Myofibrillar Myopathy via the CRYAB Gene

Alpha-B crystallinopathy (OMIM 608810) encompasses disorders of skeletal and cardiac muscle as well as the eye. Myofibrillar myopathy (MFM) refers to a genetically heterogeneous group of disorders sharing a homogeneous morphological pattern with onset of symptoms in adulthood or very early in life. Stained with trichrome, abnormal muscle fibers are seen containing hyaline structures and vacuoles with 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). Patients with classic myofibrillar myopathy present in adulthood with proximal and distal weakness and in some cases with cardiomyopathy. A variant of this disorder presents very early in life with severe and rapidly progressive symptoms including respiratory stress and progressive rigidity. Onset of symptoms are reported as early as four months of age (Forrest et al. Neuromuscul Disord 21, 37-40 2011) with death by age three (Del Bigio et al. Ann Neurol 69:866-871, 2011). Immunohistology is remarkable for presence of inclusion bodies with reactivity to the N-terminus but not the C-terminus of alpha B crystalline (Moore at al. J Neuropathol Exp Neurol 71:587-588, 2012). Other allelic disorders include dilated cardiomyopathy (Inagaki et al. Biochem Biophys Res Commun 342:379-386, 2006) and autosomal dominant congenital posterior cataract (Berry et al. Amer J Hum Genet 69:1141-1145, 2001; Liu et al. Invest Ophthalmol Vis Sci 47:1069-1075, 2006). Two cases of multisystem disease involving myofibrillar myopathy, cardiomyopathy, and cataract have also been reported (Vicart et al. Nat Genet 20:92-95, 1998; Sacconi et al. Neuromuscul Disord 2012 22:66-72, 2012).

Adult-onset alpha-B crystalline-related myofibrillar myopathy, cardiomyopathy, and congenital posterior cataract are inherited as autosomal dominant disorders. Progressive, severe, congenital myopathy due to CRYAB variants is inherited as an autosomal recessive disorder and all cases reported thus far have had truncating variants. The c.60delC variant is considered a founder variant among Canadian aboriginals of Cree descent (Del Bigio et al. 2011). A small number of CRYAB missense, nonsense, and small deletion variants have been reported in patients with MFM (Selcen and Engel, GeneReviews 2010). Other genes involved with MFM include DES, MYOT, FLNC, LDB3, and BAG3.

Adult-onset and congenital myofibrillar myopathy due to CRYAB variants are rare disorders. Among a cohort of 80 MFM patients diagnosed at the Mayo Clinic, 46% have been found to have variants in one of the six known causative genes, including 3% in CRYAB (Selcen and Engel, 2010).

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