Curation of muscular dystrophy genes - muscular dystrophies and myopathies encompass a large group of genetic diseases characterized by overlapping and indistinguishable clinical features but are…

The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) awarded The Washington University a Cooperative Agreement valued at $190,137 (Award Date: September 18, 2025; Ultimate Completion Date: August 31, 2028) under the Arthritis, Musculoskeletal and Skin Diseases Research program (CFDA 93.846). This award funds a comprehensive curation initiative focused on muscular dystrophy genes to bridge the critical gap between genetic testing and patient care. The project will systematically evaluate the clinical validity of gene-disease relationships and assess the pathogenicity of individual genetic variants across more than 200 genes associated with muscular dystrophies and myopathies, leveraging the infrastructure and frameworks of the NIH-funded Clinical Genome Resource.

The deliverables under this Cooperative Agreement include rigorous clinical genetic curation that will enable development of more focused and comprehensive multi-gene diagnostic panels, clarify patient diagnoses to support eligibility for emerging therapies and clinical trials, and establish standardized, comprehensive clinical genetic knowledge to advance therapy development. The iterative curation effort will accumulate variants with confirmed, FDA-approved pathogenicity classifications to refine evaluation criteria and clinically validate large-scale functional assays, potentially reducing reliance on invasive muscle biopsies for diagnostic purposes. These outputs will address the current diagnostic gap wherein approximately 50% of muscular dystrophy and myopathy patients lack definitive molecular diagnoses despite increasing access to next-generation sequencing testing.

Curation of muscular dystrophy genes - muscular dystrophies and myopathies encompass a large group of genetic diseases characterized by overlapping and indistinguishable clinical features but are caused by sequence variants in more than 200 genes. Accurate diagnosis and prevalence estimates for these disorders are essential for timely therapeutic development and high-quality patient care, yet up to 50% of patients do not receive a definitive molecular diagnosis despite increasing access to next-generation sequencing tests. This proposal aims to bridge the GAP between genetic testing and patient care by defining the clinical relevance of genes and genetic sequence variants asserted to cause muscular dystrophies and myopathies. Using the frameworks and infrastructure of the NIH-funded clinical genome resource, we will evaluate the clinical validity of the relationships between genes and muscular dystrophies and myopathies and assess the pathogenicity of individual variants in these genes. The outcomes of these efforts will support the development of more focused, consistent, and comprehensive multi-gene panels and clarify the diagnosis of patients to ensure their eligibility for impending therapies and clinical trials. These efforts will be iterative and build over time: the accumulation of variants with confirmed, FDA-approved classifications of pathogenicity will be used to further refine the criteria used to evaluate pathogenicity and to clinically validate large-scale functional assays, potentially replacing invasive muscle biopsy as a means of diagnostic clarification. In addition, proven assertions of gene-disease validity will lay the groundwork to assess the pathogenicity of variants in an increasing number of genes. This rigorous curation effort will provide the necessary foundation of comprehensive, standardized clinical genetic knowledge to advance therapy development and improve patient care.