Hypomethylation is restricted to the D4Z4 repeat array in phenotypic FSHD

Background: Patients with facioscapulohumeral muscular dystrophy ( FSHD) show a contraction of the D4Z4 repeat array in the subtelomere of chromosome 4q. This D4Z4 contraction is associated with significant allele-specific hypomethylation of the repeat. Hypomethylation of D4Z4 is also observed in patients with phenotypic FSHD without contraction of D4Z4 and in patients with the immunodeficiency, centromeric instability, and facial anomalies ( ICF) syndrome, an unrelated disease that does not present with muscular dystrophy and is in part caused by DNMT3B mutations. Methods: In order to identify the gene defect and to find the pathogenetic epigenetic pathway in phenotypic FSHD, we have aimed to identify the differences and commonalities in phenotypic FSHD and ICF by 1) investigation of DNA methylation of non-D4Z4 repeat arrays, 2) analysis of mitogen-stimulated lymphocytes to detect pericentromeric abnormalities involving chromosomes 1, 9, and 16, 3) determination of IgA, IgG, and IgM levels, and 4) mutational analysis of candidate genes to identify a second disease locus involved in the pathogenesis of phenotypic FSHD. Results: Our results do not show epigenetic or phenotypic commonalities between phenotypic FSHD and ICF other than the earlier observed D4Z4 hypomethylation. We could not identify any mutations in the candidate genes tested for. Conclusion: Our data suggest that in phenotypic FSHD hypomethylation is restricted to D4Z4 and that phenotypic FSHD and ICF do not share a defect in the same molecular pathway.