MOLECULAR DIAGNOSIS OF CHARCOT-MARIE-TOOTH IA DISEASE AND HEREDITARY NEUROPATHY WITH LIABILITY TO PRESSURE PALSIES BY QUANTIFYING CMTIA-REPSEQUENCES - CONSEQUENCES OF RECOMBINATIONS AT VARIANT SITES ON CHROMOSOME 17P11.2-12

The most frequent form of Charcot-Marie-Tooth disease (CMT1A; OMIM118. 220) is the result of a duplication on chromosome 17 in p11.2-p12. Thi s region contains PMP22, a gene expressed in peripheral myelin. The mu tation results fi-om an unequal crossing-over involving repeated seque nces, CMT1A-REP, located on both sides of the duplicated region, The r eciprocal product of this recombination is a deletion of the same regi on, which is associated with hereditary neuropathy with liability to p ressure palsies (HNPP; OMIM162.500), Proximal and distal CMT1A-REP seq uences can be distinguished by the presence of a variant EcoRI site, W e quantified the number of these repeat sequences in 36 CMT1A and 40 H NPP patients, CMT1A-REP sequences are involved in almost all of the mu tations, The majority of recombination breakpoints occur distally from the variant EcoRI site, However, a few have a breakpoint proximal to this site, which creates the risk of misinterpretation with respect to a duplicated/deleted status.