Résumé :
|
The aim of this study was to identify the genetic and epigenetic defects in patients presenting with a FSHD clinical phenotype without D4Z4 contractions on chromosome 4q35 tested by linear gel electrophoresis (LGE) and Southern blot analysis. We studied 16 patients displaying FSHD-like phenotype, with normal cardiovascular and respiratory function, a myopathic pattern on EMG, and muscle biopsy normal or displaying only mild and aspecific dystrophic changes.We sequenced calpain 3 (CAPN3), valosin containing protein (VCP) and four and a half LIM domains protein 1 gene (FHL1) gene and we analyzed the D4Z4 repeat arrays by extensive genotyping and DNA methylation analysis. We found one patient carrying a complex rearrangement in the FSHD locus that masked the D4Z4 contraction associated with FSHD1 in standard genetic testing, one patient with a somatic mosaicism for D4Z4 4q35 contraction, six patients that were diagnosed with FSHD2, four patients with CAPN3 mutations, two with a VCP mutation, No mutations were found in FHL1, while, for two patients we could not identify the genetic defect.In conclusion, in patients presenting an FSHD-like clinical phenotype with a negative molecular testing for FSHD consider: 1) detailed genetic testing including D4Z4 contraction of permissive hybrid D4Z4 repeat arrays, p13E-11 probe deletions, D4Z4 hypomethylation in absence of repeat contraction as observed in FSHD2, 2) mutations in CAPN3 even in the absence of protein deficiency on Western blot analysis 3) VCP mutations even in the absence cognitive impairment, Paget disease and typical inclusion in muscle biopsy.
|