Genetic modifiers of Duchenne and facioscapulohumeral muscular dystrophies

Abstract

Muscular dystrophy is defined as the progressive wasting of skeletal muscles that is caused by inherited or spontaneous genetic mutations. Next-generation sequencing has greatly improved the accuracy and speed of diagnosis for different types of muscular dystrophy. Advancements in depth of coverage, convenience, and overall reduced cost have led to the identification of genetic modifiers that are responsible for phenotypic variability in affected patients. These genetic modifiers have been postulated to explain key differences in disease phenotypes, including age of loss of ambulation, steroid responsiveness, and the presence or absence of cardiac defects in patients with the same form of muscular dystrophy. This review highlights recent findings on genetic modifiers of Duchenne and facioscapulohumeral muscular dystrophies based on animal and clinical studies. These genetic modifiers hold great promise to be developed into novel therapeutic targets for the treatment of muscular dystrophies. Muscle Nerve 57: 6-15, 2018.

Keywords: DMD; genetic modifier; muscle disease; muscular dystrophy; variant.

Figure 1. Schematic of significant genetic modifiers of Duchenne and Facioscapulohumeral muscular dystrophies and their sub-cellular localization in skeletal muscle

Dystrophin and the dystrophin-associated protein complex (DAPC) have an important functional role in the transmission of intercellular force to the extracellular matrix (ECM). Of note, Smchd1 is a chromatin-modifier protein that is believed to allow a permissive state for transcriptional activation of the pathogenic DUX4 transcription factor in FSHD Type 2.