OCCURRENCE OF NEW MUTANTS IN X-LINKED RECESSIVE LESCH-NYHAN DISEASE

Abstract

In a population at equilibrium for a sex-linked lethal, 1/3 of the genes for that lethal must arise anew each generation. Therefore, 1/3 of all cases of Lesch-Nyhan disease, a severe X-linked recessive lethal disorder, should be new mutants. To test this hypothesis, 47 families were collected, 20 with a single proband and 27 with multiple affected males in which the patients'' mothers and other female relatives were studied for heterozygosity. Available carrier detection tests identify heterozygous females on the level of the molecular defect by demonstration of mosaicism for hypoxanthine phosphoribosyltransferase deficiency in hair roots and skin fibroblasts. Only 4 mothers were not carriers. This result deviates significantly from expected (P < .001). Statistical tests for ascertainment effects indicated absence of bias for multiple proband families but strong bias in favor of families with many heterozygous females. When the analysis was limited to single proband familes, the deviation from expected was still significant (P < .01). The incidence of new mutants among the heterozygous mothers, as determined by the ratio of +/+ to +/- maternal grandmothers, should be 1/2. Of all 20 maternal grandmothers studied, 5 were +/+ and 15 were +/- (P < .05). Considering only the single proband families, the ratio of 5 +/+ to 8 +/- was not significantly different from expected. In 4 of the 5 cases in which the heterozygous mother of an affected individual was a new mutation, the age of her parents was considerably higher than the mean parental age in the population. This raises the possibility of a paternal age effect on X-linked mutations. There is apparently a true deficiency of new mutants among males but not among females. Data on additional Lesch-Nyhan families are needed before conclusions regarding a possible higher mutation rate in males can be drawn.