Recurrence risks for relatives in families with an isolated case of the fragile X syndrome

The proportion of sporadic cases among affected males with fragile X-related mental impairment was reinvestigated in a new sample of family data and compared to previous studies. It was found that the estimate has increased over time from 0 in the original study to 0.24 in the present study. This difference indicated that the correction used for the ascertainment of families in the original study may not have been adequate and that the suggestion that all mothers of affected males are obligate carriers may be wrong. Based on this new information, recurrence risks for relatives in a family with an isolated case of the fragile X or Martin-Bell syndrome were calculated under different assumptions in order to investigate the effect of 1) the knowledge of the phenotype of ancestors of the proband, 2) the dependence of expression of the mutation on the sex of the carrier parent, 3) the value of the penetrance of mental impairment (MI), and 4) the equality of mutation rates in egg and sperm. The assumptions made for modelling the mutational process had the greatest effect on the recurrence risk in sibs of an isolated case, whereas small differences in penetrance parameters and assumptions based on whether the ancestors were known to be normal or of unknown phenotype made little difference. Recurrence risks for the sibs and first cousins of an isolated case calculated under different assumptions are presented.