Autosomal dominant nonsyndromic hearing loss 58

Summary

Autosomal dominant nonsyndromic hearing loss 58 (MONDO:0014293) is a disease with 3 cohort genes.

At a glance

• Cohort genes: 3
• ClinVar variants: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal dominant nonsyndromic hearing loss 58
Mondo ID	MONDO:0014293
OMIM	615654
DOID	DOID:0110582
UMLS	C3888210
MedGen	854817
GARD	0018139
Is cancer (heuristic)	no

Also known as: autosomal dominant deafness 58 · autosomal dominant nonsyndromic deafness 58 · autosomal dominant nonsyndromic deafness type 58 · deafness, autosomal dominant 58 · DFNA58

Data availability: 1 ClinVar variant · 2 GenCC gene-disease records · 2 cell lines.

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 58

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 28, 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 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

1 retrieved; paginated sample, class counts are floors:

1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3252105	NC_000002.12:g.68218674_68450455dup	CNRIP1	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · Orphanet: 0 · 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
PLEK	Limited	Autosomal dominant	autosomal dominant nonsyndromic hearing loss 58
PPP3R1	Limited	Autosomal dominant	autosomal dominant nonsyndromic hearing loss 58

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PLEK	HGNC:9070	ENSG00000115956	P08567	Pleckstrin	gencc
PPP3R1	HGNC:9317	ENSG00000221823	P63098	Calcineurin subunit B type 1	gencc
CNRIP1	HGNC:24546	ENSG00000119865	Q96F85	CB1 cannabinoid receptor-interacting protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PLEK	Pleckstrin	Major protein kinase C substrate of platelets.
PPP3R1	Calcineurin subunit B type 1	Regulatory subunit of calcineurin, a calcium-dependent, calmodulin stimulated protein phosphatase.
CNRIP1	CB1 cannabinoid receptor-interacting protein 1	Suppresses cannabinoid receptor CNR1-mediated tonic inhibition of voltage-gated calcium channels.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 2 · 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	1	5.8×	0.327
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PLEK	Scaffold/PPI	no		DEP_dom, PH_domain, PH-like_dom_sf
PPP3R1	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, EF_Hand_1_Ca_BS
CNRIP1	Other/Unknown	no		CNRIP1

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
leukocyte	1
monocyte	1
mononuclear cell	1
Brodmann (1909) area 9	1
cortical plate	1
nucleus accumbens	1
middle temporal gyrus	1
oocyte	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PLEK	234	broad	marker	monocyte, mononuclear cell, leukocyte
PPP3R1	274	ubiquitous	marker	cortical plate, Brodmann (1909) area 9, nucleus accumbens
CNRIP1	252	ubiquitous	marker	secondary oocyte, oocyte, middle temporal gyrus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PLEK	4,119
CNRIP1	582
PPP3R1	266

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PPP3R1	P63098	21
PLEK	P08567	8

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CNRIP1	Q96F85	94.94

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 26. Enrichment computed across 3 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
Calcineurin activates NFAT	1	634.4×	0.016	PPP3R1
CLEC7A (Dectin-1) induces NFAT activation	1	519.1×	0.016	PPP3R1
Downstream signaling events of B Cell Receptor (BCR)	1	407.9×	0.016	PPP3R1
Activation of BAD and translocation to mitochondria	1	380.7×	0.016	PPP3R1
Activation of BH3-only proteins	1	248.3×	0.016	PPP3R1
DARPP-32 events	1	237.9×	0.016	PPP3R1
FCERI mediated Ca+2 mobilization	1	178.4×	0.016	PPP3R1
Signaling by the B Cell Receptor (BCR)	1	173.0×	0.016	PPP3R1
Intrinsic Pathway for Apoptosis	1	146.4×	0.016	PPP3R1
Beta-catenin independent WNT signaling	1	146.4×	0.016	PPP3R1
Fc epsilon receptor (FCERI) signaling	1	135.9×	0.016	PPP3R1
Opioid Signalling	1	132.8×	0.016	PPP3R1
C-type lectin receptors (CLRs)	1	119.0×	0.017	PPP3R1
Ca2+ pathway	1	89.2×	0.021	PPP3R1
Apoptosis	1	84.0×	0.021	PPP3R1
Programmed Cell Death	1	73.2×	0.021	PPP3R1
CLEC7A (Dectin-1) signaling	1	71.4×	0.021	PPP3R1
Signaling by WNT	1	56.0×	0.026	PPP3R1
Platelet degranulation	1	43.9×	0.031	PLEK
GPCR downstream signalling	1	21.7×	0.059	PPP3R1
Signaling by GPCR	1	20.0×	0.060	PPP3R1
G alpha (i) signalling events	1	19.5×	0.060	PPP3R1
Adaptive Immune System	1	14.9×	0.075	PPP3R1
Innate Immune System	1	12.8×	0.083	PPP3R1
Immune System	1	6.5×	0.154	PPP3R1
Signal Transduction	1	5.1×	0.187	PPP3R1

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of cell diameter	1	5617.3×	0.003	PLEK
protein secretion by platelet	1	5617.3×	0.003	PLEK
negative regulation of inositol phosphate biosynthetic process	1	2808.7×	0.003	PLEK
phospholipase C-inhibiting G protein-coupled receptor signaling pathway	1	2808.7×	0.003	PLEK
negative regulation of thrombin-activated receptor signaling pathway	1	1872.4×	0.003	PLEK
regulation of trans-synaptic signaling by endocannabinoid, modulating synaptic transmission	1	1872.4×	0.003	CNRIP1
negative regulation of signaling receptor activity	1	1872.4×	0.003	CNRIP1
platelet degranulation	1	1123.5×	0.004	PLEK
regulation of signaling receptor activity	1	1123.5×	0.004	CNRIP1
negative regulation of calcium ion import across plasma membrane	1	1123.5×	0.004	PPP3R1
thrombin-activated receptor signaling pathway	1	802.5×	0.004	PLEK
negative regulation of calcium-mediated signaling	1	702.2×	0.004	PLEK
positive regulation of actin filament depolymerization	1	624.1×	0.004	PLEK
positive regulation of integrin activation	1	624.1×	0.004	PLEK
lung epithelial cell differentiation	1	624.1×	0.004	PPP3R1
positive regulation of calcium ion import across plasma membrane	1	561.7×	0.005	PPP3R1
positive regulation of platelet activation	1	432.1×	0.005	PLEK
ruffle organization	1	432.1×	0.005	PLEK
positive regulation of actin filament bundle assembly	1	401.2×	0.005	PLEK
negative regulation of G protein-coupled receptor signaling pathway	1	401.2×	0.005	PLEK
regulation of synaptic vesicle cycle	1	374.5×	0.005	PPP3R1
inositol phosphate metabolic process	1	330.4×	0.006	PLEK
myelination in peripheral nervous system	1	295.6×	0.006	PPP3R1
calcineurin-NFAT signaling cascade	1	280.9×	0.006	PPP3R1
positive regulation of calcineurin-NFAT signaling cascade	1	267.5×	0.006	PPP3R1
obsolete vesicle docking involved in exocytosis	1	224.7×	0.007	PLEK
postsynaptic modulation of chemical synaptic transmission	1	224.7×	0.007	PPP3R1
regulation of postsynaptic neurotransmitter receptor internalization	1	208.1×	0.007	PPP3R1
cortical actin cytoskeleton organization	1	200.6×	0.007	PLEK
branching involved in blood vessel morphogenesis	1	175.5×	0.008	PPP3R1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) 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
PPP3R1	CYCLOSPORINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PPP3R1	1	4
PLEK	0	0
CNRIP1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CYCLOSPORINE	4	PPP3R1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
PLEK	1	Binding:1
PPP3R1	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 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)
CYCLOSPORINE	4	PPP3R1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PPP3R1
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	PLEK, CNRIP1

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)
PLEK	1	—
CNRIP1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.