Facioscapulohumeral Muscular Dystrophy: Genetic Overview and Recent Advancements

FSHD Genetic Overview

Facioscapulohumeral muscular dystrophy (FSHD) is a complex disorder both on the clinical and molecular level. Clinical presentations can be highly variable between families and within families. The clinical spectrum of FSHD ranges from asymptomatic or very few, mild symptoms to a severe and progressive presentation with infantile onset. This clinical variability can be related to a number of different factors.

First, the size of the repeat length of the D4Z4 repeat region on chromosome 4q varies across individuals. This region contains a 3.3 kilobase (kb) unit that is typically repeated between 11 and 100 times in the general population. Individuals who are affected with FSHD type 1 have a contraction of this repeat region down to 1-10 repeats.

Secondly, evidence suggests that the repeat contraction has to occur on a certain haplotype in order to result in disease. A haplotype is a group of single nucleotide polymorphisms that are inherited together. In FSHD type 1, there are two main haplotypes: A and B. When referring to the haplotypes in FSHD type 1, it is often written as 4qA and 4qB. FSHD type 1 is thought to occur when the D4Z4 repeat contraction occurs on 4qA, while the same contraction on the 4qB haplotype is not thought to be associated with disease.

Advancements in FSHD Research

Many endeavors have been initiated to increase our understanding of the mechanisms underlying FSHD including gathering data on the different clinical presentations, increasing access to patients, expanding and developing clinical trials, and identifying biomarkers. Publications of clinical presentation data seem to coincide with the launch of patient registries. For example, just recently some clinical data from the patient registry in the United Kingdom was published.1

Additionally, efforts are being aimed at combining the data from all national patient registries into one global repository of information.2 Advancing our understanding of the variability in clinical presentations may allow us to identify other genetic modifiers of disease. Results of a recent study suggested that mutations in the DNMT3B gene may modify the FSHD phenotype.3

As progress is made to further characterize the visible clinical symptoms and progression of FSHD, there have also been advancements in identifying biomarkers to help further measure disease progression in affected individuals. Since the majority of individuals with FSHD have slow progression of the disease, identifying and measuring biomarkers in serum or through imaging (i.e., MRI) may be a more sensitive and objective approach to determining disease progression/involvement than measuring indices like muscle strength alone. Petek et al. (2016) identified levels of biomarkers in two independent FSHD patient cohorts that were significantly different than those in the control cohorts.4

The combined momentum generated by all of these projects involving different facets of FSHD provides great promise for advancing our understanding and awareness of FSHD in our community.

We recently presented a live, online webinar covering the clinical history, molecular mechanism and molecular diagnostic approaches of FSHD. Watch the webinar here.


1. Evangelista, T, et al., (2016) J Neurol.[Epub ahead of print]. (PMID: 27159994)

2. Shaw, G. (2016, April, 29). Grant Awarded to Expand FSHD Patient Registries [Web log posted]. Retrieved fromĀ

3. van den Boogaard, ML, et al., (2016) Am J Hum Genet. 2016 May 5;98(5):1020-9. (PMID: 27153398)

4. Petek, LM, et al., (2016) Neuromuscul Disord. [Epub ahead of print] (PMID: 27185459)

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