Phenotypic Variability of MEGF10 Variants Causing Congenital Myopathy: Report of Two Unrelated Patients from a Highly Consanguineous Population

Abstract

Congenital myopathies are rare neuromuscular hereditary disorders that manifest at birth or during infancy and usually appear with muscle weakness and hypotonia. One of such disorders, early-onset myopathy, areflexia, respiratory distress, and dysphagia (EMARDD, OMIM: 614399, MIM: 612453), is a rare autosomal recessive disorder caused by biallelic mutations (at homozygous or compound heterozygous status) in MEGF10 (multiple epidermal growth factor-like domains protein family). Here, we report two unrelated patients, who were born to consanguineous parents, having two novel MEGF10 deleterious variants. Interestingly, the presence of MEGF10 associated EMARDD has not been reported in Saudi Arabia, a highly consanguineous population. Moreover, both variants lead to a different phenotypic onset of mild and severe types. Our work expands phenotypic features of the disease and provides an opportunity for genetic counseling to the inflicted families.

Clinical, radiological, and genetic characterization of SLC13A5 variants in Saudi families: Genotype phenotype correlation and brief review of the literature

“…After library preparation, captured fragments were run on an Illumina HiSeq 2500 Sequencer and mapped against UCSC hg19 (Illumina, Inc., San Diego, CA, United States). Comprehensive filtering of the detected variants was done as previously published (8)(9)(10)(11). Especially, variants based on homozygosity, coding, and splicing features, being within the autozygome of the affected individuals in the families, were prioritized during filtering analysis.…”

“…Additionally, publicly available databases and local resources, such as the program for Saudi Human Genome-based data outputs, were also screened during filtering. In silico pathogenicity was carried out as reported before (8)(9)(10)(11).…”

Mutations in proteins involved in E-C coupling and SOCE and congenital myopathies

“…The MEGF10 gene encodes the multiple EGF-like domain 10 protein, a transmembrane receptor belonging to the multiple epidermal growth factor–like domains family, that is upregulated in activated satellite cells and regulates the progression of the myogenic program ( Holterman et al, 2007 ). Mutations in MEGF10 have been detected in a few cases of MmD ( Boyden et al, 2012 ; Liewluck et al, 2016 ; Takayama et al, 2016 ; AlMuhaizea et al, 2021 ). The CACNA1S gene encodes Cav1.1, the pore-forming subunit of the skeletal muscle voltage-gated Ca 2+ channel (DHPR).…”

Special Issue “Genetics and Epigenetics of Neuromuscular Diseases”

“…Various MEGF10 mutations have so far been identified in patients with neuromuscular disorders, such as minicore myopathy, LGMD, and early onset myopathy, areflexia, respiratory distress, and dysphagia (EMARDD). This report by AlMuhaizea and co-workers [ 3 ] contributes to the list of known pathogenic MEGF10 mutations and their genotype–phenotype correlations. A case report is also included in this Special Issue, authored by Serrano-Lorenzo and coworkers [ 4 ], which focuses on metabolic myopathies.…”

“…In a brief report, AlMuhaizea and co-workers [ 3 ] describe two novel variants of MEGF10 identified in two unrelated patients with congenital myopathies who were born to consanguineous parents from Saudi Arabia. Furthermore, the authors reviewed the literature and provided a list of the previously reported pathogenic variants of MEGF10 and the associated congenital myopathies.…”