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A number of disorders affecting speech, learning, and behavior have a 3:1 or greater male:female ratio. This has usually been explained on the basis of a developmental model postulating a difference in the young male versus female brain. Tourette syndrome is a hereditary neurobehavioral disorder due to a single major autosomal gene. It is associated with learning disorders and attention deficit disorder with hyperactivity and shows a similar predilection for males. Because of the more obvious nature of the tics and vocal noises, it is uniquely suited for examining an alternative hypothesis of an X-linked modifying gene to account for the increased incidence in males. Two alternative models tested were an autosomal modifying gene and the developmental model. Family pedigrees on a series of 430 consecutive cases of Tourette syndrome with 966 age-corrected offspring were used to compare the observed affected and unaffected sons and daughters for nine different phenotype matings with the expected ratios for three different models. The X-linked modifier model provided a better fit to the observed data and accounted for marked differences in the percentage of affected sons and daughters when the father versus the mother transmitted the Tourette syndrome gene. A similar model may account for the male predominance in other genetically influenced disorders of speech, learning, and behavior.

proceedings of the national academy of sciences of the united states of america

Evidence for an X-linked modifier gene affecting the expression of Tourette syndrome and its relevance to the increased frequency of speech, cognitive, and behavioral disorders in males.