Molecular analysis of 4q35 rearrangements in facioscapulohumeral muscular dystrophy (FSHD): application to family studies for a correct genetic advice and a reliable prenatal diagnosis of the disease

In the majority of facioscapulohumeral muscular dystrophy (FSHD) families ( about 95%) the genetic defect has been identified as a deletion of a variab le number of KpnI repeats in the 4q35 region, although no specific transcri pts from this locus have been isolated so far. Molecular diagnosis is based on the detection by probe p13E-11 of EcoRI small fragments, in the range 1 0-28 kb, that are resistant to BlnI digestion. In family studies this probe is used with other 4q35 polymorphic markers to assign the haplotype associ ated with the disease. So far, we performed DNA analysis in 145 FSHD famili es and identified the 4q35 DNA rearrangement not only in affected individua ls, but also in healthy subjects at risk of transmitting the disease, such as non-penetrant gene carriers and somatic mosaics. In addition we applied prenatal tests to 19 fetuses, using DNA extracted from chorionic villi samp les (CVS) at 10-11 weeks of gestation. The FSHD status, as determined by th e presence of BlnI-resistant small fragments associated with the at risk ha plotype, was assessed in nine fetuses; in the remaining 10 cases the diseas e was excluded. Our results show that molecular analysis of 4q35 rearrangem ents is a reliable indirect method to perform diagnostic, predictive and pr enatal tests in FSHD. (C) 1999 Elsevier Science B.V. All rights reserved.