Autosomal recessive nonsyndromic hearing loss 9

Summary

Autosomal recessive nonsyndromic hearing loss 9 (MONDO:0010986) is a disease caused by OTOF (GenCC Definitive), with 4 cohort genes and 4 clinical trials.

At a glance

• Causal gene: OTOF (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 459
• Clinical trials: 4

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive nonsyndromic hearing loss 9
Mondo ID	MONDO:0010986
OMIM	601071
DOID	DOID:0110535
UMLS	C1832828
MedGen	331376
GARD	0022588
Is cancer (heuristic)	no

Also known as: auditory neuropathy, autosomal recessive, 1 · auditory neuropathy, nonsyndromic recessive · autosomal recessive deafness 9 · autosomal recessive nonsyndromic deafness 9 · autosomal recessive nonsyndromic deafness caused by mutation in OTOF · autosomal recessive nonsyndromic deafness type 9 · autosomal recessive nonsyndromic hearing loss 9 · deafness, autosomal recessive 9 · deafness, autosomal recessive type 9 · DFNB9 · neurosensory nonsyndromic recessive deafness 9 · NRSD9 · OTOF autosomal recessive nonsyndromic deafness

Data availability: 459 ClinVar variants · 2 ClinGen variant curations · 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 9

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 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 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

459 retrieved; paginated sample, class counts are floors:

119 conflicting classifications of pathogenicity, 99 uncertain significance, 90 pathogenic, 63 likely pathogenic, 27 benign/likely benign, 25 not provided, 19 benign, 15 pathogenic/likely pathogenic, 2 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
424809	NM_194248.2(OTOF):c.[4227+1G>T];[5193-1G>A]		Pathogenic	no assertion criteria provided
634823	NC_000016.9:g.(21575218_21624036)_(21747738_21777910)del	IGSF6	Pathogenic	criteria provided, single submitter
1185110	NM_194248.3(OTOF):c.5109_5110insTTC (p.Arg1703_Leu1704insPhe)	LOC112840921	Pathogenic	criteria provided, single submitter
3601550	NM_194248.3(OTOF):c.5082dup (p.Asp1695fs)	LOC112840921	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3601552	NM_194248.3(OTOF):c.5103+1G>A	LOC112840921	Pathogenic	criteria provided, single submitter
48253	NM_194248.3(OTOF):c.5098G>C (p.Glu1700Gln)	LOC112840921	Pathogenic	reviewed by expert panel
65787	NM_194248.3(OTOF):c.2239G>T (p.Glu747Ter)	LOC129933334	Pathogenic	criteria provided, multiple submitters, no conflicts
3601557	NM_194248.3(OTOF):c.568del (p.Glu190fs)	LOC129933336	Pathogenic	criteria provided, single submitter
1185082	NM_194248.3(OTOF):c.2985C>A (p.Cys995Ter)	OTOF	Pathogenic	no assertion criteria provided
1185578	NM_194248.3(OTOF):c.3049G>T (p.Glu1017Ter)	OTOF	Pathogenic	criteria provided, multiple submitters, no conflicts
1185627	NM_194248.3(OTOF):c.1364_1366delinsTTGC (p.Tyr455fs)	OTOF	Pathogenic	no assertion criteria provided
1185651	NM_194248.3(OTOF):c.1962dup (p.Pro655fs)	OTOF	Pathogenic	no assertion criteria provided
1202582	NM_194248.3(OTOF):c.4882C>A (p.Pro1628Thr)	OTOF	Pathogenic	criteria provided, single submitter
1211668	NM_194248.3(OTOF):c.5668T>C (p.Trp1890Arg)	OTOF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
133309	NM_194248.3(OTOF):c.1172del (p.Lys391fs)	OTOF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
164841	NM_194248.3(OTOF):c.4799+1G>A	OTOF	Pathogenic	criteria provided, multiple submitters, no conflicts
1677282	NM_194248.3(OTOF):c.2406+4A>G	OTOF	Pathogenic	no assertion criteria provided
1699487	NM_194248.3(OTOF):c.4885del (p.His1629fs)	OTOF	Pathogenic	criteria provided, single submitter
1703044	NM_194248.3(OTOF):c.2407-2del	OTOF	Pathogenic	no assertion criteria provided
1703045	NM_194248.3(OTOF):c.5833del (p.Ile1945fs)	OTOF	Pathogenic	no assertion criteria provided
1703047	NM_194248.3(OTOF):c.3592dup (p.Leu1198fs)	OTOF	Pathogenic	no assertion criteria provided
1703050	NM_194248.3(OTOF):c.4110_4120dup (p.Lys1374fs)	OTOF	Pathogenic	no assertion criteria provided
179828	NM_194248.3(OTOF):c.2977_2978del (p.Gln994fs)	OTOF	Pathogenic	criteria provided, multiple submitters, no conflicts
1799530	NM_194248.3(OTOF):c.3192C>G (p.Tyr1064Ter)	OTOF	Pathogenic	criteria provided, multiple submitters, no conflicts
1972386	NM_194248.3(OTOF):c.1962del (p.Arg656fs)	OTOF	Pathogenic	criteria provided, multiple submitters, no conflicts
21825	NM_194248.3(OTOF):c.1651del (p.Glu551fs)	OTOF	Pathogenic	criteria provided, single submitter
21831	NM_194248.3(OTOF):c.2122C>T (p.Arg708Ter)	OTOF	Pathogenic	reviewed by expert panel
21834	NM_194248.3(OTOF):c.2348del (p.Gly783fs)	OTOF	Pathogenic	criteria provided, multiple submitters, no conflicts
21840	NM_194248.3(OTOF):c.2887C>T (p.Arg963Ter)	OTOF	Pathogenic	criteria provided, multiple submitters, no conflicts
21849	NM_194248.3(OTOF):c.4275G>A (p.Trp1425Ter)	OTOF	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 5 · 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
OTOF	Definitive	Unknown	autosomal recessive nonsyndromic hearing loss 9	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
OTOF	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
MYO15A	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
RAI1	Orphanet:1713	17p11.2 microduplication syndrome
RAI1	Orphanet:477817	PMP22-RAI1 contiguous gene duplication syndrome
RAI1	Orphanet:819	Smith-Magenis syndrome

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
OTOF	HGNC:8515	ENSG00000115155	Q9HC10	Otoferlin	gencc,clinvar
IGSF6	HGNC:5953	ENSG00000140749	O95976	Immunoglobulin superfamily member 6	clinvar
MYO15A	HGNC:7594	ENSG00000091536	Q9UKN7	Unconventional myosin-XV	clinvar
RAI1	HGNC:9834	ENSG00000108557	Q7Z5J4	Retinoic acid-induced protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
OTOF	Otoferlin	Key calcium ion sensor involved in the Ca(2+)-triggered synaptic vesicle-plasma membrane fusion and in the control of neurotransmitter release at these output synapses.
MYO15A	Unconventional myosin-XV	Myosins are actin-based motor molecules with ATPase activity.
RAI1	Retinoic acid-induced protein 1	Transcriptional regulator of the circadian clock components: CLOCK, BMAL1, BMAL2, PER1/3, CRY1/2, NR1D1/2 and RORA/C.

Protein-family classification

Druggable: 1 · Difficult: 2 · Unknown: 1 · Druggable fraction: 0.25

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
Antibody/Immunoglobulin	1	7.3×	0.424
Scaffold/PPI	1	4.3×	0.424
Transcription factor	1	2.1×	0.538
Other/Unknown	1	0.5×	0.962

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
OTOF	Other/Unknown	no		C2_dom, Ferlin_B-domain, FerIin_dom
IGSF6	Antibody/Immunoglobulin	yes		Ig-like_dom, Ig_V-set, Ig-like_fold
MYO15A	Scaffold/PPI	no		IQ_motif_EF-hand-BS, FERM_domain, MyTH4_dom
RAI1	Transcription factor	no		Znf_PHD, Znf_RING/FYVE/PHD, EPHD

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
caudate nucleus	1
nucleus accumbens	1
putamen	1
blood	1
leukocyte	1
monocyte	1
adenohypophysis	1
left testis	1
pituitary gland	1
nipple	1
palpebral conjunctiva	1
pigmented layer of retina	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
OTOF	109	tissue_specific	marker	nucleus accumbens, putamen, caudate nucleus
IGSF6	135	broad	marker	monocyte, leukocyte, blood
MYO15A	170	tissue_specific	marker	pituitary gland, adenohypophysis, left testis
RAI1	264	ubiquitous	marker	pigmented layer of retina, nipple, palpebral conjunctiva

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RAI1	1,979
MYO15A	1,256
OTOF	1,251
IGSF6	1,250

Intra-cohort edges

A	B	Sources
MYO15A	OTOF	string_interaction

Structural data

PDB: 1 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MYO15A	Q9UKN7	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
IGSF6	O95976	79.03
OTOF	Q9HC10	76.98
RAI1	Q7Z5J4	39.62

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 4 evidence-associated genes (3 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 3 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 inner hair cells of the cochlea	2	108.8×	8e-04	OTOF, MYO15A
Insertion of tail-anchored proteins into the endoplasmic reticulum membrane	1	158.6×	0.017	OTOF
Sensory processing of sound	1	102.9×	0.017	MYO15A
Expression of BMAL (ARNTL), CLOCK, and NPAS2	1	97.6×	0.017	RAI1
Heme signaling	1	71.8×	0.017	RAI1
Sensory processing of sound by outer hair cells of the cochlea	1	68.0×	0.017	MYO15A
Sensory Perception	1	31.7×	0.031	MYO15A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
sensory perception of sound	2	50.5×	0.009	OTOF, MYO15A
negative regulation of multicellular organism growth	1	280.9×	0.017	RAI1
response to light stimulus	1	221.7×	0.017	MYO15A
synaptic vesicle exocytosis	1	191.5×	0.017	OTOF
regulation of neurotransmitter secretion	1	191.5×	0.017	OTOF
membrane fusion	1	156.0×	0.017	OTOF
inner ear morphogenesis	1	75.2×	0.030	MYO15A
circadian regulation of gene expression	1	58.5×	0.034	RAI1
locomotory behavior	1	44.8×	0.039	MYO15A
skeletal system development	1	31.4×	0.048	RAI1
actin filament organization	1	29.7×	0.048	MYO15A
endocytosis	1	23.8×	0.055	MYO15A
cell surface receptor signaling pathway	1	16.0×	0.075	IGSF6
immune response	1	11.8×	0.094	IGSF6
positive regulation of DNA-templated transcription	1	7.0×	0.145	RAI1
regulation of transcription by RNA polymerase II	1	2.9×	0.302	RAI1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 4 evidence-associated genes (25%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
OTOF	0	0
IGSF6	0	0
MYO15A	0	0
RAI1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
MYO15A	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	1	IGSF6
E	Difficult family or no structure, no drug	3	OTOF, MYO15A, RAI1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
OTOF	0	—
IGSF6	0	—
MYO15A	1	—
RAI1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 4.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06370351	PHASE1/PHASE2	RECRUITING	A Phase I/II Clinical Trial with SENS-501 in Children Suffering from Severe to Profound Hearing Loss Due to Otoferlin (OTOF) Mutations
NCT05402813	Not specified	RECRUITING	Natural History in Children up to 16 Years With Mild to Profound Hearing Loss Due to Mutations in GJB2 / OTOF Genes
NCT06722170	Not specified	RECRUITING	A Study of EH002 Gene Therapy for Otoferlin Gene Mutation-mediated Hearing Loss
NCT05901480	Not specified	UNKNOWN	An Investigator Initiated Study for OTOV101N+OTOV101C Injection