Biallelic PAX7 variants cause a novel Satellite Cell-opathy with progressive muscle involvement resembling facioscapulohumeral muscular dystrophy

Abstract Inherited myopathies are genetic disorders characterised by declining motor function due to progressive muscle weakening and wasting. Recently, pathogenic variants in PAX7 , the master transcriptional regulator of muscle stem cells, have been associated with myopathies of variable severity, arguing for impaired satellite cell function as the main pathogenic driver. Here, we report the characterisation of two missense PAX7 variants in a patient with asymmetric, progressive muscle weakness affecting facial, upper and lower body muscles, and myopathic changes on muscle pathology. Despite this disorder closely phenocopying the clinical presentation of Facioscapulohumeral muscular dystrophy (FSHD), genetic, epigenetic and transcriptomic profiling indicated that FSHD was unlikely. However, exome sequencing revealed two heterozygous variants in PAX7 : c.335 C > T, (p.Pro112Leu) and c.1328 G > A (p.Cys443Tyr). Modelling these PAX7 variants in human myoblasts resembled the transcriptomic findings found in the muscle biopsy from the patient. Specifically, these PAX7 variants caused upregulation of splicing factors, an increase in mitochondrial reactive oxygen species levels and reduced cell proliferation. The phenotypic cell changes caused by the PAX7 variants support a pathomechanism whereby diminished satellite cell function impairs muscle homoeostasis. Together, multimodal investigation suggests that these variants in PAX7 are likely causative of an FSHD-like autosomal recessive myopathy and expand the spectrum of neuromuscular disorders originating from impaired satellite cell function.