Family studies of the Lesch‐Nyhan syndrome: the use of a restriction fragment length polymorphism (RFLP) closely linked to the disease gene for carrier state and prenatal diagnosis

Abstract

Abstract We have investigated the usefulness of a full‐length cDNA probe for the hypoxanthine phosphoribosyltransferase, HPRT gene in the diagnosis of the carrier state for the Lesch‐Nyhan syndrome in 13 families. The products of DNA digestion by 21 different restriction enzymes were examined by Southern analysis. The only useful polymorphism detected was a three allele polymorphism with Bam HI; others were found with Msp I and Hind III but they were not linked to the disease. None of the boys with the Lesch‐Nyhan syndrome had a unique polymorphism and therefore a detectable gene deletion or other major structural alteration. A DNA polymorphism capable of giving additional diagnostic information with respect to carrier status was present in 8 of the 13 families, but not for all of the family members at risk. The cDNA probe and restriction enzyme analysis gave an unequivocal diagnosis to 20 women out of 28 who might have been carriers and for whom it would not have been available on the basis of pedigree analysis and biochemical tests alone. If a linked polymorphism is to be useful for carrier detection it must be present in only one of the mother's X‐chromosomes (i.e. the mother must carry a different allele on each X‐chromosome). Although this polymorphism is detected by an HPRT probe it is not at the site of the specific gene lesion. In spite of considerable genetic heterogeneity, most cases of the Lesch‐Nyhan syndrome appear to be due to either single base substitutions or small deletions which are not detectable by Southern analysis. None of the propositi in these families was due to a new mutation arising in the maternal germ line. One family was identified in which the evidence was compatible with a mutation having arisen in the X‐chromosome which the mother of the propositus inherited from her father, and in another family the mutation arose in the maternal grandmother. A case illustrating the application of this restriction fragment length polymorphism to the first trimester prenatal diagnosis of the Lesch‐Nyhan syndrome is also reported. This study illustrates the limitations as well as the value of using a linked DNA polymorphism for carrier state diagnosis in X‐linked diseases.