MOSAICISM FOR THE CHARCOT-MARIE-TOOTH DISEASE TYPE 1A DUPLICATION SUGGESTS SOMATIC REVERSION

A female patient with clinical signs and symptoms of a demyelinating n europathy was shown to have a duplication of the 1.5-Mb region on chro mosome 17p11.2, typical of the great majority of cases of Charcot-Mari e-Tooth disease type IA (CMT1A). However, analysis of DNA extracted fr om peripheral blood revealed a 2:2.4 instead of the usual 2:3 ratio be tween the 7.8- and 6.0-kb EcoRI fragments in the proximal and distal r epetitive extragenic palindromic (REP) elements of CMT1A. Detection of a 3.2-kb EcoRI/SacI kb junction fragment with probe pLR7.8 confirmed the CMT1A duplication. The dosage of this junction fragment, compared with a 2.8-kb EcoRI/SacI fragment of the proximal REP elements of CMT1 A, was 2:0.58 instead of the expected 2:1 dosage for heterozygous CMT1 A duplications. We hypothesized that the lower dosages of these restri ction fragments specific for the CMT1A duplication were due to mosaici sm; this was confirmed by fluorescence in situ hybridization analysis with the D17S122-specific probe pVAW409R1. In peripheral blood lymphoc ytes the percentage of interphase nuclei with a duplication in 17p11.2 was 49%. In interphase nuclei extracted from buccal mucosa, hair-root cells or paraffin-embedded nervous tissue the duplication was detecta ble in 51%, 66% and 74%, respectively. This is the first report of mos aicism in a patient with a CMT1A duplication identified by three diffe rent and independent techniques.