Diversity challenges and reconciles genetics in facioscapulohumeral muscular dystrophy.

Facioscapulohumeral muscular dystrophy (FSHD) is a rare genetic disease with an estimated prevalence of no more than 1 in 8000; however, it is among the most common myopathies affecting global populations. This condition is classically categorised into two genetic types, FSHD1 (MIM: 158900) and FSHD2 (MIM: 158901), which, although have different genetic causes, are phenotypically indistinguishable, manifesting as progressive muscle weakness primarily affecting the face and periscapular muscles, as well as other muscle groups in later stages. The intense efforts of clinical and basic studies to understand this disease have revealed the critical necessity for disease manifestation: ectopic activation of the embryogenic and germline gene DUX4 (double homeobox 4, MIM: 606009) in skeletal muscles and the genetic and epigenetic backgrounds allowing DUX4 expression. Thus, the potential target therapies of FSHD include silencing DUX4 transcription or blocking its translation. Although the central role of DUX4 in FSHD pathology has almost reached a consensus, the mechanism of its activation remains largely unclear. Notably, the clinical dissection of genotype-epigenotype-phenotype observations, including non-penetrant and asymptomatic carriers of permissive genetic backgrounds, highlights the yet unsolved clinical diversity with potential additional layers of DUX4 regulation or other disease-modifying factors. This review provides an overview of essential findings with potential implications for further understanding the mechanisms underlying diverse clinical cases of FSHD and endogenous DUX4 activation in FSHD pathology.