Autosomal dominantly inherited disorders are caused by mutation on one of the two alleles of one gene. One of he most intriguing questions would be then: is it possible to find patients bearing more than just one disease-causing mutation on one allele? The answer to this question is important, especially in the context of the clinical interpretation of a genetic test. As the screening of the entire coin region becomes available on larger scale and at lower costs, several are the cases in whom it is possible to detect in one single patient one clear disease-causing mutation in addition to at least one or more variants of uncertain significance. The geneticist then wonders if these additional variants may have clinical consequences and, especially in consideration of the recurrence risk, whether they may segregate separately within one family as a consequence of recombination. One very interesting article that may give an answer to such questions is about tuberous sclerosis. Indeed, cases of individuals bearing more than one disease-causing mutation in the TSC2 gene have been described by Le Caignec C et al. In their families, those multiple disease-causing mutations have also been demonstrated to segregate with different haplotypes in affected individuals (Le Caignec C et al, 2009, PMID: 19259131). Of course, the probability to detect more than one disease-causing mutation in individuals affected with autosomal dominantly inherited disorders remains an unlikely event. Yet, such possibility should not be excluded a priori.
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