Phenotype-genotype relations in facioscapulohumeral muscular dystrophy type 1.

Karlien Mul,Richard J.L.F Lemmers,Patrick J Van Der Vliet,George W Padberg,Corinne G.C Horlings,Marianne A Jonker,Baziel G.M Van Engelen,Silvère M Van Der Maarel,Nicol C Voermans

doi:10.1111/cge.13446

Abstract

To determine how much of the clinical variability in facioscapulohumeral muscular dystrophy type 1 (FSHD1) can be explained by the D4Z4 repeat array size, D4Z4 methylation and familial factors, we included 152 carriers of an FSHD1 allele (23 single cases, 129 familial cases from 37 families) and performed state-of-the-art genetic testing, extensive clinical evaluation and quantitative muscle MRI. Familial factors accounted for 50% of the variance in disease severity (FSHD clinical score). The explained variance by the D4Z4 repeat array size for disease severity was limited (approximately 10%), and varied per body region (facial muscles, upper and lower extremities approximately 30%, 15% and 3%, respectively). Unaffected gene carriers had longer repeat array sizes compared to symptomatic individuals (7.3 vs 6.0 units, P = 0.000) and slightly higher Delta1 methylation levels (D4Z4 methylation corrected for repeat size, 0.96 vs -2.46, P = 0.048). The D4Z4 repeat array size and D4Z4 methylation contribute to variability in disease severity and penetrance, but other disease modifying factors must be involved as well. The larger effect of the D4Z4 repeat array on facial muscle involvement suggests that these muscles are more sensitive to the influence of the FSHD1 locus itself, whereas leg muscle involvement seems highly dependent on modifying factors.

Highlights

Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common inherited muscle disorders.[1]
This hypothesis was supported by the lower CpG methylation level that was found in symptomatic individuals with 7 to 10 repeat units compared to asymptomatic and non-penetrant gene carriers with the same repeat size.[22]
The high clinical variability in FSHD raises the question which factors contribute to disease severity and penetrance

Summary

| INTRODUCTION

Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common inherited muscle disorders.[1]. Gene instead of a repeat contraction.[9,10] Both gene products are necessary to establish or maintain a repressive D4Z4 chromatin structure in somatic tissue Both in FSHD1 and FSHD2 the mutations only lead to disease if they are present on specific haplotypes that provide the necessary polyadenylation signal (DUXPAS) to stabilize the DUX4 transcript.[7,11] A small number of FSHD patients cannot be genetically explained by these two mechanisms. Observations that pathogenic variants in SMCHD1 aggravate disease severity in FSHD1 families suggested that D4Z4 chromatin modifiers influence DUX4 expression in skeletal muscle.[21] This hypothesis was supported by the lower CpG methylation level that was found in symptomatic individuals with 7 to 10 repeat units compared to asymptomatic and non-penetrant gene carriers with the same repeat size.[22]. We use family data to estimate the influence of familial factors on disease severity and include a detailed description of clinical features to further refine phenotype-genotype correlations

| MATERIALS AND METHODS

| RESULTS

Findings

| DISCUSSION