We ascertained a nuclear family in which three of four siblings were affected with an unclassified autosomal recessive myopathy
characterized by severe weakness, respiratory impairment, scoliosis, joint contractures, and an unusual combination of dystrophic
and myopathic features on muscle biopsy. Whole genome sequence from one affected subject was filtered using linkage data and
variant databases. A single gene, MEGF10, contained nonsynonymous mutations that co-segregated with the phenotype. Affected subjects were compound heterozygous for
missense mutations c.976T > C (p.C326R) and c.2320T > C (p.C774R). Screening the MEGF10 open reading frame in 190 patients with genetically unexplained myopathies revealed a heterozygous mutation, c.211C > T (p.R71W),
in one additional subject with a similar clinical and histological presentation as the discovery family. All three mutations
were absent from at least 645 genotyped unaffected control subjects. MEGF10 contains 17 atypical epidermal growth factor-like domains, each of which contains eight cysteine residues that likely form
disulfide bonds. Both the p.C326R and p.C774R mutations alter one of these residues, which are completely conserved in vertebrates.
Previous work showed that murine Megf10 is required for preserving the undifferentiated, proliferative potential of satellite cells, myogenic precursors that regenerate
skeletal muscle in response to injury or disease. Here, knockdown of megf10 in zebrafish by four different morpholinos resulted in abnormal phenotypes including unhatched eggs, curved tails, impaired
motility, and disorganized muscle tissue, corroborating the pathogenicity of the human mutations. Our data establish the importance
of MEGF10 in human skeletal muscle and suggest satellite cell dysfunction as a novel myopathic mechanism.