Myofibrillar Myopathy via the FLNC 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. Cardiac involvement has been reported in FLNC-related MFM (Luan et al. Neuromuscul Disord 20:390-396, 2010).

Filamin-related myofibrillar myopathy (OMIM 609524) is inherited as an autosomal dominant disorder. Filamin-C, a member of a small family of proteins known to bind actin, interacts with gamma and delta sarcoglycans (Thompson et al. J Cell Biol 148:115-126, 2000). Elevated levels of membrane-associated filamin-C have been found in patients with limb girdle muscular dystrophy type 2C (gamma sarcoglycanopathy) and dystrophinopathy (Thompson et al. 2000). A small number of pathogenic gene variants have been reported in the FLNC gene; they include missense, nonsense, small deletions and an insertion/deletion variant. A dominant-negative effect has been documented for a single nucleotide deletion within the dimerization domain of the filamin-C protein (Kono et al. Neurol 75:547-554, 2010). Other genes involved with MFM include MYOT, DES, LDB3, CRYAB, and BAG3.

Myofibrillar myopathy due to FLNCvariants is a rare disorder. 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 was LDB3 (14%), MYOT (13%), DES (8%), FLNC (4%), BAG3 (4%), and CRYAB (3%). Thus, myofibrillar myopathy appears to be a genetically heterogeneous disorder, and the clinical sensitivity for testing any of the known myofibrillar myopathy-related genes is likely low.

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