Aural atresia, congenital

Summary

Aural atresia, congenital (MONDO:0011921) is a disease caused by TSHZ1 (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: TSHZ1 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 22

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	aural atresia, congenital
Mondo ID	MONDO:0011921
MeSH	C564321
OMIM	607842
UMLS	C1842937
MedGen	375051
GARD	0018275
Is cancer (heuristic)	no

Also known as: aural atresia, congenital · CAA

Data availability: 22 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary otorhinolaryngologic disease › aural atresia, congenital

Related subtypes (20): otosclerosis, isolated congenital anosmia, second branchial cleft anomaly, familial congenital nasolacrimal duct obstruction, Meniere disease, motion sickness, familial thyroglossal duct cyst, bifid nose, autosomal recessive, X-linked mixed hearing loss with perilymphatic gusher, nasal dermoid cyst, short stature-auditory canal atresia-mandibular hypoplasia-skeletal anomalies syndrome, choanal atresia, BNAR syndrome, familial nasal acilia, tympanic paraganglioma, X-linked external auditory canal atresia-dilated internal auditory canal-facial dysmorphism syndrome, cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome, tonsillar lymphoma, benign paroxysmal positional vertigo, vertigo, benign recurrent, 1

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

22 retrieved; paginated sample, class counts are floors:

10 uncertain significance, 4 benign, 3 no classifications from unflagged records, 2 likely pathogenic, 2 likely benign, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
13281	NM_000141.5(FGFR2):c.870G>C (p.Trp290Cys)	FGFR2	Pathogenic	criteria provided, multiple submitters, no conflicts
4082068	NC_000018.10:g.75201406_75410919del	LOC126862802	Likely pathogenic	no assertion criteria provided
1710246	NM_001308210.2(TSHZ1):c.853del (p.Arg285fs)	TSHZ1	Likely pathogenic	no assertion criteria provided
1703674	GRCh37/hg19 4q34.3(chr4:178126365-179868269)	AGA	Uncertain significance	no assertion criteria provided
1049280	NM_001308210.2(TSHZ1):c.1892C>T (p.Pro631Leu)	TSHZ1	Uncertain significance	criteria provided, single submitter
1098620	NM_001308210.2(TSHZ1):c.2753T>C (p.Met918Thr)	TSHZ1	Uncertain significance	criteria provided, single submitter
3062035	NM_001308210.2(TSHZ1):c.3G>A (p.Met1Ile)	TSHZ1	Uncertain significance	criteria provided, single submitter
3065736	NM_001308210.2(TSHZ1):c.1414C>T (p.Pro472Ser)	TSHZ1	Uncertain significance	criteria provided, single submitter
31185	NM_001308210.2(TSHZ1):c.1081_1082insA (p.Pro361fs)	TSHZ1	no classifications from unflagged records	no classifications from unflagged records
31186	NM_001308210.2(TSHZ1):c.858G>A (p.Trp286Ter)	TSHZ1	no classifications from unflagged records	no classifications from unflagged records
3780752	NM_001308210.2(TSHZ1):c.463dup (p.Ala155fs)	TSHZ1	Uncertain significance	criteria provided, single submitter
3780753	NM_001308210.2(TSHZ1):c.463_464dup (p.Thr157fs)	TSHZ1	no classifications from unflagged records	no classifications from unflagged records
3892747	NM_001308210.2(TSHZ1):c.3077T>G (p.Leu1026Arg)	TSHZ1	Uncertain significance	criteria provided, single submitter
4293551	NM_001308210.2(TSHZ1):c.1A>C (p.Met1Leu)	TSHZ1	Uncertain significance	criteria provided, single submitter
4846954	NM_001308210.2(TSHZ1):c.469_470del (p.Thr157fs)	TSHZ1	Uncertain significance	criteria provided, single submitter
930291	NM_001308210.2(TSHZ1):c.2127C>G (p.Asp709Glu)	TSHZ1	Uncertain significance	criteria provided, single submitter
327819	NM_001308210.2(TSHZ1):c.1524T>C (p.Pro508=)	LOC125371439	Benign	criteria provided, multiple submitters, no conflicts
327806	NM_001308210.2(TSHZ1):c.642T>C (p.Tyr214=)	TSHZ1	Benign	criteria provided, multiple submitters, no conflicts
327810	NM_001308210.2(TSHZ1):c.906T>C (p.Asp302=)	TSHZ1	Benign	criteria provided, multiple submitters, no conflicts
327832	NM_001308210.2(TSHZ1):c.1997T>C (p.Leu666Pro)	TSHZ1	Benign	criteria provided, multiple submitters, no conflicts
3780754	NM_001308210.2(TSHZ1):c.463_464insGCCC (p.Ala155fs)	TSHZ1	Likely benign	criteria provided, single submitter
3892746	NM_001308210.2(TSHZ1):c.2048C>T (p.Thr683Met)	TSHZ1	Likely benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 14 · 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
TSHZ1	Strong	Autosomal dominant	aural atresia, congenital	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TSHZ1	Orphanet:141074	External auditory canal aplasia/hypoplasia
AGA	Orphanet:93	Aspartylglucosaminuria
FGFR2	Orphanet:1540	Jackson-Weiss syndrome
FGFR2	Orphanet:1555	Cutis gyrata-acanthosis nigricans-craniosynostosis syndrome
FGFR2	Orphanet:168624	Familial scaphocephaly syndrome, McGillivray type
FGFR2	Orphanet:207	Crouzon syndrome
FGFR2	Orphanet:2363	Lacrimoauriculodentodigital syndrome
FGFR2	Orphanet:313855	FGFR2-related bent bone dysplasia
FGFR2	Orphanet:596008	Antley-Bixler syndrome without genital anomaly or disorder of steroidogenesis
FGFR2	Orphanet:794	Saethre-Chotzen syndrome
FGFR2	Orphanet:87	Apert syndrome
FGFR2	Orphanet:93258	Pfeiffer syndrome type 1
FGFR2	Orphanet:93259	Pfeiffer syndrome type 2
FGFR2	Orphanet:93260	Pfeiffer syndrome type 3

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
TSHZ1	HGNC:10669	ENSG00000179981	Q6ZSZ6	Teashirt homolog 1	gencc,clinvar
AGA	HGNC:318	ENSG00000038002	P20933	N(4)-(beta-N-acetylglucosaminyl)-L-asparaginase	clinvar
FGFR2	HGNC:3689	ENSG00000066468	P21802	Fibroblast growth factor receptor 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TSHZ1	Teashirt homolog 1	Probable transcriptional regulator involved in developmental processes.
AGA	N(4)-(beta-N-acetylglucosaminyl)-L-asparaginase	Cleaves the GlcNAc-Asn bond which joins oligosaccharides to the peptide of asparagine-linked glycoproteins.
FGFR2	Fibroblast growth factor receptor 2	Tyrosine-protein kinase that acts as a cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of cell proliferation, differentiation, migration and apoptosis, and in the regulation of embryonic de…

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.67

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
Protease	1	12.2×	0.157
Kinase	1	9.2×	0.157
Transcription factor	1	2.8×	0.321

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TSHZ1	Transcription factor	no		HD, Znf_C2H2_type, Teashirt_fam
AGA	Protease	yes	3.5.1.26	Peptidase_T2, Ntn_hydrolases_N
FGFR2	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Ig_sub2

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
cerebellar vermis	1
ileal mucosa	1
jejunal mucosa	1
epithelium of esophagus	1
esophagus squamous epithelium	1
squamous epithelium	1
C1 segment of cervical spinal cord	1
corpus callosum	1
spinal cord	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TSHZ1	255	ubiquitous	marker	jejunal mucosa, cerebellar vermis, ileal mucosa
AGA	287	ubiquitous	marker	esophagus squamous epithelium, squamous epithelium, epithelium of esophagus
FGFR2	272	broad	marker	C1 segment of cervical spinal cord, spinal cord, corpus callosum

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AGA	929
TSHZ1	848
FGFR2	449

Intra-cohort edges

A	B	Sources
AGA	TSHZ1	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FGFR2	P21802	63
AGA	P20933	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TSHZ1	Q6ZSZ6	54.57

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 21. 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
Signaling by FGFR2 amplification mutants	1	5710.0×	0.002	FGFR2
Signaling by FGFR2 fusions	1	5710.0×	0.002	FGFR2
FGFR2b ligand binding and activation	1	571.0×	0.009	FGFR2
FGFR2c ligand binding and activation	1	439.2×	0.009	FGFR2
Activated point mutants of FGFR2	1	335.9×	0.009	FGFR2
Phospholipase C-mediated cascade; FGFR2	1	317.2×	0.009	FGFR2
Signaling by FGFR2 IIIa TM	1	300.5×	0.009	FGFR2
PI-3K cascade:FGFR2	1	248.3×	0.009	FGFR2
SHC-mediated cascade:FGFR2	1	237.9×	0.009	FGFR2
FRS-mediated FGFR2 signaling	1	219.6×	0.009	FGFR2
FGFR2 alternative splicing	1	211.5×	0.009	FGFR2
Negative regulation of FGFR2 signaling	1	184.2×	0.009	FGFR2
PI3K Cascade	1	135.9×	0.011	FGFR2
Signaling by FGFR2 in disease	1	132.8×	0.011	FGFR2
Constitutive Signaling by Aberrant PI3K in Cancer	1	63.4×	0.022	FGFR2
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	1	48.4×	0.027	FGFR2
PIP3 activates AKT signaling	1	33.4×	0.037	FGFR2
RAF/MAP kinase cascade	1	30.5×	0.038	FGFR2
Innate Immune System	1	12.8×	0.085	AGA
Neutrophil degranulation	1	11.5×	0.089	AGA
Immune System	1	6.5×	0.148	AGA

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
fibroblast growth factor receptor signaling pathway involved in negative regulation of apoptotic process in bone marrow cell	1	5617.3×	0.003	FGFR2
fibroblast growth factor receptor signaling pathway involved in hemopoiesis	1	5617.3×	0.003	FGFR2
fibroblast growth factor receptor signaling pathway involved in positive regulation of cell proliferation in bone marrow	1	5617.3×	0.003	FGFR2
lateral sprouting from an epithelium	1	5617.3×	0.003	FGFR2
protein deglycosylation	1	2808.7×	0.003	AGA
orbitofrontal cortex development	1	2808.7×	0.003	FGFR2
prostate gland morphogenesis	1	2808.7×	0.003	FGFR2
squamous basal epithelial stem cell differentiation involved in prostate gland acinus development	1	2808.7×	0.003	FGFR2
mammary gland bud formation	1	2808.7×	0.003	FGFR2
branch elongation involved in salivary gland morphogenesis	1	2808.7×	0.003	FGFR2
mesenchymal cell differentiation involved in lung development	1	2808.7×	0.003	FGFR2
regulation of osteoblast proliferation	1	1872.4×	0.004	FGFR2
fibroblast growth factor receptor signaling pathway involved in orbitofrontal cortex development	1	1872.4×	0.004	FGFR2
prostate epithelial cord elongation	1	1872.4×	0.004	FGFR2
ventricular zone neuroblast division	1	1404.3×	0.004	FGFR2
embryonic organ morphogenesis	1	1404.3×	0.004	FGFR2
reproductive structure development	1	1404.3×	0.004	FGFR2
regulation of morphogenesis of a branching structure	1	1404.3×	0.004	FGFR2
positive regulation of phospholipase activity	1	1123.5×	0.004	FGFR2
regulation of smooth muscle cell differentiation	1	1123.5×	0.004	FGFR2
soft palate development	1	1123.5×	0.004	TSHZ1
branching involved in prostate gland morphogenesis	1	1123.5×	0.004	FGFR2
epithelial cell proliferation involved in salivary gland morphogenesis	1	1123.5×	0.004	FGFR2
mesenchymal cell proliferation involved in lung development	1	1123.5×	0.004	FGFR2
epidermis morphogenesis	1	936.2×	0.004	FGFR2
gland morphogenesis	1	802.5×	0.004	FGFR2
branching morphogenesis of a nerve	1	802.5×	0.004	FGFR2
bud elongation involved in lung branching	1	802.5×	0.004	FGFR2
positive regulation of epithelial cell proliferation involved in lung morphogenesis	1	802.5×	0.004	FGFR2
prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis	1	802.5×	0.004	FGFR2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) 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
FGFR2	PONATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FGFR2	59	4
TSHZ1	0	0
AGA	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PONATINIB	4	FGFR2
PEMIGATINIB	4	FGFR2
NINTEDANIB	4	FGFR2
FEDRATINIB	4	FGFR2
LENVATINIB	4	FGFR2
AXITINIB	4	FGFR2
SORAFENIB	4	FGFR2
INFIGRATINIB PHOSPHATE	4	FGFR2
INFIGRATINIB	4	FGFR2
IBRUTINIB	4	FGFR2
CERITINIB	4	FGFR2
VANDETANIB	4	FGFR2
NINTEDANIB ESYLATE	4	FGFR2
BRIGATINIB	4	FGFR2
ERDAFITINIB	4	FGFR2
FUTIBATINIB	4	FGFR2
PAZOPANIB	4	FGFR2
SUNITINIB	4	FGFR2
DASATINIB	4	FGFR2
ERLOTINIB	4	FGFR2
MIDOSTAURIN	4	FGFR2
LINIFANIB	3	FGFR2
SEMAXANIB	3	FGFR2
BRIVANIB	3	FGFR2
CEDIRANIB	3	FGFR2
DOVITINIB	3	FGFR2
LESTAURTINIB	3	FGFR2
TANDUTINIB	2	FGFR2
DORAMAPIMOD	2	FGFR2
FORETINIB	2	FGFR2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
FGFR2	966	Binding:940, Functional:22, ADMET:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
AGA	3.5.1.26	N4-(beta-N-acetylglucosaminyl)-L-asparaginase
FGFR2	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
FGFR2	966

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

30 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)
PONATINIB	4	FGFR2
PEMIGATINIB	4	FGFR2
NINTEDANIB	4	FGFR2
FEDRATINIB	4	FGFR2
LENVATINIB	4	FGFR2
AXITINIB	4	FGFR2
SORAFENIB	4	FGFR2
INFIGRATINIB PHOSPHATE	4	FGFR2
INFIGRATINIB	4	FGFR2
IBRUTINIB	4	FGFR2
CERITINIB	4	FGFR2
VANDETANIB	4	FGFR2
NINTEDANIB ESYLATE	4	FGFR2
BRIGATINIB	4	FGFR2
ERDAFITINIB	4	FGFR2
FUTIBATINIB	4	FGFR2
PAZOPANIB	4	FGFR2
SUNITINIB	4	FGFR2
DASATINIB	4	FGFR2
ERLOTINIB	4	FGFR2
MIDOSTAURIN	4	FGFR2
LINIFANIB	3	FGFR2
SEMAXANIB	3	FGFR2
BRIVANIB	3	FGFR2
CEDIRANIB	3	FGFR2
DOVITINIB	3	FGFR2
LESTAURTINIB	3	FGFR2
TANDUTINIB	2	FGFR2
DORAMAPIMOD	2	FGFR2
FORETINIB	2	FGFR2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	FGFR2
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	AGA
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	TSHZ1

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)
TSHZ1	0	—
AGA	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.