Myotilinopathy via the MYOT Gene

Variants in the myotilin gene (MYOT), also referred to as the titin immunoglobulin domain protein gene (TTID), cause limb girdle muscular dystrophy type 1A (LGMD1A; OMIM 159000; Hauser et al. Hum Mol Genet 9:2141-2147, 2000) and myofibrillar myopathy (OMIM 609200; Selcen and Engel. Neurology 62:1363-1371, 2004). Patients with the LGMD phenotype exhibit distal weakness with mean age at onset of 27 years. Proximal weakness develops later in life, and approximately half of all patients exhibit a distinct nasal, dysarthric pattern of speech (Hauser at al. Amer J Hum Genet 71:1428-1432, 2002). CK levels are generally elevated 1.6 to 9-fold above normal range (Hauser et al. 2002). Myotilin-related MFM exhibits later onset (50 - 77 years) and has features of peripheral neuropathy with hyporeflexia, cardiomyopathy, and distal weakness greater than proximal weakness (Selcen and Engel, 2004). 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). Based upon studies of small cohorts, LGMD1A patients developed hyporeflexia later in the disease than myotilin-related MFM patients, thus tentatively differentiating these allelic disorders.

Myotilinopathy is inherited in an autosomal dominant manner. The MYOT gene (OMIM 604103) encodes myotilin, a sarcomeric protein that binds actin either alone or in conjunction with alpha-actinin, an actin crosslinking protein. Thus, myotilin plays a key role in stabilization and anchorage of thin filaments, which may be a prerequisite for correct Z disc organization (Salmikangas et al. Hum Mol Genet 12:189-203, 2003). Nearly all reported MYOT variants result in amino acid substitutions in the serine rich exon 2. One missense variant in exon 9 has been reported to be causative for LGMD1A (Shalby et al. J Neuropath Exp Neurol 68:701-707, 2009). Other genes involved with MFM include DES, FLNC, LDB3, CRYAB, and BAG3.

Myotilinopathy is a rare disorder (see for example, Moore et al. J Neuropathol Exp Neurol. 65:995-1003, 2006). Hauser et al. screened 86 muscular dystrophy families, 44 of which demonstrated autosomal dominant inheritance. One with a causative MYOT variant was found (Hauser et al. Am J Hum Genet 71:1428–1432, 2002). The relative frequencies of variants found in the Mayo Clinic MFM cohort was LDB3 (14%), MYOT (13%), DES (8%), FLNC (4%), BAG3 (4%), and CRYAB (3%) (Selcen and Engel, GeneReviews 2010).

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