Expert Panel Curation of 31 Genes in Relation to Limb Girdle Muscular Dystrophy

Area of Science:

• Genetics
• Neuromuscular Disorders
• Molecular Biology

Background:

• Limb girdle muscular dystrophies (LGMDs) are a group of genetically diverse conditions characterized by progressive proximal muscle weakness.
• Recent advances in genetic sequencing have identified numerous genes associated with LGMD, necessitating robust clinical validity assessments.

Approach:

• The ClinGen Muscular Dystrophies and Myopathies gene curation expert panel (MDM GCEP) evaluated 31 genes implicated in LGMD using the ClinGen gene-disease clinical validity framework.
• The panel assessed gene-disease relationships (GDRs) for LGMD and related phenotypes, including dominant and recessive inheritance patterns.

Key Points:

• Out of 35 curated GDRs, 30 (86%) were classified as Definitive, 4 (11%) as Moderate, and 1 (3%) as Limited.
• Four genes were split into separate disease entities due to exhibiting both dominant and recessive inheritance.
• Two genes, POMGNT1 and DAG1, showed definitive links to myopathy but lacked sufficient evidence for a specific LGMD association.

Conclusions:

• Expert-reviewed assertions on the clinical validity of LGMD-associated genes offer a crucial resource for clinicians and geneticists.
• The study encourages the neuromuscular community to share case-level data to refine understanding of LGMD genetics.