Retrospective analysis and reclassification of DYSF variants in a large French series of dysferlinopathy patients

PURPOSE: Recent evolution of sequencing technologies and the development of international standards in variant interpretation have profoundly changed the diagnostic approaches in clinical genetics. As a consequence, many variants that were initially claimed to be disease-causing can be now reclassified as benign or uncertain in light of the new data available. Unfortunately, the misclassified variants are still present in the scientific literature and variant databases, greatly interfering with interpretation of diagnostic sequencing results. Despite the urgent need, large-scale efforts to update the classifications of these variants are still not sufficient. METHODS: We retrospectively analyzed 176 DYSF gene variants that were identified in dysferlinopathy patients referred to the Marseille Medical Genetics Department for diagnostic sequencing since 2001. RESULTS: We reclassified all variants into five-tier American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) pathogenicity classes, revealing changed pathogenicity for 17 variants. We then updated the information for the variants that have been previously published in the variant database and submitted 46 additional DYSF variants. CONCLUSION: Besides direct benefit for dysferlinopathy diagnostics, our study contributes to the much needed effort to reanalyze variants from previously published cohorts and to work with curators of variant databases to update the entries for erroneously classified variants.

Automated summary

Recent advances in sequencing technologies and the establishment of international standards for variant interpretation have led to a significant shift in diagnostic approaches in clinical genetics. However, the reclassification of variants that were originally considered pathogenic is still lacking in scientific literature and variant databases, hindering the interpretation of diagnostic sequencing results.