FSHD Genetic Modifiers

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Abstract Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common forms of muscular dystrophy. Individuals with FSHD have progressive muscle weakness in a specific pattern, involving the face, shoulders, distal legs and hamstrings. The symptoms of FSHD are caused by ectopic expression of the DUX4 homeodomain transcription factor due to contraction of the subtelomeric D4Z4 repeats on chromosome 4. Larger contractions (e.g., 1-3 repeats remaining) are associated with more severe disease, though this relationship is weak. Mutations in methylation genes such as SMCHD1 have been shown to exacerbate the severity of FSHD1 as well as cause FSHD in the absence of a contraction (FSHD2). These findings suggest other genetic modifiers may modulate the severity of the primary mutation. Prior studies to evaluate genetic modifiers of disease severity have been limited by small sample sizes and inability to control for the variation associated with the length of the contraction. The current proposal utilizes a historically significant pedigree to overcome these challenges. A Utah pioneer with FSHD has had 18,181 descendants. In the past five years, 13,424 were known to be living in the state of Utah, 550 of which may have the contraction based on an autosomal dominant inheritance pattern. Prior research and characterization of this pedigree have confirmed that the contraction size is moderate in this family (6 repeats) and stable between generations. This pedigree overcomes prior design challenges for a GWAS study given the sample size and control of the primary mutation. Therefore, this proposal seeks to phenotype clinically affected and unaffected members of this family to understand the penetrance of the mutation and identify genetic modifiers that modify the age of onset or clinical severity. In Aim 1, we will enroll 600 members of the family, half of which are currently symptomatic. Enrolled participants will provide age of onset and a clinical severity score. In Aim 2, we will calculate the penetrance of the mutation and perform a GWAS study. A pedigree-based GWAS algorithm will be used to identify those variants associated with age of onset, clinical severity, or change in methylation pattern. In Aim 3, identified modifiers will be validated in functional models detailed elsewhere in the proposal and in a preliminary validation cohort. At completion, we will have identified those variants associated with the variability seen in FSHD. Identification of these variants will allow for improved clinical trial design, new insight into the pathogenesis of FSHD, and identification of novel therapeutic targets. !