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Congenital malformations such as secondary cleft palate can be exclusively monogenic or polygenic, but most cases have a multifactorial origin involving both environmental and genetic factors, making genetic analysis difficult. The new techniques of molecular genetics have allowed the successful chromosomal localization of mutant genes in disorders that show a simple Mendelian segregation, whether autosomal dominant (e.g. Huntington's disease), autosomal recessive (cystic fibrosis) or X-linked (Duchenne muscular dystrophy). Recently, a large Icelandic family (over 280 members) with X-linked secondary cleft palate and ankyloglossia (tongue-tied) has been used as a model to localize the mutant gene associated with this craniofacial clefting. The gene has been sub-chromosomally localized to Xq13-q21.1, using anonymous probe DXYS1; a LOD score of 3.07 was obtained. We are preparing cosmid libraries from DNA from mouse cell lines containing only the relevant part of the human X chromosome, introduced by chromosome-mediated gene transfer. Cosmids that contain human X-chromosome sequences will be isolated and analysed for overlapping sequences and RFLPs (restriction fragment length polymorphisms) and the regions further defined by pulsed-field gel electrophoresis and the identification of coding sequences. This should give data on the location and structure of a gene involved in the craniofacial development of the human palatine shelves. This gene, and its protein product, will identify one component of the pathway that causes nonfusion of the palate. In the long term, the understanding of the expression of this sex-linked gene for secondary cleft palate and ankyloglossia will provide a model for the molecular identification of other genes regulating processes in craniofacial development whose expression is hidden in phenotypic, polygenic complexity.

Many congenital malformations, such as cleft palate and neural tube defects, have a multifactorial origin involving both environmental and genetic factors. Conditions such as these may be exclusively monogenic, polygenic or environmental, but in most cases both genetic and environmental factors are involved. This study describes the sub-chromosomal localization of a single gene defect causing cleft palate and ankyloglossia (tongue-tied) in a large Icelandic family. This defect is a model for the analysis of other neural-crest malformations that show a more complex multifactorial inheritance pattern.