Myofibrillar Myopathy via the DES Gene

Myofibrillar myopathy (MFM) refers to a genetically heterogeneous group of disorders sharing a homogeneous morphological pattern and, most often, onset of clinical symptoms in adulthood. Stained with trichome, abnormal muscle fibers are seen containing hyaline structures and vacuoles that contain membrane fragments from disintegrated sarcomeric Z disc and myofibrils (Selcen et al. Brain 127:439-451, 2004). With electron microscopy, affected muscle fibers reveal progressive degeneration of myofibrils beginning at the Z-disk. Immunohistochemical staining of the structurally abnormal fibers reveals abnormal expression and accumulation of several proteins, including myotilin, desmin, alpha-B crystalline, dystrophin, and β-amyloid precursor protein (Selcen et al. 2004). Clinically, patients present in adulthood with proximal and distal weakness and in some cases with cardiomyopathy. Dilated cardiomyopathy is present in 15-30% of desmin-related MFM (Selcen and Engel. GeneReviews 2010). Cardiac manifestations include conduction blocks, arrhythmias, and restrictive heart failure (Li et al. Circulation 100:461-464, 1999; Goldfarb et al. Nat Genet 19:402-403, 1998; Dalakas et al. N Eng J Med 342:770-780, 2000).

Desmin, a cytoskeletal protein that functions as an attachment between the terminal Z disc and membrane-associated proteins (Tidball, Exp Cell Res 199:206-212, 1992), is expressed in smooth, cardiac, and skeletal muscles. Desmin-related myofibrillar myopathy (OMIM 601419) is inherited as an autosomal dominant disorder. Approximately 25% of affected individuals have an affected parent, but the proportion of de novo variants is unknown (Selcen and Engel, 2010). Other genes involved with MFM include MYOT, FLNC, LDB3, CRYAB, and BAG3.

Among a cohort of 80 MFM patients diagnosed at the Mayo Clinic, only 46% were found to have variants in one of the six known causative genes (Selcen and Engel, 2010). The relative frequencies of variants found in the Mayo Clinic cohort were LDB3 (14%), MYOT (13%), DES (8%), FLNC (4%), BAG3 (4%), and CRYAB (3%). Among eight other families with dominantly inherited MFM and two patients with sporadic disease, Dalakas et al. (2000) found variants in four of the families and in one of the sporadic cases. Of the twelve total affected individuals with DES variants in this study, seven had cardiomyopathy. MFM appears to be a genetically heterogeneous disorder, and the clinical sensitivity for testing any of the known genes is likely low.

This test provides full coverage of all coding exons of the DES 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).