An epigenetic basis for genetic anticipation in facioscapulohumeral muscular dystrophy type 1

We recently read with great interest the Brain article ‘Methylation of the 4q35 D4Z4 repeat defines disease status in facioscapulohumeral muscular dystrophy (FSHD)’ by Erdmann and colleagues.1 The study verified that methylation of the D4Z4 repeat array was informative for FSHD severity and for age of FSHD onset. The data from the study were particularly interesting given previous FSHD1 studies of two-generation and three-generation families2–4 that have reported evidence consistent with genetic anticipation—a term referring to phenomenon of progressively earlier age at disease onset and increase of clinical severity in the next generation. Genetic anticipation has been demonstrated in genetic disorders of the nervous and muscular systems including Huntington’s disease, spinocerebellar ataxia (SCA), and myotonic dystrophy.2,5 Specifically, it was intriguing that the Erdmann study reported hypermethylation of the unaffected grandfather’s D4Z4 repeat array, which was in sharp contrast to the hypomethylation detected in his severely clinically affected daughter and his grandchildren.