Localization of a mutant gene for cleft palate and ankyloglossia in an X-linked Icelandic family.

Common congenital malformations such as cleft lip and cleft palate are in most cases multifactorial in origin, involving both environmental and genetic components. Molecular biology techniques have enabled the successful chromosomal localization of many mutant genes from disorders that exhibit simple Mendelian segregation, whether autosomally dominant (e.g., Huntington's disease), autosomal recessive (e.g., cystic fibrosis), or X-linked (e.g., Duchenne muscular dystrophy). Studying the genetic aspect of multifactorial disorders is more complex. It requires a model family or families within which the common multifactorial phenotype is displayed as a single gene defect. Such a model has been recently exploited in the form of a large Icelandic family (over 280 members) exhibiting X-linked secondary cleft palate (CP) and ankyloglossia (A) (tongue-tied) as a single gene mutation. Using this family and the large bank of well-characterized DNA probes available for the human X chromosome, the gene for CP + A was localized by linkage analysis to Xq13-q21.1 (LOD score = 3.07, linked to anonymous probe DXYS1). Further fine mapping, using other X probes from this region (confirmed by analysis of DNA from a deletion cell-line) has placed the gene between markers DXYS12 and DXS17 (LOD score = 4.1) at Xq21.3-q22. The approximate distance between these two probes is 5 centimorgans (cM), equivalent to approximately 5 million base pairs. Now that the limits of genetic linkage have been fully tested and there are two markers flanking the defect locus, strategies are being pursued to clone the gene responsible.(ABSTRACT TRUNCATED AT 250 WORDS)