Chronological Patterns of Pathogenic Variant Distributions in Muscular Dystrophy Genes

Background Newly discovered genetic subtypes of muscular dystrophy tend to be rarer than older ones, as occurs for other genetically heterogeneous classes of inherited disorders. Epidemiologically, there is a higher likelihood of ascertaining more prevalent genetic subtypes, but it is unclear why pathogenic variants are more abundant in certain genetic subtypes than others. We hypothesized that distributions of pathogenic variant types and molecular consequences of those variants for each genetic subtype vary based on the year of discovery of the muscular dystrophy gene. Methods We compiled a list of genes associated with muscular dystrophy with pathogenic or likely pathogenic variants listed in ClinVar, then extracted those variants for analysis. To explore the relationship between the year of gene discovery and distribution of variant types, we performed Kendall's τ-b test for each variant type. Results Sixty-four muscular dystrophy genes had pathogenic or likely pathogenic variants listed in ClinVar. We found a significant negative correlation with year of gene discovery in the proportion of frameshift, splice acceptor, and splice donor variants and a corresponding significant positive correlation in missense variants for muscular dystrophy genes. There was a decrease in the observed / expected missense score and an increase in missense z-score by year of discovery, indicating intolerance to missense changes in more recently discovered genes. Other trends included fewer insertions and deletions, and increased single nucleotide variants (SNVs) by year of gene discovery. Discussion Our findings suggest that recently discovered muscular dystrophy genes are less tolerant of variation, potentially explaining why variants and cases are less abundant in these genes.