PREVALENCE AND ORIGIN OF DE-NOVO DUPLICATIONS IN CHARCOT-MARIE-TOOTH DISEASE TYPE-1A - FIRST REPORT OF A DE-NOVO DUPLICATION WITH A MATERNAL ORIGIN

Charcot-Marie-Tooth disease (CMT) is the most common inherited periphe ral neuropathy. Sporadic cases of CMT have been described since the ea rliest reports of the disease. The most frequent form of the disorder, CMT1A, is associated with a 1.5-Mb DNA duplication on chromosome 17p1 1.2, which segregates with the disease. In order to investigate the pr evalence of de novo CMT1A duplications, this study examined 118 duplic ation-positive CMT1A families. In 10 of these families it was demonstr ated that the disease had arisen as the result of a de novo mutation. By taking into account the ascertainment of families, it can be estima ted that greater than or equal to 10% of autosomal dominant CMT1 famil ies are due to de novo duplications. The CMT1A duplication is thought to be the product of unequal crossing over between parental chromosome 17 homologues during meiosis. Polymorphic markers from within the dup licated region were used to determine the parental origin of these de novo duplications in eight informative families. Seven were of paterna l and one of maternal origin. This study represents the first report o f a de novo duplication with a maternal origin and indicates that it i s not a phenomenon associated solely with male meioses. Recombination fractions for the region duplicated in CMT1A are larger in females tha n in males. That suggests that oogenesis may be afforded greater prote ction from misalignment during synapsis, and/or that there may be lowe r activity of those factors or mechanisms that lead to unequal crossin g over at the CMT1A locus.