Limb Girdle Muscular Dystrophy (LGMD) Panel

Limb girdle muscular dystrophy (LGMD) is a descriptive term for a group of disorders with atrophy and weakness of proximal limb girdle muscles, typically sparing the heart and bulbar muscles. Clinical severity, age of onset, and disease progression are highly variable among the subtypes (Sáenz et al. 2005. PubMed ID: 15689361). Serum creatine kinase levels are typically elevated, and muscle biopsies demonstrate a dystrophic process. For a comprehensive review see Pegoraro et al. 2012. PubMed ID: 20301582.

Over twenty genes have been implicated in recessively inherited limb girdle muscular dystrophy: ANO5, CAPN3, CRPPA/ISPD, DYSF, FKRP, FKTN, GMPPB, LIMS2, PNPLA2, SGCA, SGCB, SGCD, SGCG, TCAP, TOR1AIP1, TRAPPC11, TRIM32, PLEC, POMGNT1, POMK, POMT1, POMT2, and GAA. Pathogenic variants in these genes include missense, nonsense, splicing, small deletions/insertions, and a few large deletions/duplications (Human Gene Mutation Database). The CAV3, DES, LMNA, and TTN genes can exhibit both recessive and dominant inheritance.

Dominant forms of limb girdle muscular dystrophy include LGMD1A, LGMD1B, LGMD1C, LGMD1E, LGMD1F, LGMD1G caused by pathogenic variants in the MYOT, LMNA, CAV3, DNAJB6, TNPO3, and HNRNPDL genes, respectively. Another dominantly inherited muscular dystrophy with a limb girdle pattern of weakness is facioscapulohumeral muscular dystrophy 2 (FSHD2). This is caused by the combination of a heterozygous mutation in the SMCHD1 gene on chromosome 18p and presence of a haplotype on chromosome 4 that is permissive for DUX4 expression. Pathogenic variants in the VCP and BVES genes can also cause limb girdle-like weakness and are inherited in an autosomal dominant manner.

See individual gene test descriptions for information on molecular biology of gene products and spectra of pathogenic variants.

In a cohort of 4656 individuals from the United States suspected to have limb girdle muscular dystrophy (LGMD), a molecular diagnosis was established in 27% of cases (Nallamilli et al. 2018. PubMed ID: 30564623). The four most commonly mutated genes were: CAPN3 (17%), DYSF (16%), FKRP (9%) and ANO5 (7%). Childhood onset LGMD is more likely to be caused by defects in the sarcoglycan genes (Vainzof et al. 1999. PubMed ID: 10385046), and late onset LGMD often results from pathogenic variants in the ANO5 gene (Sarkozy et al. 2013. PubMed ID: 23606453). Many of the genes in this panel have no or very few large deletions/duplications reported. However, the DYSF, GAA, and SGCG genes have a higher proportion of gross deletions/duplications reported (Human Gene Mutation Database).

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

This panel typically provides 98.5% 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).