Gonadal mosaicism and genetic counseling for X linked recessive lethals

In this paper a first order refinement of the theory of genetic counseling for X linked recessive disorders is presented. Biological data suggest that some 6 million oocytes are produced during the fetal life of the female. A model describing the random appearance and spread of mutant oocytes, gonadal mosaicism, as a branching process is derived. With no selection, the expected proportion of mutant oocytes remaining at any time is identical with the proportion of mutants existing at the 6 million stage. A method of moments estimator of the probability of a particular proportion of mutants being produced in terms of the number of cell divisions and the probability of a mutation occurring during mitosis (λ) is derived in terms of the mutation rate per generation. Approximations to the moments of the distribution of mutants were obtained from the formula for the individual probabilities, as was a method for inserting these values of the moments into an expression describing the risk to the next son. Partial gonadal mosaicism has a small effect only on the classical risk of recurrence. From the clinical standpoint the main implication of the paper is that it provides reassurance that, in any realistic size of family, ignoring the effect of gonadal mosaicism will have little effect on the estimate of the risk for the next child. The application of the model to other areas, particularly spermatogenesis, is briefly discussed.