X-linked Cleft Palate via the TBX22 Gene

Pathogenic variants in the TBX22 gene are associated with X-linked cleft palate (CPX) and Abruzzo-Erickson syndrome. CPX is a non-syndromic (isolated) form of cleft palate. The palatal phenotype ranges from a high arched palate, bifid uvula or submucous cleft to complete cleft of the secondary palate (Baybrook et al. 2001. PubMed ID: 11559848; Marcano et al. 2004. PubMed ID: 14729838). Velopharyngeal insufficiency and ankyloglossia may accompany palatal anomalies or occur in isolation. Although CPX predominantly affects males, a proportion of carrier females present with ankyloglossia with or without cleft palate, bifid uvula or velopharyngeal insufficiency (Baybrook et al. 2001. PubMed ID: 11559848; Marcano et al. 2004. PubMed ID: 14729838).

At the other end of the spectrum is Abruzzo-Erickson syndrome, a rare syndromic form of cleft palate. To date, a single multigenerational family with this syndrome has been reported (Abruzzo and Erickson. 1977. PubMed ID: 839509; Pauws et al. 2013. PubMed ID: 22784330). The clinical features of Abruzzo-Erickson syndrome in this family include cleft palate, palatal rugosity, coloboma, malar hypoplasia, large ears, hearing impairment, hypospadias, radioulnar synostosis, wide-spaced second and third fingers, and short stature.

CPX and Abruzzo-Erickson syndrome are inherited in an X-linked dominant manner, although the phenotype displays incomplete dominance in females. The clinical phenotype in affected males is the result of complete loss of TBX22 protein function, whilst the clinical phenotype in females is a consequence of haploinsufficiency. Pathogenic frameshift, missense, nonsense, and splice site variants in TBX22 have been reported to cause CPX (Braybrook et al. 2002. PubMed ID: 12374769; Marcano et al. 2004. PubMed ID: 14729838; Pauws et al. 2013. PubMed ID: 22784330). Pathogenic missense variants causing CPX are localized to the highly conserved TBX22 DNA-binding T box domain and likely result in loss of function (Braybrook et al. 2002. PubMed ID: 12374769; Pauws et al. 2009. PubMed: 19648124). A single pathogenic TBX22 splice site variant has been reported to cause Abruzzo-Erickson syndrome (Abruzzo and Erickson. 1977. PubMed ID: 839509; Pauws et al. 2013. PubMed ID: 22784330).

TBX22 encodes the T-box 22 protein. This protein is a T-box-containing transcription factor that is primarily expressed in the palatal shelves and lingual frenulum during palatogenesis in the developing embryo (Braybrook et al. 2002. PubMed ID: 12374769). Studies of TBX22 null mice suggest that loss of TBX22 function results in a failure of palatal osteoblast differentiation and maturation, which reduces ossification and leads to craniofacial anomalies (Pauws et al. 2009. PubMed ID: 19648291).

Up to 5% of unselected cases with non-syndromic cleft palate may be explained by pathogenic variants in the TBX22 gene (Marcano et al. 2004. PubMed ID: 14729838). The clinical sensitivity increases if individuals are selected based on a positive personal and family history of X-linked cleft palate and ankyloglossia (Braybrook et al. 2001. PubMed ID: 11559848).

This test provides full coverage of all coding exons of the TBX22 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).