Molecular diagnosis of Charcot-Marie-Tooth IA disease and hereditary neuropathy with liability to pressure palsies by quantifying CMTIA-REP sequences: consequences of recombinations at variant sites on chromosome 17pl 1.2-12

The most frequent form of Charcot-Marie-Tooth disease (CMT1A; OMIM118.220) is the result of a duplication on chromosome 17 in p1 l.2-pl2. This region contains PMP22, a gene expressed in peripheral myein. The mutation results from an unequal crossing-over involving repeated sequences, CMT1A-REP, located on both sides of the duplicated region. The reciprocal product of this recombmation is a deletion of the same region, which is associated with hereditary neuropathy with liability to pressure palsies (HNPP; 0M1M162.500). Proximal and distal CMT1A-REP sequences can be distinguished by the presence of a variant EcoPJ site. We quantified the number of these repeat sequences in 36 CMT1A and 40 HNPP patients. CM1’lAREP sequences are involved in almost all of the mutations. The majority of recombination breakpoints occur distally from the variant EcoP.J site. However, a few have a breakpoint proximal to this site, which creates the risk of misinterpretation with respect to a duplicated/deleted status.