Emery-Dreifuss Muscular Dystrophy (EDMD1) via the EMD Gene

Emery-Dreifuss muscular dystrophy (EDMD) is a genetically heterogeneous disorder characterized by: 1) joint contractures with early childhood onset, 2) slowly progressing muscle weakness and wasting, and 3) cardiac conduction defects. Typically, the presenting symptom of X-linked EDMD is joint contractures of elbows, Achilles tendon, and post cervical muscles. Loss of ambulation may result from severe contractures of the spine and lower limbs but is rare in X-linked EDMD. Muscle weakness and wasting is slowly progressive until after the third decade of life. The initial muscle groups affected follow a humero-peroneal distribution, and scapular and pelvic girdle muscles become affected later in the course of the disease. The presenting clinical signs of muscle weakness include toe-walking and a waddling gait. Cardiac conduction defects are the most severe manifestation of EDMD, and female carriers without signs of skeletal muscle weakness or of contractures have been reported with cardiac disease (Emery. J Med Genet 26:637-641, 1989; Buckley et al. Heart 82:105-108, 1999). Cardiac disease can present in teenagers and includes conduction defects, dilated cardiomyopathy, and infiltration of the myocardium by fibrous and adipose tissue (Buckley et al. Heart 82:105-108, 1999). Serum CK levels are moderately elevated, most commonly in the early stages of disease (Bonne et al. Ann Neurol. 48:170–180, 2000). Age of onset and disease severity demonstrate both inter-and intra-familial variability (Mercuri et al. Neurology 54:1704–1705, 2000).

Emery-Dreifuss muscular dystrophy can be inherited as an autosomal dominant disorder secondary to variants in LMNA, SYNE1,or SYNE2; as an autosomal recessive disorder secondary to LMNA variants; or as an X-linked recessive disorder secondary to FHL1 or EMD variants. EMD (OMIM 300384) encodes emerin, an inner nuclear membrane-localized protein with a role in membrane anchorage to the cytoskeleton through association with lamin A (Bione et al. Proc Natl Acad Sci USA 90:10977-10981, 1993). Immunostaining of muscle biopsy from most EDMD1 patients shows complete absence of emerin. Consistent with this finding, the majority of pathogenic variants in EMD are nonsense variants; small, out-of-frame insertions and deletions; splice site variants; and gross deletions.

EMD gene sequencing is reported to detect ~99% of individuals who have all three major clinical symptoms, have established X-linked inheritance, and have absent emerin by western blot or immunohistocytochemistry (Manilal et al. Hum Mol Genet 7:855–864, 1998). EMD is the most common cause of X-linked EDMD, but over-all EMD is less common than autosomal dominant EDMD caused by LMNA variants.

This test provides full coverage of all coding exons of the EMD gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.