPS8L2	Uncertain significance	criteria provided, single submitter
3362824	NM_022772.4(EPS8L2):c.985-5C>A	EPS8L2	Uncertain significance	criteria provided, single submitter
804774	NM_022772.4(EPS8L2):c.80T>C (p.Met27Thr)	EPS8L2	Uncertain significance	criteria provided, multiple submitters, no conflicts
508700	NM_004447.6(EPS8):c.104A>G (p.His35Arg)	EPS8	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1185465	NM_022772.4(EPS8L2):c.100+72T>C	EPS8L2	Benign	criteria provided, multiple submitters, no conflicts
1185466	NM_022772.4(EPS8L2):c.165+72G>A	EPS8L2	Benign	criteria provided, multiple submitters, no conflicts
1185467	NM_022772.4(EPS8L2):c.301C>T (p.Leu101=)	EPS8L2	Benign	criteria provided, multiple submitters, no conflicts
1185468	NM_022772.4(EPS8L2):c.774C>T (p.Ile258=)	EPS8L2	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 2 · 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
EPS8L2	Strong	Autosomal recessive	hearing loss, autosomal recessive 106	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
EPS8L2	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
EPS8	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
EPS8L2	HGNC:21296	ENSG00000177106	Q9H6S3	Epidermal growth factor receptor kinase substrate 8-like protein 2	gencc,clinvar
EPS8	HGNC:3420	ENSG00000151491	Q12929	Epidermal growth factor receptor kinase substrate 8	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
EPS8L2	Epidermal growth factor receptor kinase substrate 8-like protein 2	Stimulates guanine exchange activity of SOS1.
EPS8	Epidermal growth factor receptor kinase substrate 8	Signaling adapter that controls various cellular protrusions by regulating actin cytoskeleton dynamics and architecture.

Protein-family classification

Druggable: 0 · Difficult: 2 · 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
Scaffold/PPI	2	17.3×	0.003

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
EPS8L2	Scaffold/PPI	no		SH3_domain, PTB/PI_dom, PH-like_dom_sf
EPS8	Scaffold/PPI	no		SH3_domain, PTB/PI_dom, PH-like_dom_sf

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
esophagus mucosa	1
lower esophagus mucosa	1
metanephros cortex	1
colonic mucosa	1
jejunal mucosa	1
mucosa of sigmoid colon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
EPS8L2	230	ubiquitous	marker	lower esophagus mucosa, metanephros cortex, esophagus mucosa
EPS8	299	ubiquitous	marker	jejunal mucosa, mucosa of sigmoid colon, colonic mucosa

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EPS8	1,634
EPS8L2	966

Intra-cohort edges

A	B	Sources
EPS8	EPS8L2	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EPS8L2	Q9H6S3	2
EPS8	Q12929	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 2 evidence-associated genes (2 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 2 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	203.9×	4e-05	EPS8L2, EPS8
Sensory processing of sound by inner hair cells of the cochlea	2	163.1×	4e-05	EPS8L2, EPS8

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 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 ruffle assembly	2	991.3×	2e-05	EPS8L2, EPS8
regulation of Rho protein signal transduction	2	510.7×	3e-05	EPS8L2, EPS8
Rho protein signal transduction	2	247.8×	9e-05	EPS8L2, EPS8
regulation of actin filament length	1	2106.5×	0.002	EPS8
actin polymerization-dependent cell motility	1	1203.7×	0.003	EPS8
dendritic cell migration	1	936.2×	0.003	EPS8
behavioral response to ethanol	1	601.9×	0.004	EPS8
actin crosslink formation	1	601.9×	0.004	EPS8
exit from mitosis	1	526.6×	0.004	EPS8
barbed-end actin filament capping	1	401.2×	0.004	EPS8
Rac protein signal transduction	1	280.9×	0.005	EPS8
regulation of postsynaptic membrane neurotransmitter receptor levels	1	247.8×	0.006	EPS8
actin filament bundle assembly	1	227.7×	0.006	EPS8
adult locomotory behavior	1	150.5×	0.008	EPS8
cellular response to leukemia inhibitory factor	1	79.5×	0.014	EPS8
regulation of cell shape	1	61.5×	0.017	EPS8
sensory perception of sound	1	50.5×	0.020	EPS8L2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 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
EPS8L2	0	0
EPS8	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	2	EPS8L2, EPS8

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
EPS8L2	0	—
EPS8	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.