Autosomal dominant nonsyndromic hearing loss 64

Summary

Autosomal dominant nonsyndromic hearing loss 64 (MONDO:0013593) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 9

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal dominant nonsyndromic hearing loss 64
Mondo ID	MONDO:0013593
OMIM	614152
DOID	DOID:0110585
UMLS	C3279948
MedGen	481578
GARD	0018134
Is cancer (heuristic)	no

Also known as: autosomal dominant deafness 64 · autosomal dominant nonsyndromic deafness 64 · autosomal dominant nonsyndromic deafness caused by mutation in DIABLO · autosomal dominant nonsyndromic deafness type 64 · deafness, autosomal dominant 64 · deafness, autosomal dominant type 64 · DFNA64 · DIABLO autosomal dominant nonsyndromic deafness

Data availability: 9 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 dominant disease › autosomal dominant nonsyndromic hearing loss › autosomal dominant nonsyndromic hearing loss 64

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 33, autosomal dominant nonsyndromic hearing loss 4B, autosomal dominant nonsyndromic hearing loss 56, autosomal dominant nonsyndromic hearing loss 54, autosomal dominant nonsyndromic hearing loss 58, 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

9 retrieved; paginated sample, class counts are floors:

3 uncertain significance, 3 likely pathogenic, 2 conflicting classifications of pathogenicity, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3250381	NM_001371333.1(DIABLO):c.718T>C (p.Ter240Arg)	B3GNT4	Likely pathogenic	criteria provided, single submitter
3250382	NM_001371333.1(DIABLO):c.248_251del (p.Asp83fs)	DIABLO	Likely pathogenic	criteria provided, single submitter
3601069	NM_001371333.1(DIABLO):c.381GGA[1] (p.Glu129del)	DIABLO	Likely pathogenic	criteria provided, single submitter
2440779	NM_001371333.1(DIABLO):c.605G>A (p.Arg202Gln)	B3GNT4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
30449	NM_001371333.1(DIABLO):c.377C>T (p.Ser126Leu)	DIABLO	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1279938	NM_001371333.1(DIABLO):c.219G>C (p.Leu73Phe)	DIABLO	Uncertain significance	criteria provided, single submitter
2688925	NM_001371333.1(DIABLO):c.234_235del (p.Ser79fs)	DIABLO	Uncertain significance	criteria provided, single submitter
3393394	NM_001371333.1(DIABLO):c.274A>G (p.Thr92Ala)	DIABLO	Uncertain significance	criteria provided, single submitter
1225653	NM_001371333.1(DIABLO):c.51-318dup	DIABLO	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
DIABLO	Supportive	Autosomal dominant	autosomal dominant nonsyndromic hearing loss	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DIABLO	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA

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
DIABLO	HGNC:21528	ENSG00000184047	Q9NR28	Diablo IAP-binding mitochondrial protein	gencc,clinvar
B3GNT4	HGNC:15683	ENSG00000176383	Q9C0J1	N-acetyllactosaminide beta-1,3-N-acetylglucosaminyltransferase 4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DIABLO	Diablo IAP-binding mitochondrial protein	Promotes apoptosis by activating caspases in the cytochrome c/Apaf-1/caspase-9 pathway.
B3GNT4	N-acetyllactosaminide beta-1,3-N-acetylglucosaminyltransferase 4	Beta-1,3-N-acetylglucosaminyltransferase involved in the synthesis of poly-N-acetyllactosamine.

Protein-family classification

Druggable: 0 · Difficult: 0 · 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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DIABLO	Other/Unknown	no		Smac/DIABLO-like_sf, Smac_DIABLO
B3GNT4	Other/Unknown	no		Glyco_trans_31

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
islet of Langerhans	1
left testis	1
right testis	1
olfactory bulb	1
oocyte	1
type B pancreatic cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DIABLO	142	ubiquitous	marker	right testis, left testis, islet of Langerhans
B3GNT4	181	broad	yes	oocyte, olfactory bulb, type B pancreatic cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DIABLO	2,259
B3GNT4	484

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DIABLO	Q9NR28	16

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
B3GNT4	Q9C0J1	87.51

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 14. 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
Release of apoptotic factors from the mitochondria	1	815.7×	0.004	DIABLO
SMAC (DIABLO) binds to IAPs	1	815.7×	0.004	DIABLO
SMAC(DIABLO)-mediated dissociation of IAP:caspase complexes	1	815.7×	0.004	DIABLO
SMAC, XIAP-regulated apoptotic response	1	815.7×	0.004	DIABLO
Regulation of the apoptosome activity	1	519.1×	0.005	DIABLO
Keratan sulfate/keratin metabolism	1	248.3×	0.009	B3GNT4
Keratan sulfate biosynthesis	1	190.3×	0.010	B3GNT4
Glycosaminoglycan metabolism	1	109.8×	0.016	B3GNT4
O-linked glycosylation of mucins	1	92.1×	0.017	B3GNT4
O-linked glycosylation	1	72.3×	0.019	B3GNT4
Metabolism of carbohydrates and carbohydrate derivatives	1	60.1×	0.021	B3GNT4
Post-translational protein modification	1	9.6×	0.118	B3GNT4
Metabolism of proteins	1	6.2×	0.165	B3GNT4
Metabolism	1	5.8×	0.165	B3GNT4

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
poly-N-acetyllactosamine biosynthetic process	1	1053.2×	0.009	B3GNT4
keratan sulfate proteoglycan biosynthetic process	1	495.6×	0.009	B3GNT4
intrinsic apoptotic signaling pathway in response to oxidative stress	1	421.3×	0.009	DIABLO
protein O-linked glycosylation via N-acetylgalactosamine	1	216.1×	0.010	B3GNT4
extrinsic apoptotic signaling pathway via death domain receptors	1	200.6×	0.010	DIABLO
intrinsic apoptotic signaling pathway	1	179.3×	0.010	DIABLO
protein O-linked glycosylation	1	112.3×	0.012	B3GNT4
apoptotic signaling pathway	1	112.3×	0.012	DIABLO
neuron apoptotic process	1	92.6×	0.013	DIABLO
positive regulation of apoptotic process	1	28.4×	0.038	DIABLO
apoptotic process	1	14.3×	0.068	DIABLO

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DIABLO	0	0
B3GNT4	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
B3GNT4	1	Binding:1

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	DIABLO, B3GNT4

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)
DIABLO	0	—
B3GNT4	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.