P.265 - Monosomy 18p: Risks for developing FSHD

Abstract

Facioscapulohumeral dystrophy (FSHD) is one of the most common myopathies, having an estimated incidence of 1:8500. FSHD patients suffer from a progressive, often asymmetric wasting of muscles of the face, shoulder and upper arms. Two genetically distinct, but clinically identical forms of the disease, FSHD1 and FSHD2, are characterized by somatic DUX4 expression from the D4Z4 repeat array on chromosome 4. The D4Z4 array is normally kept in a heterochromatic state in somatic cells, but this repressed state is lost in FSHD patients. In most FSHD2 cases, the disease can be explained by mutations in the chromatin modifier Structural Maintenance of Chromosomes Hinge Domain containing 1 (SMCHD1), which is necessary to repress the D4Z4 repeat. SMCHD1 is located on the short arm of chromosome 18 (18p), and resides in a chromosomal region which is lost in cases of 18p deletion syndrome (18p-). 18p- syndrome has an incidence of 1:50.000, and has thus far not been linked to muscular dystrophy. To determine the probability of developing FSHD in 18p- syndrome individuals, we investigated genetic and clinical features of 18p- syndrome patients, and of FSHD2 families with SMCHD1 monosomy. We demonstrate that in these families, as well as in 18p- syndrome individuals, DUX4 and its targets can be expressed in myocytes, but that this largely depends on the size of the D4Z4 repeat on the disease permissive haplotype of chromosome 4. This study shows that reduced SMCHD1 levels can increase the risk for somatic expression of DUX4 and FSHD disease presentation.