Hearing loss, autosomal recessive 108

Summary

Hearing loss, autosomal recessive 108 (MONDO:0033200) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 8

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hearing loss, autosomal recessive 108
Mondo ID	MONDO:0033200
OMIM	617654
DOID	DOID:0080263
UMLS	C4539997
MedGen	1627841
GARD	0022658
Is cancer (heuristic)	no

Also known as: autosomal recessive nonsyndromic deafness 108 · deafness, autosomal recessive 108 · DFNB108

Data availability: 8 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 recessive disease › hearing loss, autosomal recessive › hearing loss, autosomal recessive 108

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 106, hearing loss, autosomal recessive 107, 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

8 retrieved; paginated sample, class counts are floors:

4 benign, 2 uncertain significance, 1 conflicting classifications of pathogenicity, 1 no classifications from unflagged records

ClinVar	Variant (HGVS)	Gene	Classification	Review
1647252	NM_005012.4(ROR1):c.1356G>C (p.Glu452Asp)	ROR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1028328	NM_005012.4(ROR1):c.2728T>G (p.Tyr910Asp)	ROR1	Uncertain significance	criteria provided, single submitter
1424363	NM_005012.4(ROR1):c.1639C>T (p.Pro547Ser)	ROR1	Uncertain significance	criteria provided, multiple submitters, no conflicts
437889	NM_005012.4(ROR1):c.2207G>C (p.Arg736Thr)	ROR1	no classifications from unflagged records	no classifications from unflagged records
1240716	NM_005012.4(ROR1):c.180C>T (p.Leu60=)	ROR1	Benign	criteria provided, multiple submitters, no conflicts
1246995	NM_005012.4(ROR1):c.1553C>T (p.Thr518Met)	ROR1	Benign	criteria provided, multiple submitters, no conflicts
1260721	NM_005012.4(ROR1):c.1353A>G (p.Val451=)	ROR1	Benign	criteria provided, multiple submitters, no conflicts
1284154	NM_005012.4(ROR1):c.1170G>T (p.Ala390=)	ROR1	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · 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
ROR1	Moderate	Autosomal recessive	hearing loss, autosomal recessive 108	5
RORA	Moderate	Autosomal recessive	hearing loss, autosomal recessive 108	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ROR1	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
RORA	Orphanet:528084	Non-specific syndromic intellectual disability

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
ROR1	HGNC:10256	ENSG00000185483	Q01973	Inactive tyrosine-protein kinase transmembrane receptor ROR1	gencc,clinvar
RORA	HGNC:10258	ENSG00000069667	P35398	Nuclear receptor ROR-alpha	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ROR1	Inactive tyrosine-protein kinase transmembrane receptor ROR1	Has very low kinase activity in vitro and is unlikely to function as a tyrosine kinase in vivo.
RORA	Nuclear receptor ROR-alpha	Nuclear receptor that binds DNA as a monomer to ROR response elements (RORE) containing a single core motif half-site 5’-AGGTCA-3’ preceded by a short A-T-rich sequence.

Protein-family classification

Druggable: 2 · 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	192.9×	0.010
Kinase	1	13.9×	0.071

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ROR1	Kinase	yes	2.7.10.1	Kringle, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom
RORA	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt

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
germinal epithelium of ovary	1
popliteal artery	1
tibial artery	1
lateral nuclear group of thalamus	1
skin of hip	1
upper leg skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ROR1	213	ubiquitous	marker	germinal epithelium of ovary, popliteal artery, tibial artery
RORA	284	ubiquitous	marker	upper leg skin, lateral nuclear group of thalamus, skin of hip

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ROR1	1,333
RORA	68

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ROR1	Q01973	5
RORA	P35398	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 32. 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
WNT5A-dependent internalization of FZD2, FZD5 and ROR2	1	439.2×	0.020	ROR1
Phosphorylation of CLOCK, acetylation of BMAL1 (ARNTL) at target gene promoters	1	439.2×	0.020	RORA
R-HSA-1368082	1	356.9×	0.020	RORA
The CRY:PER:kinase complex represses transactivation by the BMAL:CLOCK (ARNTL:CLOCK) complex	1	356.9×	0.020	RORA
Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genes	1	237.9×	0.020	RORA
RORA,B,C and NR1D1 (REV-ERBA) regulate gene expression	1	203.9×	0.020	RORA
R-HSA-400253	1	173.0×	0.020	RORA
SUMOylation of intracellular receptors	1	167.9×	0.020	RORA
PCP/CE pathway	1	150.3×	0.020	ROR1
Beta-catenin independent WNT signaling	1	146.4×	0.020	ROR1
Expression of BMAL (ARNTL), CLOCK, and NPAS2	1	146.4×	0.020	RORA
Heme signaling	1	107.7×	0.025	RORA
Nuclear Receptor transcription pathway	1	100.2×	0.025	RORA
SUMO E3 ligases SUMOylate target proteins	1	89.2×	0.026	RORA
SUMOylation	1	81.6×	0.026	RORA
Regulation of lipid metabolism by PPARalpha	1	70.5×	0.028	RORA
Signaling by WNT	1	56.0×	0.033	ROR1
Interleukin-4 and Interleukin-13 signaling	1	51.4×	0.034	RORA
PPARA activates gene expression	1	47.2×	0.036	RORA
Signaling by Interleukins	1	32.1×	0.049	RORA
Cytokine Signaling in Immune system	1	20.4×	0.074	RORA
Cellular responses to stress	1	18.4×	0.078	RORA
Metabolism of lipids	1	15.8×	0.083	RORA
Cellular responses to stimuli	1	15.7×	0.083	RORA
RNA Polymerase II Transcription	1	11.3×	0.111	RORA
Post-translational protein modification	1	9.6×	0.125	RORA
Gene expression (Transcription)	1	8.9×	0.129	RORA
Generic Transcription Pathway	1	7.5×	0.146	RORA
Immune System	1	6.5×	0.164	RORA
Metabolism of proteins	1	6.2×	0.165	RORA

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
cGMP metabolic process	1	2106.5×	0.007	RORA
cellular response to sterol	1	1685.2×	0.007	RORA
regulation of steroid metabolic process	1	1203.7×	0.007	RORA
T-helper 17 cell differentiation	1	1203.7×	0.007	RORA
cerebellar granule cell precursor proliferation	1	766.0×	0.007	RORA
regulation of macrophage activation	1	648.1×	0.007	RORA
positive regulation of circadian rhythm	1	601.9×	0.007	RORA
astrocyte development	1	561.7×	0.007	ROR1
cerebellar Purkinje cell differentiation	1	526.6×	0.007	RORA
intracellular receptor signaling pathway	1	495.6×	0.007	RORA
muscle cell differentiation	1	421.3×	0.008	RORA
nitric oxide biosynthetic process	1	351.1×	0.009	RORA
regulation of smoothened signaling pathway	1	312.1×	0.009	RORA
regulation of glucose metabolic process	1	280.9×	0.009	RORA
positive regulation of vascular endothelial growth factor production	1	247.8×	0.009	RORA
triglyceride homeostasis	1	240.7×	0.009	RORA
inner ear development	1	187.2×	0.011	ROR1
negative regulation of fat cell differentiation	1	156.0×	0.013	RORA
cellular response to interleukin-1	1	140.4×	0.013	RORA
circadian regulation of gene expression	1	117.0×	0.015	RORA
obsolete positive regulation of NF-kappaB transcription factor activity	1	102.8×	0.017	ROR1
cell surface receptor protein tyrosine kinase signaling pathway	1	86.9×	0.018	ROR1
negative regulation of canonical NF-kappaB signal transduction	1	86.0×	0.018	RORA
cellular response to tumor necrosis factor	1	81.8×	0.018	RORA
cholesterol homeostasis	1	78.0×	0.018	RORA
xenobiotic metabolic process	1	74.6×	0.019	RORA
negative regulation of inflammatory response	1	68.5×	0.019	RORA
cellular response to hypoxia	1	60.6×	0.021	RORA
cell population proliferation	1	51.4×	0.024	ROR1
sensory perception of sound	1	50.5×	0.024	ROR1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 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
RORA	TRETINOIN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RORA	2	4
ROR1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
TRETINOIN	4	RORA
CINTIRORGON	1	RORA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
RORA	115	Binding:111, Functional:3, Unclassified:1
ROR1	40	Binding:40

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ROR1	2.7.10.1	receptor protein-tyrosine kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
RORA	115

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

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)
TRETINOIN	4	RORA
CINTIRORGON	1	RORA

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	RORA
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	ROR1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
ROR1	40	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.