Mutations in MEGF10, a regulator of satellite cell myogenesis, cause early onset myopathy, areflexia, respiratory distress and dysphagia (EMARDD)

Abstract

Infantile myopathies with diaphragmatic paralysis are genetically heterogeneous, and clinical symptoms do not assist in differentiating between them. We used phased haplotype analysis with subsequent targeted exome sequencing to identify MEGF10 mutations in a previously unidentified type of infantile myopathy with diaphragmatic weakness, areflexia, respiratory distress and dysphagia. MEGF10 is highly expressed in activated satellite cells and regulates their proliferation as well as their differentiation and fusion into multinucleated myofibers, which are greatly reduced in muscle from individuals with early onset myopathy, areflexia, respiratory distress and dysphagia.

Identification of autosomal recessive disease loci using out-bred nuclear families

“…2). Within this region, a 10-bp duplication in exon 19 of MEGF10 (c.2288_2297dup) resulting in a truncated protein (p.Asp766GlufsX4) was subsequently identified [Logan et al, 2011].…”

“…S3) represents an extended consanguineous family in which three members presented with early-onset myopathy with respiratory distress and dysphagia (EMARDD). These individuals were found to be homozygous for a 10-bp duplication (NM_032446.2:c.2288_2297dup) in the coding sequence of exon 19 of MEGF10, causing a frame-shift mutation (p.Asp766GlufsX4) [Logan et al, 2011].…”

Clinical massively parallel sequencing for the diagnosis of myopathies

“…In 2011, massively parallel sequencing was applied for the first time to myology, leading to the discovery of mutations in the MEGF10 gene in patients with a previously uncharacterized muscle disorder early onset myopathy, areflexia, respiratory distress and dysphagia (EMARDD) [15]. Since then, excluding genes involved in cardiomyopathy, 23 other novel myopathycausing genes were discovered (Table 3).…”

“…Exome and genome sequencing has revolutionized this mutation discovery process by allowing rapid identification of the homozygous nucleotide change present in all affected family members. Mutations in seven genes, MEGF10, ISPD, KLHL40, TRAPPC11, HACD1, KLHL41, MICU1, were identified using this approach (see Table 3 for muscle disorders caused by mutations in these genes) [15,21,[24][25][26][27][28]. In several cases of dominant myopathies, the list of candidate genes was narrowed down using genome-wide linkage analysis and subjected to massively parallel sequencing.…”

The wide spectrum of clinical phenotypes of spinal muscular atrophy with respiratory distress type 1: A systematic review

“…Up to now only five families have been described. This form is associated to autosomal recessive mutations in MEGF10 gene, which encodes the multiple epidermal growth factor-like domains-10 protein-a regulator of satellite cell myogenesis [36,37].…”