Distal Myopathy Panel

The hereditary distal myopathies are a genetically and clinically heterogeneous group of disorders characterized by prominent weakness beginning in the anterior or posterior compartment of either the distal upper or the distal lower limbs. Weakness of the wrists and ankles is a common pattern of muscle involvement. Age of onset, disease severity, rate of progression, and muscle pathology all vary among the many genetic subtypes of this disorder. For example, patients with Laing myopathy may present as early as 4 years of age (Meredith et al. 2004. PubMed ID: 15322983), while patients affected by Udd myopathy or Welander myopathy may not become clinically affected until the 5th decade of life (Udd et al. 1993. PubMed ID: 8503797; Klar et al. 2013. PubMed ID: 23348830). Serum CpK levels are typically normal or slightly elevated. However, patients with Miyoshi myopathy, Miyoshi-like myopathy, and TCAP related myopathy have CpK levels 100-fold elevated over normal. Muscle pathology of the distal myopathies often reveal varied fiber size and abnormal vacuoles, and those subtypes with myofibrillar changes show accumulation of desmin. A diagnostic algorithm for the distal myopathies using clinical and laboratory data has been proposed (Udd. 2009. PubMed ID: 19477645). For a recent review of distal myopathies see Dimachkie and Barohn 2014 (Dimachkie and Barohn. 2014. PubMed ID: 25037092).

Hereditary distal myopathies can be inherited as autosomal dominant, autosomal recessive, or X linked conditions. The following genes are involved in autosomal dominant distal myopathies: BAG3, CRYAB, DNAJB6, FLNC, LDB3, KLHL9, MATR3, MYOT, TIA1, SQSTM1 and VCP. The following genes are involved in autosomal recessive distal myopathies: ADSS1/ADSSL1, ANO5, DYSF, GNE, and TCAP. Some genes can exhibit both dominant and recessive inheritance: CAV3, DES, MYH7, and TTN. Scapuloperoneal myofibrillar myopathy (FHL1) is an X-linked dominant disorder. See individual gene test descriptions for information on molecular biology of gene products and spectra of pathogenic variants.

Many of the subtypes of the distal hereditary myopathies are prevalent only in particular geographic regions. For this reason it is not possible to predict an over-all clinical sensitivity. Analytical sensitivity for the genes in this panel should be high as most pathogenic variants are detectable by this method. Gross deletions/duplications are a rare form of pathogenic variation among the genes in this test panel.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 97.8% coverage of all coding exons of the genes 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 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).