The occurrence of new mutants in the X linked recessive Lesch Nyhan disease

U. Francke, J. Felsenstein, S. M. Gartler, B. R. Migeon, J. Dancis, J. E. Seegmiller, F. Bakay, W. L. Nyhan

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58 Scopus citations


In a population at equilibrium for a sex linked lethal, one third of the genes for that lethal must arise anew each generation. Therefore, one third of all cases of Lesch Nyhan disease, a severe X linked recessive lethal disorder, should be new mutants. To test this hypothesis, the authors have collected 47 families, 20 with a single proband and 27 with multiple affected males in which the patients' mothers and other female relatives had been studied for heterozygosity. Available carrier detection tests identify heterozygous females on the level of the molecular defect by demonstration of mosaicism for HPRT deficiency in hair roots and skin fibroblasts. Only four mothers were found not to be 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 families, 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 one half. Of all 20 maternal grandmothers studied, five 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 four of the five 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 appears to be 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.

Original languageEnglish (US)
Pages (from-to)123-137
Number of pages15
JournalAmerican journal of human genetics
Issue number2
StatePublished - Dec 1 1976
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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