Myofibrillar Myopathy via the LDB3 (ZASP) 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. Patients with LDB3-related MFM (OMIM 609452) demonstrate distal more than proximal weakness, peripheral neuropathy, and sometimes cardiac involvement (Selcen and Engel. Ann Neurol 57:269-276, 2005).

Myofibrillar myopathy and dilated cardiomyopathy related to LDB3 are inherited as autosomal dominant disorders. The LIM domain-binding protein-3, or Zasp, interacts with alpha-actinin and protein kinase C, and is an integral component of the Z-disc. All variants thus far reported cause amino acid substitutions. Other genes involved with MFM include DES, MYOT, FLNC, CRYAB, and BAG3.

The LIM domain-binding protein-3 is coded by exons 1 - 16 of the LDB3 gene on chromosome 10q23. Four isoforms result from alternative splicing of the 16 exons.

Among a cohort of 80 MFM patients diagnosed at the Mayo Clinic, only 46% have been found to have variants in one of the six known causative genes (Selcen and Engel, GeneReviews 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, MFM appears to be a genetically heterogeneous disorder and the clinical sensitivity for testing any of the known genes is likely low. In a study of 100 probands with dilated cardiomyopathy, six patients were found to have LDB3 variants (Vatta et al. J Amer Coll Cardiol 42:2014-2027, 2003).

This test provides full coverage of all coding exons of the LDB3 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).