Spectrum of genetic mechanisms in FSHD

This figure displays the spectrum of the genetic mechanisms in FSHD. Normal: in healthy individuals, both copies of 4q35 contain 11 to 100 repeats with normal methylation or, rarely, a contraction with hypomethylation on a nonpermissive B allele. In this figure, we display only 1 copy of 4q35 with a permissive A allele, which is necessary to cause FSHD. In FSHD1, 1 copy of the 4q35 is contracted with hypomethylation of the D4Z4 repeat array. In patients with 1 to 6 repeats, the repeat number is associated with disease severity. In patients with 7 to 10 repeats, nonpenetrance is more common and epigenetic factors (such as mutations in SMCHD1) play a larger role. In FSHD2, 1 copy of the 4q35 contains 11 to 20 repeats. A mutation in SMCHD1 or DNMT3B gene is present and D4Z4 repeat arrays are hypomethylated on both 4q35 copies.