Limb Girdle Muscular Dystrophy Type 2W (LGMD2W) via the LIMS2 Gene

Limb girdle muscular dystrophy (LGMD) is a descriptive term for a group of disorders with atrophy and weakness of proximal girdle muscles and typical sparing of the heart and bulbar muscles. Clinical severity, age of onset, and disease progression are highly variable among the subtypes (Saenz et al. 2005). Serum creatine kinase levels are typically elevated, and muscle biopsies demonstrate a dystrophic process. For a comprehensive review see Pegoraro and Hoffman (2012) or Nigro and Savarese (2014).

Through whole exome sequencing, one family with pathogenic variants in LIMS2 has been reported to date (Chardon et al. 2015). Two affected siblings presented at around 5 years of age with proximal weakness, calf hypertrophy, and macroglossia. Their weakness progressed to severe quadriparesis, and both were wheelchair bound in adolescent years. Both siblings presented with moderate to mild dilated cardiomyopathy in the third decade. A triangular shaped tongue was a unique clinical feature seen in both siblings (Chardon et al. 2015).

Limb girdle muscular dystrophy type 2W (tentative assignment, Nigro and Savarese 2014) is inherited as an autosomal recessive disorder. So far, only missense pathogenic variants have been observed (Chardon et al. 2015). The LIMS2 protein consists of five LIM domains which include two zinc-finger motfis and is expressed in cardiac and muscle tissue. The LIMS2 protein is part of a larger ternary complex that is a core component in the integrin-actin cytoskeleton and functions as a signaling mediator (Chiswell et al. 2010).

Clinical sensitivity cannot be estimated because only a small number of patients have been reported. Analytical sensitivity should be high because all reported pathogenic variants are detectable by sequencing.

This test provides full coverage of all coding exons of the LIMS2 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).