Genetic modifiers of disease progression and severity in FSHD

Background
Facioscapulohumeral muscular dystrophy (FSHD) is a progressive muscle disease for which no cure is available. There are two genetic forms of FSHD, FSHD1 and FSHD2, which converge in the misexpression of the transcription factor DUX4 in skeletal muscle. Clinically, FSHD is characterized by marked heterogeneity in disease onset and progression. This suggests the presence of additional (genetic) modifiers of FSHD disease severity. Although we have previously shown that the FSHD2 disease genes SMCHD1 and DNMT3B can act as modifiers of disease severity in FSHD1 families, still a significant degree of the variation between patients remains unexplained. In this project we take a genetic approach to identify new genetic causes and modifiers of FSHD.

Methods
We use unbiased and targeted (epi)genetic (next generation sequencing) approaches to identify modifiers of FSHD clinical presentation. We study (epi)genetic factors both within and outside the FSHD1 locus. For this, we utilize genomics and transcriptomics strategies on samples available  from our large cohort of clinically well-defined patients and we confirm our findings in patient-derived primary muscle cell lines.

Relevance
This project aims to identify genetic factors that determine disease presentation and progression. This helps us to better understand the pathophysiology of FSHD. Moreover, identified factors may have prognostic value.

Financiering: National Institutes of Health; Prinses Beatrix Spierfonds; Spieren voor Spieren