Facioscapulohumeral Muscular Dystrophy—a Tale of Heterogeneity and the Power of Clinical Assessments

The clinical picture of facioscapulohumeral muscular dystrophy (FSHD1, OMIM 158900; FSHD2, OMIM 158901) was described 130 years ago by Landouzy and Dejerine.¹ The disease was genetically linked to the 4q35 locus (by linkage analysis) in the early 1990s.² Since then, clinical^3,4 and genetic⁵ observations have challenged our understanding of the disease in finding a unifying model that fully addresses the complexity of this frequent myopathy, which has an estimated prevalence of 1 in 10 000 individuals.

Importantly, FSHD1 is associated with a heterozygous reduced number of D4Z4 repeats located at the 4q35 locus, segregating with a permissive haplotype (4qA) downstream of the last D4Z4 element. In the general population, most individuals carry D4Z4 reduced alleles (DRAs) with 11 repeat units, while individuals with FSHD1 carry between 1 and 10 DRA.

In their study, Ruggiero et al⁶ present clinical data gathered from a large panel of 422 individuals, with 187 probands (defined by carrying a permissive 4qA DRA with 7 to 8 repeat units) and 235 relatives. To stratify this cohort, Ruggerio et al⁶ used a Comprehensive Clinical Evaluation Form (CCEF), which has been previously described.⁷ The CCEF separates individuals in 4 categories following a straight-forward evaluation, from full penetrance to asymptomatic and atypical presentation. The categories are as follows: A, facial, scapular, and humeral weakness, including typical FSHD with full penetrance; B, facial or scapular and humeral weakness, representing limited facial weakness (subcategory B1) or scapulohumeral weakness (subcategory B2); C, asymptomatic (ie, no motor impairment with or without scapular weakness); and D, atypical FSHD, including uncommon features with or without facioscapulohumeral weakness.

The authors report a wide panel of phenotypes, all from people carrying similar DRAs, with 47.1% of probands falling into categories B or D (20.4% and 26.7%, respectively). Furthermore, phenotype heterogeneity also prevailed within families. Indeed, the category was heterogeneous between probands and their first-degree relatives, with 52.8% of relatives remaining asymptomatic. More than 70% of first-degree relatives’ fell in categories C and B and did not present any association with the probands. Notably, most affected participants in this cohort reported symptom onset after the age of 20 years, confirming the late onset of the disease for individuals with DRA with 7 to 8 repeat units. However, the authors also reported that 35% of families included only 1 affected individual (ie, the proband), whereas other carriers remained asymptomatic, independent of the proband’s category. This high percentage highlights the variable penetrance of FSHD and advocates for complex cofactors yet to be identified.

Interestingly, a rough genotype-phenotype correlation between the number of repeats and the severity of the disease has been proposed and holds well among those who carry DRA with 1 to 4 repeat units. However, this is often challenged by the high level of intrafamilial and interindividual variability that characterizes the disease. In their work, Ruggerio et al⁶ chose to focus on patients carrying DRA with 7 to 8 repeat units. This restricted DRA size corresponds to approximately 21% of individuals with FSHD1 (in the Italian National Registry for FSHD), is usually associated with milder clinical manifestations, and represents the threshold of the so-called grey zone that encompasses those with DRA with 8 to 10 repeat units. In this grey zone, genetic counseling is particularly challenging.⁸ By including relatives and narrowing down the DRA to a single genomic factor causative for FSHD, the authors⁶ artificially reduced the genetic heterogeneity to solely focus on clinical classification parameters. Their results, balanced by a strict classification and a large number of patients, seem to indicate a sustained heterogeneity of phenotypes in individuals carrying DRA with as few as 7 repeat units. Echoing former studies on smaller cohorts reporting clinical heterogeneity, incomplete penetrance, and atypical cases, the current study underlines the difficulties of genetic counseling and prediction of the course of the disease with such variability.

Beyond demonstrating the clinical heterogeneity of FSHD, this work asks researchers to consider the definition and validation of a minimal representative cohort for fundamental research. Should we focus on molecular heterogeneity (eg, representative DRAs) or on clinical evaluation, which can be represented by DRA size? Likewise, should the inclusion of patients in randomized clinical trials targeting FSHD be based on their molecular features or on their clinical evaluations?

By highlighting the heterogeneous nature of FHSD, the study by Ruggiero et al⁶ brings FSHD back to the clinics. This work underlines the need for combinatory approaches (ie, genetics and clinics) and the importance of standardized assessments that allow clinicians to deliver the best clinical management possible.

Published: May 1, 2020. doi:10.1001/jamanetworkopen.2020.5004

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Nguyen K et al. JAMA Network Open.

Corresponding Author: Jérôme D. Robin, PhD, Aix Marseille University, Marseille Medical Genetics MMG, Campus La Timone, 27 Blvd Jean Moulin, 4 étage Aile verte, Marseille 13005, France (Jerome.robin@univ-amu.fr).

Conflict of Interest Disclosures: None reported.