In a British Columbia Indian family, Lowry (1970) found 12 males with incomplete cleft of the secondary palate. In some the cleft was submucous. Palatopharyngeal incompetence was a leading feature. The pedigree pattern suggested X-linked recessive inheritance. The ... In a British Columbia Indian family, Lowry (1970) found 12 males with incomplete cleft of the secondary palate. In some the cleft was submucous. Palatopharyngeal incompetence was a leading feature. The pedigree pattern suggested X-linked recessive inheritance. The high sex ratio for cleft palate in British Columbia Indians could be due to the existence of an X-linked form of submucous cleft palate (Lowry and Renwick, 1969). Lowry (1974) observed other cases born into this family. In an Italian-American kindred, Rushton (1979) reported 4 males with cleft palate in 4 generations in a typical X-linked recessive pedigree pattern. Rollnick and Kaye (1986) reported 2 families with cleft palate in a pattern consistent with X-linked recessive inheritance. Bifid uvula was found in 3 females in these families, 2 of them obligatory carriers. In family A there was an obligate affected but nonexpressing male who had 2 normal carrier daughters who had 3 affected sons. Hall (1987) described another possible instance of a nonexpressing obligate affected male in an X-linked cleft palate family. As pointed out by Rollnick and Kaye (1987), 'nonexpression' is not proved because the male in question was not examined for bifid uvula or submucous cleft palate. Bixler (1987) found 2 pedigrees consistent with X-linked inheritance among 956 Danish and 229 Indiana isolated cleft palate families.
Braybrook et al. (2001) identified 6 different missense, splice site, and nonsense mutations in the TBX22 gene (300307.0001-300307.0006) in families segregating X-linked cleft palate and ankyloglossia.
Braybrook et al. (2002) reported 2 additional familial cases of ... Braybrook et al. (2001) identified 6 different missense, splice site, and nonsense mutations in the TBX22 gene (300307.0001-300307.0006) in families segregating X-linked cleft palate and ankyloglossia. Braybrook et al. (2002) reported 2 additional familial cases of cleft palate with ankyloglossia with novel missense and insertion mutations (300307.0007 and 300307.0008), each occurring within the DNA-binding T-box domain. Marcano et al. (2004) performed analysis of the TBX22 gene in a large sample of patients with cleft palate with no preselection for inheritance or ankyloglossia. They found coding mutations in 5 of 200 patients in North American and Brazilian cohorts, with an additional 4 putative splice site mutations. They also identified mutations in previously unreported CPX families (see, e.g., 300307.0004) and presented a combined genotype/phenotype analysis of previously reported familial cases. Males frequently exhibited cleft palate and ankyloglossia together (78%), as did a smaller percentage of carrier females. A range of severity was observed, including complete cleft of the secondary palate, submucous cleft, bifid uvula, absent tonsils, or high vaulted palate. Ankyloglossia was the sole phenotype in 4% of male patients and 45% of female carriers. Cleft palate was the sole presenting feature in 6% of female carriers. Not all female carriers escaped a cleft, which affected 16% regardless of tongue phenotype. Mutations within families could result in either cleft palate only, ankyloglossia only, or both, indicating that these defects are distinct parts of the phenotypic spectrum. Among 53 unrelated Thai patients with nonsyndromic cleft palate, Suphapeetiporn et al. (2007) identified 4 patients, each with a different potentially pathogenic mutation in the TBX22 gene (see, e.g., 300307.0010). Two of the patients were found to have a family history of the disorder. The authors concluded that TBX22 mutations are a cause of nonsyndromic isolated cleft palate in the Thai population. In the proband of a family segregating X-linked cleft palate, later shown to represent a branch of a family originally studied by Marcano et al. (2004), Pauws et al. (2013) identified a splice site mutation in the TBX22 gene (300307.0004). The proband had a submucous cleft palate, ankyloglossia, speech and language delay, and left-sided eustachian tube dysfunction. His carrier mother had ankyloglossia, which was widely present in the extended family; affected males in the family also had submucous or soft palate cleft. Pauws et al. (2013) also identified another TBX22 splice site mutation in a sporadic male patient with soft palate cleft and significant ankyloglossia. Neither variant was found in the dbSNP database or in 539 control chromosomes.