Autosomal recessive nonsyndromic hearing loss 98

Summary

Autosomal recessive nonsyndromic hearing loss 98 (MONDO:0013929) is a disease with 4 cohort genes. The dominant Reactome pathway is Keratinization (3 cohort genes).

At a glance

• Cohort genes: 4
• ClinVar variants: 25

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive nonsyndromic hearing loss 98
Mondo ID	MONDO:0013929
OMIM	614861
DOID	DOID:0110540
UMLS	C3553932
MedGen	766846
GARD	0022644
Is cancer (heuristic)	no

Also known as: autosomal recessive deafness 98 · autosomal recessive nonsyndromic deafness 98 · autosomal recessive nonsyndromic deafness caused by mutation in TSPEAR · autosomal recessive nonsyndromic deafness type 98 · autosomal recessive nonsyndromic hearing loss 98 · deafness, autosomal recessive 98 · deafness, autosomal recessive type 98 · DFNB98 · TSPEAR autosomal recessive nonsyndromic deafness

Data availability: 25 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 › autosomal recessive nonsyndromic hearing loss 98

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 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

25 retrieved; paginated sample, class counts are floors:

9 conflicting classifications of pathogenicity, 7 uncertain significance, 6 pathogenic, 2 likely benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
37311	NM_144991.3(TSPEAR):c.1728del (p.Lys577fs)	LOC126653398	Pathogenic	criteria provided, single submitter
2081026	NM_144991.3(TSPEAR):c.1093C>T (p.Gln365Ter)	TSPEAR	Pathogenic	criteria provided, multiple submitters, no conflicts
2891535	NM_144991.3(TSPEAR):c.2T>C (p.Met1Thr)	TSPEAR	Pathogenic	criteria provided, multiple submitters, no conflicts
2986614	NM_144991.3(TSPEAR):c.1463C>A (p.Ser488Ter)	TSPEAR	Pathogenic	criteria provided, multiple submitters, no conflicts
4081842	NM_144991.3(TSPEAR):c.1238_1239del (p.Phe413fs)	TSPEAR	Pathogenic	criteria provided, single submitter
4081843	NM_144991.3(TSPEAR):c.1794T>A (p.Tyr598Ter)	TSPEAR	Pathogenic	criteria provided, single submitter
1301812	NM_198699.1(KRTAP10-12):c.248C>T (p.Ser83Leu)	KRTAP10-12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
505194	NM_144991.3(TSPEAR):c.1697A>G (p.Tyr566Cys)	LOC126653398	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1033112	NM_144991.3(TSPEAR):c.1856+19C>T	TSPEAR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1188184	NM_144991.3(TSPEAR):c.1493_1494delinsTG (p.Gly498Val)	TSPEAR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1197259	NM_144991.3(TSPEAR):c.1877T>C (p.Phe626Ser)	TSPEAR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
227135	NM_144991.3(TSPEAR):c.1915G>A (p.Asp639Asn)	TSPEAR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
229377	NM_144991.3(TSPEAR):c.364C>T (p.Arg122Trp)	TSPEAR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
493326	NM_144991.3(TSPEAR):c.1870G>T (p.Glu624Ter)	TSPEAR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
594076	NM_144991.3(TSPEAR):c.1469T>A (p.Leu490Gln)	TSPEAR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1033115	NM_144991.3(TSPEAR):c.304-5450G>T	KRTAP10-1	Uncertain significance	criteria provided, single submitter
684487	NM_144991.3(TSPEAR):c.1675T>C (p.Tyr559His)	LOC126653398	Uncertain significance	criteria provided, single submitter
1177644	NM_144991.3(TSPEAR):c.533C>T (p.Pro178Leu)	TSPEAR	Uncertain significance	criteria provided, multiple submitters, no conflicts
1379649	NM_144991.3(TSPEAR):c.358G>A (p.Gly120Ser)	TSPEAR	Uncertain significance	criteria provided, multiple submitters, no conflicts
3587696	NM_144991.3(TSPEAR):c.1882G>A (p.Ala628Thr)	TSPEAR	Uncertain significance	criteria provided, single submitter
3780755	NM_144991.3(TSPEAR):c.1336+5G>A	TSPEAR	Uncertain significance	criteria provided, single submitter
4081844	NM_144991.3(TSPEAR):c.1919G>A (p.Trp640Ter)	TSPEAR	Uncertain significance	criteria provided, single submitter
1301811	NM_144991.3(TSPEAR):c.303+9641C>A	KRTAP10-3	Likely benign	criteria provided, single submitter
228046	NM_144991.3(TSPEAR):c.1515G>A (p.Ser505=)	TSPEAR	Likely benign	criteria provided, multiple submitters, no conflicts
228053	NM_144991.3(TSPEAR):c.44C>T (p.Ala15Val)	TSPEAR	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · 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
TSPEAR	Supportive	Autosomal recessive	hearing loss, autosomal recessive	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TSPEAR	Orphanet:685067	Hypodontia-scalp hypotrichosis-facial dysmorphism 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
TSPEAR	HGNC:1268	ENSG00000175894	Q8WU66	Thrombospondin-type laminin G domain and EAR repeat-containing protein	gencc,clinvar
KRTAP10-12	HGNC:20533	ENSG00000189169	P60413	Keratin-associated protein 10-12	clinvar
KRTAP10-1	HGNC:22966	ENSG00000215455	P60331	Keratin-associated protein 10-1	clinvar
KRTAP10-3	HGNC:22968	ENSG00000212935	P60369	Keratin-associated protein 10-3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TSPEAR	Thrombospondin-type laminin G domain and EAR repeat-containing protein	Plays a critical role in tooth and hair follicle morphogenesis through regulation of the Notch signaling pathway.
KRTAP10-12	Keratin-associated protein 10-12	In the hair cortex, hair keratin intermediate filaments are embedded in an interfilamentous matrix, consisting of hair keratin-associated proteins (KRTAP), which are essential for the formation of a rigid and resistant hair shaft through t…
KRTAP10-1	Keratin-associated protein 10-1	In the hair cortex, hair keratin intermediate filaments are embedded in an interfilamentous matrix, consisting of hair keratin-associated proteins (KRTAP), which are essential for the formation of a rigid and resistant hair shaft through t…
KRTAP10-3	Keratin-associated protein 10-3	In the hair cortex, hair keratin intermediate filaments are embedded in an interfilamentous matrix, consisting of hair keratin-associated proteins (KRTAP), which are essential for the formation of a rigid and resistant hair shaft through t…

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 4 · 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	4	1.8×	0.097

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TSPEAR	Other/Unknown	no		EPTP, EAR, ConA-like_dom_sf
KRTAP10-12	Other/Unknown	no		KAP
KRTAP10-1	Other/Unknown	no		KAP
KRTAP10-3	Other/Unknown	no		KAP

Expression context

Cohort genes with no expression data: 0.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	2
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
primordial germ cell in gonad	2
colonic epithelium	2
adenohypophysis	1
pituitary gland	1
male germ line stem cell (sensu Vertebrata) in testis	1
cortical plate	1
ventricular zone	1
bone marrow cell	1
skin of abdomen	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TSPEAR	88	tissue_specific	yes	primordial germ cell in gonad, adenohypophysis, pituitary gland
KRTAP10-12	27		yes	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, colonic epithelium
KRTAP10-1	7		yes	colonic epithelium, ventricular zone, cortical plate
KRTAP10-3	13	tissue_specific	yes	sural nerve, skin of abdomen, bone marrow cell

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TSPEAR	839
KRTAP10-3	486
KRTAP10-1	457
KRTAP10-12	92

Intra-cohort edges

A	B	Sources
KRTAP10-1	TSPEAR	string_interaction

Structural data

PDB: 0 · AlphaFold-only: 4 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TSPEAR	Q8WU66	87.47
KRTAP10-12	P60413	39.25
KRTAP10-3	P60369	39.11
KRTAP10-1	P60331	35.72

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
Keratinization	3	55.7×	1e-05	KRTAP10-12, KRTAP10-1, KRTAP10-3
Developmental Biology	3	14.5×	3e-04	KRTAP10-12, KRTAP10-1, KRTAP10-3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
tooth mineralization	1	5617.3×	0.001	TSPEAR
hair cycle process	1	2808.7×	0.001	TSPEAR
regulation of Notch signaling pathway	1	842.6×	0.002	TSPEAR
Notch signaling pathway	1	141.6×	0.011	TSPEAR
sensory perception of sound	1	100.9×	0.012	TSPEAR
signal transduction	1	16.1×	0.062	TSPEAR

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 4 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
TSPEAR	0	0
KRTAP10-12	0	0
KRTAP10-1	0	0
KRTAP10-3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	0
E	Difficult family or no structure, no drug	4	TSPEAR, KRTAP10-12, KRTAP10-1, KRTAP10-3

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)
TSPEAR	0	—
KRTAP10-12	0	—
KRTAP10-1	0	—
KRTAP10-3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.