GLIA-CTN Genomic Expert Curation Panel

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Abstract: Leukodystrophies are a heterogeneous group of complex neurological conditions impacting the genesis and maintenance of myelin, or white matter. Next generation sequencing and emerging genomic technologies have improved the ability to identify molecular causes of disease, allowing for the improved characterization of disease processes and focused therapeutics. However, molecular characterization of leukodystrophies requires expert oversight as much of the current gene-disease validation and clinical actionability have not been formally characterized. Current diagnostic testing includes biochemical and genetic testing but reveals a diagnosis in only 50-80% of patients said to have a myelin disorder by brain magnetic resonance imaging. This leaves many patients with an uncertain diagnosis, which can limit treatment options, cause emotional distress, and limit access to clinical trials and, for some families, reproductive choices. The Global Leukodystrophy Initiative (GLIA) is a Rare Disease Clinical Research Network funded consortium of scientists and advocates that work collaboratively to advance the study of and clinical trials for leukodystrophies. The GLIA consortium has approached ClinGen to establish Gene and Variant Curation Expert Panels, using our disease-specific experts and bioinformaticians to curate and assess leukodystrophy-related genes and variants. There are at least 240 genes that currently fall in the purview of this group, which will be expertly curated and managed by this group. For the 25 most commonly diagnosed genes causing leukodystrophy, this group will provide comprehensive variant curation, including the most clinically actionable disease-causing variants. The overall impact of this application will be to clarify the disease-gene association in the leukodystrophies, improve understanding of clinical actionability in these disorders, and clarify the pathogenicity of variants in key high frequency genes. Together, these activities will provide the leukodystrophy community with diagnostic clarity for newborn screening, clinical trials and clinical care.