Specifications of the variant curation guidelines for ITGA2B/ITGB3: ClinGen Platelet Disorder Variant Curation Panel
Specifications of the variant curation guidelines for ITGA2B/ITGB3: ClinGen Platelet Disorder Variant Curation Panel
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DOI：
10.1182/bloodadvances.2020003712
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发表时间：
2021-01-21
期刊：
影响因子：
7.5
通讯作者：
Di Paola, Jorge
中科院分区：
文献类型：
--
作者：
Ross, Justyne E.;Zhang, Bing M.;Di Paola, Jorge
准确且一致的序列变异解释对于遗传性疾病患者的正确诊断和适当的临床管理和咨询至关重要。为了最大限度地减少不同临床实验室之间变异管理和分类的差异，美国医学遗传学和基因组学学院 (ACMG) 与分子病理学协会 (AMP) 于 2015 年发布了序列变异解释的标准和指南。由于这些规则并不普遍适用于不同的基因或疾病，临床基因组资源 (ClinGen) 血小板疾病专家小组 (PD-EP) 的任务是为遗传性血小板疾病制定 ACMG/AMP 规则规范。 ITGA2B 和 ITGB3 是常染色体隐性遗传性血小板无力症 (GT) 的基因，被选为规范的先导基因。 ClinGen PD-EP 在 GT 背景下评估了涵盖临床表型、功能数据和计算/群体数据的八种类型的证据。初步规范经过 70 个试点 ITGA2B/ITGB3 变体的验证并进一步完善。在最终的适应标准中，基于基因或疾病的规范被制定为16条规则，其中7条强度可调； S规则没有修改； 7条规则被认为不适用于GT。对试点变体采用 GT 特定的 ACMG/AMP 标准，导致未知意义的变体从 29% 减少到 20%。与最初专家断言的总体一致性为 71%。这些经过调整的标准将作为 GT 相关变异解释的指南，以提高实验室之间的特异性和一致性，并允许更好地将遗传知识临床整合到患者护理中。
Accurate and consistent sequence variant interpretation is critical to the correct diagnosis and appropriate clinical management and counseling of patients with inherited genetic disorders. To minimize discrepancies in variant curation and classification among different clinical laboratories, the American College of Medical Genetics and Genomics (ACMG), along with the Association for Molecular Pathology (AMP), published standards and guidelines for the interpretation of sequence variants in 2015. Because the rules are not universally applicable to different genes or disorders, the Clinical Genome Resource (ClinGen) Platelet Disorder Expert Panel (PD-EP) has been tasked to make ACMG/AMP rule specifications for inherited platelet disorders. ITGA2B and ITGB3, the genes underlying autosomal recessive Glanzmann thrombasthenia (GT), were selected as the pilot genes for specification. Eight types of evidence covering clinical phenotype, functional data, and computational/ population data were evaluated in the context of GT by the ClinGen PD-EP. The preliminary specifications were validated with 70 pilot ITGA2B/ITGB3 variants and further refined. In the final adapted criteria, gene- or disease-based specifications were made to 16 rules, including 7 with adjustable strength; no modification was made to S rules; and 7 rules were deemed not applicable to GT. Employing the GT-specific ACMG/AMP criteria to the pilot variants resulted in a reduction of variants classified with unknown significance from 29% to 20%. The overall concordance with the initial expert assertions was 71%. These adapted criteria will serve as guidelines for GT-related variant interpretation to increase specificity and consistency across laboratories and allow for better clinical integration of genetic knowledge into patient care.