Myofibrillar Myopathy, Childhood Onset via the BAG3 Gene

Myofibrillar myopathy (MFM) refers to a genetically heterogeneous group of adult-onset disorders sharing a homogeneous morphological pattern. 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). Unlike typical MFM, which presents in adulthood, Bag3-associated MFM (OMIM 612954) presents in childhood with markedly progressive limb and axial weakness (Selcen et al. Ann Neurol 65:83-89, 2009). Among the three Bag3 patients thus far reported, all had elevated serum CK levels (3-, 6-, and 15-fold elevated), and all developed cardiomyopathy and respiratory insufficiency as teenagers. Two patients had rigid spines, and one had peripheral neuropathy. Muscle from affected individuals showed Z-disk degeneration and accumulation of granular debris and inclusions (Selcen et al. 2009).

The BAG3 gene (OMIM 603883) encodes a Z-disc associated chaperone protein (Bag3) expressed in skeletal and cardiac muscle (Homma et al. Am J Pathol 169:761-773, 2006) that is involved with degrading misfolded and aggregated proteins (Takayama and Reed Nat Cell Biol 3:E237-E241, 2001). The reported cases of BAG3-associated myofibrillar myopathy have all been found to be heterozygous for a de novo p.Pro209Leu variant in exon 3 of the BAG3 gene, and to have an earlier and more severe clinical presentation than other forms of myofibrillar myopathy (Selcen et al. 2009).

Of the documented inherited causes of myofibrillar myopathy, variants in the DES gene may be the single most common cause. However, the molecular basis of this disorder is heterogeneous and is known in only approximately 20% of cases. Selcen et al. found three cases of Bag3-associated MFM among 53 probands in whom variants in DES, CRYAB, TTID, ZASP, and FLNC were ruled-out. All three unrelated individuals were found to have a de novo p.Pro209Leu BAG3 variant.

This test provides full coverage of all coding exons of the BAG3 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).