Congenital Myopathy Panel

Congenital myopathy (CM) refers to a genetically and clinically heterogeneous group of disorders characterized by muscle weakness and hypotonia at birth or in infancy. Five forms of congenital myopathy are recognized by the International Standards of Care Committee for Congenital Myopathies (North et al. 2014. PubMed ID: 24456932): Nemaline Myopathy, Core Myopathy, Centronuclear Myopathy, Myosin Storage Myopathy, and Congenital Fiber Type Disproportion. The clinical course of congenital myopathy is typically static or slowly progressive. Lower facial weakness leading to an open mouth is often the first sign of congenital myopathy in the newborn. Ptosis and ophthalmoplegia are also common. See North et al. (2014) for diagnostic strategies and a comprehensive review of the congenital myopathies.

The genetics of the congenital myopathies are complex because of extensive genetic heterogeneity and overlapping clinical and histopathological findings among the five different subtypes (North et al. 2014. PubMed ID: 24456932). Congenital myopathies can be inherited in an autosomal dominant (AD), autosomal recessive (AR), and X-linked (XL) manner with some genes exhibiting both AD and AR inheritance (ACTA1, COL6A1, COL6A2, COL6A3, LMNA, MYH7, RYR1, SELENON/SEPN1, TPM3, and TTN). Of note, some dominant RYR1 central core myopathy pathogenic variants can exhibit reduced penetrance (for example the c.14818G>A variant, Davis et al. 2003. PubMed ID: 12565913).

See individual gene test descriptions for information on molecular biology of gene products.

A survey of a defined pediatric population (southeastern Michigan) in the United States found the prevalence of congenital myopathy (CM) to be 1:26,000 (Amburgey et al. 2011. PubMed ID: 22028225). A genetic cause was identified in 35% of cases, and pathogenic variants in the RYR1 gene were the single most common genetic cause of CM in this cohort. Non-specific findings was the most frequently encountered muscle biopsy result followed by minicores, central cores, fiber type disproportion, central nuclei, and nemaline rods (Amburgey et al. 2011. PubMed ID: 22028225). Clinical sensitivity for copy number analysis testing is expected to be low.

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

This panel typically provides 97.1% 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).

Exons 82-105 of the NEB gene are organized in three nearly identical repetitive blocks of 8 exons each making this region difficult to analyze. Since there are six highly homologous alleles, there is some limitation in variant and zygosity calling in this region. If an undocumented or pathogenic variant is detected in this region via NextGen Sequencing, a unique PCR and Sanger sequencing method will be used for confirmation.

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).