A SINGLE POLYMORPHIC STR SYSTEM IN THE HUMAN PHENYLALANINE-HYDROXYLASE GENE PERMITS RAPID PRENATAL-DIAGNOSIS AND CARRIER SCREENING FOR PHENYLKETONURIA

Phenylketonuria (PKU) is an autosomal recessive genetic disorder cause d by phenylalanine hydroxylase (PAH) deficiency. Individuals afflicted with PKU develop irreversible mental retardation that can be largely prevented by the administration of a low-phenylalanine diet. A number of restriction fragment-length polymorphisms (RFLPs) have been identif ied in the PAH gene. Combinations of RFLPs constitute unique haplotype s that can be used to identify mutant PAH chromosomes for prenatal dia gnostic purpose in PKU families. Unfortunately, the utility of haploty pe analysis is limited in populations with a single predominant haplot ype. We have identified a novel short tandem repeat (STR) within the P AH gene that has an average level of heterozygosity of about 75% in Or ientals and about 80% in European Caucasian populations. This single m arker is as informative as haplotype analysis in Europeans and nearly twice as informative as haplotype analysis in Orientals. Although ther e is statistically significant disequilibrium between STR alleles and RFLP-based haplotypes, there is a relatively low degree of disequilibr ium between STR alleles and certain RFLP sites. Nevertheless, the comb ined use of the STR and RFLP haplotype systems increases the informati vity of linkage-based tests for prenatal diagnosis and carrier screeni ng in PKU families.