TBX22 – X-linked cleft palate with or without ankyloglossia

TBX22 is an X-linked T-box transcription factor essential for secondary palate and tongue development. Loss-of-function mutations in TBX22 underlie cleft palate with or without ankyloglossia (CPX; MONDO:0010560), an X-linked semidominant disorder characterized by submucous or overt cleft of the secondary palate and restricted tongue mobility (PMID:11559848).

Clinical Validity

Multiple unrelated CPX families harbor TBX22 variants segregating with disease, including a Tunisian kindred with 6 affected members (4 males, 2 females) carrying c.358C>T (p.Arg120Trp) (PMID:15602089) and three families with splice-site changes (c.459-5T>A, c.633+1G>A) tracking classic CPX phenotypes (PMID:22784330). Functional concordance from animal and cellular models supports a definitive gene–disease relationship.

Genetic Evidence

Inheritance is X-linked semidominant, with hemizygous males fully penetrant and heterozygous females variably affected. To date, >10 probands in ≥4 kindreds have been reported with LoF (nonsense, frameshift, canonical splice) and pathogenic missense variants in the T-BOX domain, reaching the ClinGen genetic evidence cap. A representative variant is c.358C>T (p.Arg120Trp), which abrogates DNA binding and segregates in a Tunisian CPX pedigree (PMID:15602089).

Functional Evidence

Tbx22-null mice exhibit submucous cleft palate, ankyloglossia and choanal atresia, recapitulating human CPX phenotypes and demonstrating a role in posterior palatal ossification (PMID:19648291). In vitro assays of T-BOX missense mutants show impaired DNA binding and loss of transcriptional repression, with loss of SUMO modification further compromising function (PMID:17846996). Splice-site variants abolish normal mRNA splicing in cell-based assays (PMID:22784330).

Functional Regulatory Variants

A promoter haplotype including rs41307258 reduces TBX22 transcriptional activity by up to 50% in reporter assays and associates with cleft palate plus ankyloglossia in non-coding cohorts, suggesting regulatory mechanisms contribute to phenotypic variability (PMID:19648124).

Conclusions and Clinical Utility

TBX22 has a definitive association with X-linked CPX supported by strong genetic segregation and concordant functional data. Diagnostic sequencing of TBX22, including coding and promoter regions, is recommended for males with cleft palate and ankyloglossia, and for families with an apparent non-syndromic cleft palate to identify CPX cases.

References

• Nature genetics • 2001 • The T-box transcription factor gene TBX22 is mutated in X-linked cleft palate and ankyloglossia. PMID:11559848
• Clinical dysmorphology • 2005 • Mutation analysis of TBX22 reveals new mutation in Tunisian CPX family. PMID:15602089
• Clinical genetics • 2013 • X-linked CHARGE-like Abruzzo-Erickson syndrome and classic cleft palate with ankyloglossia result from TBX22 splicing mutations. PMID:22784330
• Human molecular genetics • 2009 • Tbx22null mice have a submucous cleft palate due to reduced palatal bone formation and also display ankyloglossia and choanal atresia phenotypes. PMID:19648291
• American journal of human genetics • 2007 • TBX22 missense mutations found in patients with X-linked cleft palate affect DNA binding, sumoylation, and transcriptional repression. PMID:17846996
• Journal of medical genetics • 2009 • A functional haplotype variant in the TBX22 promoter is associated with cleft palate and ankyloglossia. PMID:19648124

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