GLIA-CTN Genomic Expert Curation Panel

摘要： 脑白质营养不良是一组异质性的复杂神经系统疾病， 髓鞘或白色物质的生成和维持。下一代测序和新兴 基因组技术提高了识别疾病分子病因的能力， 疾病过程的改进表征和集中治疗。然而，分子 脑白质营养不良的特征需要专家的监督， 验证和临床可操作性尚未得到正式表征。当前诊断测试 包括生化和基因检测，但只有50-80%的患者被诊断出患有这种疾病， 脑磁共振成像显示有髓磷脂紊乱。这使得许多患者 不确定的诊断，这可能会限制治疗选择，导致情绪困扰，并限制获得 临床试验，以及一些家庭的生育选择。全球脑白质营养不良倡议 （GLIA）是一个罕见疾病临床研究网络资助的科学家和倡导者联盟 他们合作推进脑白质营养不良的研究和临床试验。神经胶 联盟已接触ClinGen建立基因和变异治疗专家小组，使用我们的 疾病特异性专家和生物信息学家来管理和评估脑白质营养不良相关基因 和变体。目前至少有240个基因属于这个小组的研究范围， 由这个组织精心策划和管理对于25个最常见的诊断基因， 脑白质营养不良，该组将提供全面的变异治疗，包括最临床 可采取行动的致病变异。本申请的总体影响将是澄清 脑白质营养不良的疾病基因关联，提高对脑白质营养不良的临床可操作性的理解， 这些疾病，并澄清在关键的高频基因变异的致病性。所有这些 活动将为脑白质营养不良社区提供新生儿筛查的诊断清晰度， 临床试验和临床护理。

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.