Hemizygosity for SMCHD1 in Facioscapulohumeral Muscular Dystrophy Type 2: Consequences for 18p Deletion Syndrome

Facioscapulohumeral muscular dystrophy (FSHD) is most often associated with variegated expression in somatic cells of the normally repressed DUX4 gene within the D4Z4-repeat array. The most common form, FSHD1, is caused by a D4Z4-repeat array contraction to a size of 1-10 units (normal range 10-100 units). The less common form, FSHD2, is characterized by D4Z4 CpG hypomethylation and is most often caused by loss-of-function mutations in the structural maintenance of chromosomes hinge domain 1 (SMCHD1) gene on chromosome 18p. The chromatin modifier SMCHD1 is necessary to maintain a repressed D4Z4 chromatin state. Here, we describe two FSHD2 families with a 1.2-Mb deletion encompassing the SMCHD1 gene. Numerical aberrations of chromosome 18 are relatively common and the majority of 18p deletion syndrome (18p-) cases have, such as these FSHD2 families, only one copy of SMCHD1. Our finding therefore raises the possibility that 18p- cases are at risk of developing FSHD. To address this possibility, we combined genome-wide array analysis data with D4Z4 CpG methylation and repeat array sizes in individuals with 18p- and conclude that approximately 1:8 18p- cases might be at risk of developing FSHD. FSHD is caused by derepression of the DUX4 gene within the D4Z4 repeat array (11-100 units). In FSHD1 derepression results from a short (1-10 units) D4Z4 array, in FSHD2 by dominant negative or haploinsufficiency mutations in the repressor SMCHD1 in combination with a semi-short (11-25 units) D4Z4 array. We show that SMCHD1 hemizygosity can also result in FSHD2. Hemizygosity for SMCHD1 is also seen in 18p deletion individuals and about 12% of them carry a semi-short D4Z4 array which puts them at risk for FSHD.