# FSHD Genetic Modifiers

> **NIH NIH P50** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2020 · $386,158

## Abstract

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.
!

## Key facts

- **NIH application ID:** 9933944
- **Project number:** 5P50HD060848-14
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** CHARLES P. EMERSON
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $386,158
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9933944

## Citation

> US National Institutes of Health, RePORTER application 9933944, FSHD Genetic Modifiers (5P50HD060848-14). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9933944. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*