TBX22

protein-coding

T-box transcription factor 22, the group of T-box transcription factors

Gene summary

This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of developmental processes. Mutations in this gene have been associated with the inherited X-linked disorder, Cleft palate with ankyloglossia, and it is believed to play a major role in human palatogenesis. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Previous symbols:

CPX
CLPA

MANE transcript

NM_001109878.2

Inheritance

ClinVar variants

P:19U:103B:25

Top phenotype

Abruzzo-Erickson syndrome

gnomAD constraint

pLI —, LoF o/e 0.06

Max pathogenic AF

—

Genomic locus

chrX:80,014,753-80,031,774

External References & Databases

Ensembl (ENSG00000122145)

Transcript & Mutation Effects

hg38 • Region Span ~17.0 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cleft palate with or without ankyloglossia, X-linkedDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010560

Submitter: ClinGen

TBX22 was first reported in relation to X-linked cleft palate with/without ankyloglossia in 2001 (Braybrook et al., PMID: 11559848 ). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, or phenotypic variability. Therefore, the following disease entities have been lumped into one disease entity, Abruzzo-Erikson syndrome (OMIM:302905) and cleft palate with ankyloglossia (OMIM:303400). 9 variants (missense, nonsense, frameshift, splicing) that have been reported in over 30 probands in 5 publications (PMIDs: 11559848, 14729838, 22784330, 29932061, 30462376) are included in this curation. The phenotypes of some of the affected families were reported in earlier publications (PMIDs: 839509, 1570839), before TBX22 was discovered as the causative gene. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss-of-function. This gene-disease relationship is also supported by experimental evidence (mouse model, expression-level evidence; PMIDs: 19648291, 20845426). The mouse model shows that mutant mice exhibit ankyloglossia and submucous cleft palate. Expression-level data in mice embryos show expression of the gene in the palatal bone. In summary, there is definitive evidence supporting the relationship between TBX22 and X-linked cleft palate with/without ankyloglossia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Craniofacial Malformations GCEP on the meeting date 9/19/2024 (SOP Version 11).

cleft palate with or without ankyloglossia, X-linkedSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010560

Submitter: Labcorp Genetics (formerly Invitae)

cleft palate with or without ankyloglossia, X-linkedSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010560

Submitter: PanelApp Australia

Abruzzo-Erickson syndromeSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010554

Submitter: Orphanet

cleft palate with or without ankyloglossia, X-linkedSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010560

Submitter: Orphanet

Abruzzo-Erickson syndromeLIMITED

Inheritance Pattern: XL

Disease ID:MONDO:0010554

Submitter: G2P

cleft palate with or without ankyloglossia, X-linkedDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010560

Submitter: G2P

Clinical Genomic Database (CGD)

Abruzzo-Erickson syndromeXL

Manifestation: Audiologic/Otolaryngologic; Craniofacial; Genitourinary; Musculoskeletal; Ophthalmologic

Intervention: Audiologic/Otolaryngologic

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Refs: 11559848; 12374769; 14729838; 15602089; 17846996; 17868388; 21248356; 22784330

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TBX22 variants in ClinVar

10 Conditions Cataloged

not providedTotal: 51

Inborn genetic diseasesTotal: 36

Cleft palate with or without ankyloglossia, X-linkedTotal: 31

TBX22-related disorderTotal: 18

not specifiedTotal: 14

Cleft palate with ankyloglossiaTotal: 9

Abruzzo-Erickson syndromeTotal: 5

Mendelian syndromes with cleft lip/palateTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001109878.2. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			8 clinvar	17 clinvar	3 clinvar	28
missense	3 clinvar	7 clinvar	88 clinvar	4 clinvar	1 clinvar	103
nonsense		2 clinvar	2 clinvar			4
start loss			1 clinvar			1
frameshift	2 clinvar	1 clinvar				3
splice donor/acceptor (+/-2bp)	2 clinvar	2 clinvar	4 clinvar			8
Total	7	12	103	21	4	147

Highest pathogenic variant AF is 0.0000074480868

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 12 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001109878.2	RefSeq	NP_001103348.1	8	MANE Select
ENST00000373296.8	Ensembl	ENSP00000362393.3	8	MANE Select
NM_001109879.2	RefSeq	NP_001103349.1	6	Standard
NM_001303475.1	RefSeq	NP_001290404.1	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

negative regulation of transcription by RNA polymerase II
regulation of transcription, DNA-templated
multicellular organism development
negative regulation of transcription, DNA-templated

Molecular Function

RNA polymerase II regulatory region sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
DNA-binding transcription repressor activity, RNA polymerase II-specific
DNA binding
DNA-binding transcription factor activity

Cellular Component

nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000373294
Coding exons: 8
Length: 17014
Individuals with no LoFs: 125646
Homozygous LoFs: 3
Heterozygous LoFs: 6
Defined: 125655
p: 0.0000358

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.126	204	199	1.03	0.0000145	3425
Missense (PolyPhen)		55	65.412	0.84083		1072
Synonymous	-0.266	80	77.0	1.04	0.00000611	997
Loss of Function	3.47	1	16.0	0.0625	0.00000117	277

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000076	0.000062	rare
Latino/Admixed American	0.00022	0.00017	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000072	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000012	0.0000088	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Probable transcriptional regulator involved in developmental processes. This is major determinant crucial to palatogenesis.;
Disease: DISEASE: Abruzzo-Erickson syndrome (ABERS) [MIM:302905]: A disease characterized by cleft palate, coloboma, hypospadias, deafness, short stature, and radial synostosis. {ECO:0000269|PubMed:22784330}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.128

Intolerance Scores

LoFtool: 0.0586
RVIS EVS: -0.18
RVIS percentile EVS: 40.16

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.610

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium