Early-Onset Myopathy, Areflexia, Respiratory Distress, and Dysphagia (EMARDD) via the MEGF10 Gene

Early-onset myopathy, areflexia, respiratory distress, and dysphagia (EMARDD, OMIM 614399) presents at birth or during early infancy. The most serious symptoms are respiratory distress caused by diaphragmatic weakness and dysphagia, often necessitating gastrostomy feeding. Hartley et al. first reported this condition in two consanguineous sibships (Neuromusc Disord 17:174-179, 2007). The pregnancy of one patient was noted to be complicated by decreased fetal movements and growth retardation. Postnatally, the patient exhibited poor respiratory drive and eventually became ventilator-dependent. Other findings in these affected siblings included dependence on gastrostomy feeding tube, facial weakness, areflexia, and delays in walking. Involvement of the IGHMBP2 gene in these patients was ruled-out. Another small group of EMARDD patients was reported by Logan et al. (Nature Genet 43:1189-1192, 2011). Consistent with the clinical features of the previously described patients, all had respiratory distress caused by diaphragmatic paralysis at birth; all became ventilator-dependent; all had dysphagia; and all had areflexia. Hypotonia and muscle weakness were more prominent in the distal muscles of the upper limbs. EMG studies showed myopathic changes and skeletal muscle biopsies revealed small and incompletely-fused muscle fibers.

Early-onset myopathy, areflexia, respiratory distress, and dysphagia (EMARDD) is inherited as an autosomal recessive disorder caused by variants in the MEGF10 gene (OMIM 612453). MEGF10 encodes the multiple epidermal growth factor-like domains-10 protein, a regulator of satellite cell myogenesis. Thus far, five families have been reported with EMARDD, and protein truncating variants are the most common form of pathogenic changes in the MEGF10 gene (Logan et al. Nature Genet 43:1189-1192, 2011).

Too few genetically-confirmed cases of EMARDD have been reported to estimate clinical sensitivity. Analytical sensitivity may be high because all reported variants are expected to be detected by this method.

This test provides full coverage of all coding exons of the MEGF10 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).