Between-generation differences in ascertainment and penetrance: relevance to genetic hypotheses in fragile X.

Between-generation differences in ascertainment were examined in 54 extended fragile X pedigrees, where all available members were clinically, psychometrically, and cytogenetically investigated. In 24 families a diagnosis was verified by molecular characterization using the pfxa3 fragile X-specific probe. We found considerable differences between generations in relative proportions of affected fragile X subjects versus 'non-penetrant' carriers. We also found deviation in the segregation ratio in unbiased samples of relatives in pedigrees. We claim that these irregularities are influenced by different rates of ascertainment, depending on the clinical expression of the condition (penetrance) and the fertility of fragile X individuals in a pedigree, as well as by the thoroughness of clinical investigation in individual families. Penetrance and fertility were estimated in fragile X females assessed by psychometric tests, and they were compared with earlier estimates based on a subjective judgement of their intellectual status. We suggest that the standard correction for ascertainment bias, such as has been applied in segregation analysis of this condition, is not sufficient to adjust for all types of bias.