cleft palate with or without ankyloglossia, X-linked

Summary

cleft palate with or without ankyloglossia, X-linked (MONDO:0010560) is a disease caused by TBX22 (GenCC Definitive), with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: TBX22 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 39
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cleft palate with or without ankyloglossia, X-linked
Mondo ID	MONDO:0010560
MeSH	C536426
OMIM	303400
Orphanet	324601
DOID	DOID:0060613
SNOMED CT	766761000
UMLS	C1844830
MedGen	375520
GARD	0001394
Is cancer (heuristic)	no

Also known as: cleft palate with ankyloglossia · cleft palate with or without ankyloglossia, X-linked · cleft palate X-linked · cleft palate, X-linked · CPX · X-linked cleft palate · X-linked cleft palate and ankyloglossia

Data availability: 39 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › orofacial cleft › cleft palate › cleft palate with or without ankyloglossia, X-linked

Related subtypes (8): isolated cleft palate, cleft soft palate, Rapp-Hodgkin syndrome, bifid uvula, cleft hard palate, submucosal cleft palate, Kuster syndrome, soft and hard cleft palate

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

39 retrieved; paginated sample, class counts are floors:

14 uncertain significance, 8 likely benign, 7 benign, 4 conflicting classifications of pathogenicity, 3 benign/likely benign, 2 likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
11337	NM_001109878.2(TBX22):c.1252del (p.Val418fs)	TBX22	Pathogenic	no assertion criteria provided
11333	NM_001109878.2(TBX22):c.166G>T (p.Glu56Ter)	TBX22	Likely pathogenic	criteria provided, single submitter
3065426	NM_001109878.2(TBX22):c.668G>A (p.Arg223Gln)	TBX22	Likely pathogenic	criteria provided, single submitter
3065117	NM_001109878.2(TBX22):c.539C>T (p.Pro180Leu)	TBX22	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
368661	NM_001109878.2(TBX22):c.-28G>A	TBX22	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
50315	NM_001109878.2(TBX22):c.459-5T>A	TBX22	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
713489	NM_001109878.2(TBX22):c.1488C>T (p.Asp496=)	TBX22	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1685164	NM_001109878.2(TBX22):c.452G>T (p.Arg151Leu)	TBX22	Uncertain significance	criteria provided, multiple submitters, no conflicts
1698919	NM_001109878.2(TBX22):c.592C>T (p.Arg198Cys)	TBX22	Uncertain significance	criteria provided, single submitter
368665	NM_001109878.2(TBX22):c.554C>T (p.Ser185Leu)	TBX22	Uncertain significance	criteria provided, single submitter
368670	NM_001109878.2(TBX22):c.1412C>T (p.Ser471Phe)	TBX22	Uncertain significance	criteria provided, multiple submitters, no conflicts
368671	NM_001109878.2(TBX22):c.1544C>A (p.Ala515Glu)	TBX22	Uncertain significance	criteria provided, single submitter
368673	NM_001109878.2(TBX22):c.*57A>T	TBX22	Uncertain significance	criteria provided, single submitter
368674	NM_001109878.2(TBX22):c.*97C>A	TBX22	Uncertain significance	criteria provided, single submitter
368676	NM_001109878.2(TBX22):c.*533A>T	TBX22	Uncertain significance	criteria provided, single submitter
913764	NM_001109878.2(TBX22):c.*293T>C	TBX22	Uncertain significance	criteria provided, single submitter
914119	NM_001109878.2(TBX22):c.143G>A (p.Arg48Lys)	TBX22	Uncertain significance	criteria provided, single submitter
914120	NM_001109878.2(TBX22):c.224G>T (p.Gly75Val)	TBX22	Uncertain significance	criteria provided, single submitter
914122	NM_001109878.2(TBX22):c.302T>A (p.Leu101Gln)	TBX22	Uncertain significance	criteria provided, multiple submitters, no conflicts
914622	NM_001109878.2(TBX22):c.549C>G (p.Pro183=)	TBX22	Uncertain significance	criteria provided, single submitter
914624	NM_001109878.2(TBX22):c.864-11C>T	TBX22	Uncertain significance	criteria provided, single submitter
368660	NM_001109878.2(TBX22):c.-103G>A	TBX22	Benign	criteria provided, single submitter
368662	NM_001109878.2(TBX22):c.-23A>G	TBX22	Likely benign	criteria provided, single submitter
368663	NM_001109878.2(TBX22):c.-2-7C>A	TBX22	Likely benign	criteria provided, multiple submitters, no conflicts
368664	NM_001109878.2(TBX22):c.72C>T (p.Leu24=)	TBX22	Benign	criteria provided, multiple submitters, no conflicts
368666	NM_001109878.2(TBX22):c.559G>A (p.Glu187Lys)	TBX22	Benign	criteria provided, multiple submitters, no conflicts
368667	NM_001109878.2(TBX22):c.798+11T>C	TBX22	Likely benign	criteria provided, single submitter
368668	NM_001109878.2(TBX22):c.883T>C (p.Leu295=)	TBX22	Benign	criteria provided, multiple submitters, no conflicts
368669	NM_001109878.2(TBX22):c.949+12T>G	TBX22	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
368672	NM_001109878.2(TBX22):c.*6C>A	TBX22	Benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 2 · 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
TBX22	Definitive	X-linked	cleft palate with or without ankyloglossia, X-linked	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TBX22	Orphanet:324601	X-linked cleft palate and ankyloglossia
TBX22	Orphanet:921	Abruzzo-Erickson syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TBX22	HGNC:11600	ENSG00000122145	Q9Y458	T-box transcription factor TBX22	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TBX22	T-box transcription factor TBX22	Probable transcriptional regulator involved in developmental processes.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TBX22	Transcription factor	no		TF_T-box, p53-like_TF_DNA-bd_sf, TF_T-box_CS

Expression context

Cohort genes with no expression data: 0.

Breadth distribution (Bgee present_calls)

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

Top tissues across cohort

Tissue	Cohort genes
left testis	1
right testis	1
testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TBX22	44	tissue_specific	yes	left testis, right testis, testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TBX22	832

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TBX22	Q9Y458	59.38

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

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
cell fate specification	1	526.6×	0.009	TBX22
negative regulation of DNA-templated transcription	1	31.6×	0.060	TBX22
positive regulation of DNA-templated transcription	1	27.9×	0.060	TBX22
negative regulation of transcription by RNA polymerase II	1	17.7×	0.071	TBX22
regulation of transcription by RNA polymerase II	1	11.7×	0.086	TBX22

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
TBX22	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	TBX22

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TBX22	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03157076	Not specified	COMPLETED	Pilot Study to Investigate the Creation of Physiological Rhythm by Closed Loop Stimulation in hEart Failure pAtients With chronoTropic incompEtence