De novo facioscapulohumeral muscular dystrophy: Frequent somatic mosaicism, sex-dependent phenotype, and the role of mitotic transchromosomal repeat interaction between chromosomes 4 and 10

Autosomal dominant facioscapulohumeral muscular dystrophy (FSHD) is caused by deletion of most copies of the 3.3-kb subtelomeric D4Z4 repeat array on chromosome 4q. The molecular mechanisms behind the deletion and the high pr oportion of new mutations have remained elusive. We surveyed 35 de novo FSH D families and found somatic mosaicism in 40% of cases, in either the patie nt or an asymptomatic parent. Mosaic males were typically affected; mosaic females were more often the unaffected parent of a nonmosaic de novo patien t. A genotypic-severity score, composed of the residual repeat size and the degree of somatic mosaicism, yields a consistent relationship with severit y and age at onset of disease. Mosaic females had a higher proportion of so matic mosaicism than did mosaic males. The repeat deletion is significantly enhanced by supernumerary homologous repeat arrays. In 10% of normal chrom osomes, 4-type repeat arrays are present on chromosome 10. In mosaic indivi duals, 4-type repeats on chromosome 10 are almost five times more frequent. The reverse configuration, also 10% in normal chromosomes, was not found, indicating that mutations may arise from transchromosomal interaction, to w hich the increase in 4-type repeat clusters is a predisposing factor. The s omatic mosaicism suggests a mainly mitotic origin; mitotic interchromosomal gene conversion or translocation between fully homologous 4-type repeat ar rays may be a major mechanism for FSHD mutations.