Clinical Domain Working Groups

Hereditary primary muscle diseases include a range of disorders that primarily affect the skeletal muscle and result from defects in genes related to muscle structure and function. Major groups of hereditary primary muscle diseases include congenital myopathies and muscular dystrophies. Congenital myopathies are a group of neuromuscular disorders that typically present at birth with hypotonia and muscle weakness, with an estimated prevalence of ~1-5/100,000 live births. As opposed to muscular dystrophies that are characterized by progressive muscle degeneration and wasting, congenital myopathies tend to be non-progressive or slowly progressive and do not involve continuous degeneration and regeneration in the muscle. Patients often have respiratory insufficiency and feeding difficulties, and cardiac involvement may also be observed. Congenital myopathies are defined by characteristic structural changes in the skeletal muscle, which also forms a basis for their sub-classification, such as nemaline myopathy, centronuclear myopathy, central core disease, multiminicore disease, and congenital fiber type disproportion. To date, over 30 genes have been associated with various forms of congenital myopathies and our Congenital Myopathies Gene Curation Expert Panel has curated 20 genes regarding the level of evidence for their disease association so far. Sixteen genes (DNM2, KLHL40, LMOD3, ACTA1, MTM1, NEB, CFL2, PYROXD1, STAC3, TNNT1, MYPN, SEPN1/SELENON, MYH2, MEGF10, SPEG, RYR1) were identified as having Definitive evidence to have a role in congenital myopathies. Each of these genes have several hundred variants reported in patients with often limited amount of data in the literature for their association with disease, which poses a challenge in the clinical setting. The Congenital Myopathies VCEP aims to (1) define criteria for the specific classification of variants related to congenital myopathies based on the ACMG standards and guidelines for variant interpretation and classification, and (2) review the majority of reported variants that have been associated with these disorders to provide expert-approved classification for their clinical significance, starting with 5 genes that have been described as having Definitive evidence for a causal role in disease: ACTA1, NEB, MTM1, DNM2, RYR1.