Cleft Palate With Or Without Ankyloglossia, X-Linked

A number sign (#) is used with this entry because X-linked cleft palate with or without ankyloglossia (CPX) is caused by mutation in the TBX22 gene (300307) on chromosome Xq21.

Clinical Features

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.

Mapping

In an Icelandic kindred containing many persons with cleft palate and ankyloglossia ('tongue-tied') in an X-linked recessive pedigree pattern, Moore et al. (1987, 1988) localized the mutation to Xq13-q21 by linkage to a RFLP marker DXYS1 (lod = 3.07 at theta = about 0.0). The assignment of a cleft palate locus on the long arm of the X chromosome is supported by the finding of an interstitial deletion of Xq13-q21.3 in a male patient with cleft palate (Tabor et al., 1983). Ivens et al. (1987) found a considerable number of X-chromosome DNA markers to be absent from the DNA of a cell line derived from the patient of Tabor et al. (1983). These markers should be useful for linkage analysis in the Icelandic family in which Moore et al. (1987) demonstrated linkage to DXYS1.

By the combination of deletion mapping and linkage analysis, Ivens et al. (1988) localized the X-linked cleft palate gene to a site between DXYS12 proximally and DXS17 distally. The findings were consistent with localization in Xq21. Moore et al. (1991) reported further mapping studies that placed the gene between markers DXYS12 and DXS17 (lod score = 4.1) at Xq21.3-q22. The distance between the 2 probes was estimated to be approximately 5 cM.

Gorski et al. (1992) performed linkage studies in the large British Columbia Indian family first described by Lowry (1970). They found no recombination between CPX in this kindred and the DNA marker DXS72 (peak lod score = 7.44 at theta = 0.0), localized to Xq21.1. Recombination was observed between CPX and PGK1 (maximum lod = 7.35 at theta = 0.03) and between CPX and DXYS1 (maximum lod = 5.59 at theta = 0.04). Gorski et al. (1992) concluded that CPX lies between PGK1 and DXYS1 in the Xq13-q21.31 region. In further studies, Stanier et al. (1993) concluded that CPX lies within the interval Xq21.1-q21.31 between the markers DXYS1X distally and DXS326 proximally. Gorski et al. (1994) provided additional linkage analyses in the British Columbia native family and a newly identified Manitoba Mennonite family. The latter family showed mapping to the same region as in the Icelandic and B.C. families. Two-point analyses in the Manitoba family indicated a maximum lod score of 3.33 at theta = 0.0 for CPX and DXS349. A further refinement in the localization of CPX in the Icelandic kindred was provided by Forbes et al. (1995), who placed the gene in the interval between DXS95 and DXYS1X, a region estimated to be approximately 2 to 3 Mb.

Forbes et al. (1996) created an approximately 3.1-Mb YAC contig for the proximal X-Y homology breakpoint within Xq21.3 and refined the map position of CPX to a region of approximately 2.0 Mb.

Molecular Genetics

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.

Animal Model

Barra (1990) described a new X-linked mutation in the mouse characterized by cleft palate, crooked tail, and polydactyly of the hind feet. The mutation was called ptd (for palate-tail-digits). The human CPX locus is situated proximal to the region on the X chromosome that is homologous to that on the mouse X chromosome occupied by the ptd mutation. Sponenberg and Bowling (1985) described a similar disorder in Australian shepherd dogs; the features were cleft palate, syndactyly, polydactyly, tibiofibular shortening, brachygnathism, and often scoliosis. All affected males died shortly after birth. Both the canine and the murine disorders suggest one of the otopalatodigital syndromes (311300, 303400).

Pauws et al. (2009) generated a Tbx22-null mouse, which demonstrated a submucous cleft palate (SMCP) and ankyloglossia, similar to the human phenotype, with a small minority showing overt clefts. There was also persistence of the oronasal membranes or, in some mice a partial rupture, resulting in choanal atresia. Oronasal defects led to postnatal lethality in about 50% of Tbx-null mice. There was a marked reduction in intramembranous bone formation in the posterior hard palate, resulting in the classic notch associated with SMCP. Ossification was severely reduced after condensation of the palatal mesenchyme, resulting from a delay in the maturation of osteoblasts. Pauws et al. (2009) suggested that Tbx22 may play an important role in the osteogenic patterning of the posterior hard palate, rather than having a major role in palatal shelf closure.