Cleft Palate, Isolated

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2019-09-22

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Omim

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Description

Cleft palate as an isolated malformation behaves as an entity distinct from cleft lip with or without cleft palate (see 119530).

Dominantly inherited cleft soft palate in 4 generations has been reported (Jenkins and Stady, 1980); see 119570.

Inheritance

Curtis et al. (1961) estimated that the risk of recurrence in subsequently born children is about 2% if 1 child has it, 6% if 1 parent has it, and 15% if 1 parent and 1 child have it. As for cleft lip with or without cleft palate, the genetics is apparently complex.

Shields et al. (1981) analyzed family data on 561 Danish probands with nonsyndromic isolated cleft palate and concluded that neither a multifactorial-threshold model nor a single major locus model is completely compatible with the distribution of cases. They proposed the existence of 2 classes of nonsyndromic cleft palate: (1) familial CP, which appears to have an autosomal dominant component to its etiology, and (2) nonfamilial CP, which, by demonstrating an increasing frequency of CP with time and a maternal age effect, appears to be related to environmental factors.

Carter et al. (1982) reported the findings in a large series of patients who had been treated surgically for nonsyndromic cleft palate between 1920 and 1939. The probands for the family study were 167 who could be traced and who had had children. Of their 384 children, 11 had cleft palate (2.9%); of their 398 sibs, 5 had cleft palate; of their 117 grandchildren, 1 was affected; and of their 517 nephews and nieces, 1 was affected. The authors suggested that the etiology is probably heterogeneous with some families showing modified dominant inheritance.

Christensen et al. (1992) found that in the Danish population, surgical files provided more than 95% ascertainment for cleft lip (with or without cleft palate) without associated malformations/syndromes. However, surgical files were a poor source for studying isolated cleft palate and could not be used to study the prevalence of associated malformations or syndromes. The male-to-female ratio was 0.88 in surgically treated cases of CP, but was 1.5 in nonoperated CP cases, making the overall sex ratio for CP 1.1 (95% confidence limits, 0.86 to 1.4). The sex ratio for CP without associated malformations was 1.1 with similar confidence limits. One of the major criteria in CP multifactorial threshold models, namely, higher CP liability among male CP relatives, must be reconsidered if other studies confirm that a CP sex-ratio reversal to male predominance occurs when high ascertainment is achieved.

Christensen and Mitchell (1996) estimated the prevalence of nonsyndromic CP in Denmark, obtained estimates of the risks to first-, second-, and third-degree relatives, and analyzed the data for mode of inheritance. A total of 2,301 CP cases were born in Denmark during the period 1936 to 1987; 1,952 (84.8%) of these cases were nonsyndromic. This corresponded to a point prevalence of 5.1 nonsyndromic CP cases per 10,000 live births. The corresponding figure for the period 1952 to 1987 was 5.8 per 10,000 live births. The recurrence risks for the 3 classes of relatives of 1,364 nonsyndromic CP probands were 2.74%, 0.28%, and 0.00%, respectively. Analyses of these data were considered consistent with CP being determined by several interacting loci.

Mapping

In studies of 15 sibships with 2 or more sibs with isolated cleft palate, Van Dyke et al. (1983) could demonstrate no close linkage with HLA.

Molecular Genetics

Associations Pending Confirmation

The transforming growth factor-alpha gene (TGFA; 190170) on chromosome 2q33 has been implicated as a susceptibility locus for nonsyndromic cleft lip with or without cleft palate (see OFC2, 602996). Shiang et al. (1993) and Hwang et al. (1995) suggested that it may also play a role in the etiology of nonsyndromic CP.

Van den Boogaard et al. (2000) identified a stop codon in the MSX1 gene (142983.0002) on chromosome 4p16.1 in a 3-generation Dutch family with tooth agenesis (106600) and combinations of cleft palate only and cleft lip and cleft palate, providing further evidence for this gene in orofacial clefting.

See 173490.0011-173490.0013 for discussion of an association between isolated cleft palate and mutation in the PDGFRA gene on chromosome 4q12.