DETECTION OF THE CMT1A HNPP RECOMBINATION HOTSPOT IN UNRELATED PATIENTS OF EUROPEAN DESCENT/

Charcot-Marie-Tooth type 1 disease (CMT1) and hereditary neuropathy wi th liability to pressure palsies (HNPP) are common inherited disorders of the peripheral system. The majority of patients have a 1.5Mb tande m duplication (CMT1A) in chromosome 17p11.2 while most HNPP patients h ave a deletion of the same 1.5Mb region. The CMT1A duplication and HNP P deletion are the reciprocal products of an unequal crossing over eve nt between misaligned flanking CMT1A-REP elements. We analysed 162 unr elated CMT1A duplication patients and HNPP deletion patients from 11 d ifferent countries for the presence of a recombination hotspot in the CMT1A-REP sequences. A hotspot for unequal crossing over between the m isaligned flanking CMT1A-REP elements was observed through the detecti on of novel junction fragments in 76.9% of 130 unrelated CMT1A patient s and in 71.9% of 32 unrelated HNPP patients. This recombination hotsp ot was also detected in eight out of 10 de novo CMT1A duplication and in two de novo HNPP deletion patients. These data indicate that the ho tspot of unequal crossing over occurs in several populations independe ntly of ethnic background and is directly involved in the pathogenesis of CMT1A and HNPP. We conclude that the detection of junction fragmen ts from the CMT1A-REP element on Southern blot analysis is a simple an d reliable DNA diagnostic tool for the identification of the CMT1A dup lication and HNPP deletion in most patients.