Prenatal detection of Charcot-Marie-Tooth disease type 1A duplication resulting from a rare recombination event. V. Labelle1, R.B. Bernard1, S. Tardieu2, J.P.. Azulay3, P. Malzac1, E. Leguern2, N. Philip1,4, N. Lévy1,4. 1) Département de Génétique Médicale, Hôpital d'enfants de la Timone, Marseille; 2) Clinique des maladies neuromusculaires, Hôpital Timone, Marseille; 3) Inserm U289, Hôpital Pitié-Salpétrière, Paris; 4) Inserm U491 "Génétique Médicale et Développement, Marseille. FRANCE.
CMT1A is caused in most cases by a 1.5 Mb duplication arising after unequal crossing-over between repeated sequences (CMT1A-REPs), flanking the 1.5 Mb unit. Reiter et al. and Lopes et al. (1996), described a recombination "hotspot" within a 3.2 Kb junction fragment between EcoRI (distal CMT1A-REP) and SacI (proximal CMT1A-REP), then reduced to 1.7 Kb between EcoRI and NsiI (Reiter et al.,1996) and recently to a 731 bp "hotspot" region within the EcoRI/NsiI fragment (Lopes et al., 1998). We report a 28-year-old woman requesting prenatal diagnosis because of CMT1A familial history in her husband's family. The duplication was initially evidenced in the father's family by Southern blot analysis showing a 3.2 Kb EcoRI/SacI junction fragment segregating with the duplication. Here we used a CMT1A-REPs based PCR strategy to characterize the foetus's status, since this approach detects the entire set of duplications occuring after recombination within the "hotspot". Surprisingly, the expected 1.7 kb (EcoRI/NsiI) junction fragment was absent from the father's and foetus's DNAs. After EcoRI/SacI digestion of the PCR product, a 3.2 Kb fragment was observed in their DNAs but not in mother and controls, indicating the duplication originated from a 1.5 Kb rare recombination zone. Although the karyotype was normal in the foetus, parents decided to interrupt the pregnancy because of a possible severe phenotype. Indeed, a large clinical heterogeneity was observed in this family. We report the interest of the CMT1A-REPs based PCR assay for use on trophoblastic tissues with obtention of results within 6 days. Opportunity and feasibility of preimplantation diagnosis will be compared to the ability of early prenatal diagnosis, to limit psychological distress due to pregnancy termination, particularly in diseases with unpredictible phenotype's severity.