Interpretation and classification of FBN1 variants associated with Marfan syndrome: consensus recommendations from the Clinical Genome Resource's FBN1 variant curation expert panel.

IF 10.4 1区 生物学 Q1 GENETICS & HEREDITY
A Drackley, C Somerville, P Arnaud, L M Baudhuin, N Hanna, M L Kluge, K Kotzer, C Boileau, L Bronicki, B Callewaert, A Cecchi, H Dietz, D Guo, S Harris, O Jarinova, M Lindsay, L Little, B Loeys, G MacCarrick, J Meester, D Milewicz, T Morisaki, H Morisaki, D Murdock, M Renard, J Richer, L Robert, M Ouzounian, L Van Laer, J De Backer, L Muiño-Mosquera
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引用次数: 0

Abstract

Background: In 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) developed standardized variant curation guidelines for Mendelian disorders. Although these guidelines have been widely adopted, they are not gene- or disease-specific. To mitigate classification discrepancies, the Clinical Genome Resource FBN1 variant curation expert panel (VCEP) was established in 2018 to develop adaptations to the ACMG/AMP criteria for FBN1 in association with Marfan syndrome.

Methods: The specific recommendations were developed through literature review, surveys, online expert panel discussions, and pilot testing of a set of 60 different variants. Consensus among experts was considered reached if at least 75% of the members agreed with a given rule specification. The final set of rules received approval from the ClinGen Sequence Variant Interpretation Working Group.

Results: The developed specifications introduce modifications to 14 of the 28 ACMG/AMP evidence criteria and deem 6 criteria non-applicable. Some of these specifications include refining the minor allele frequency thresholds, creating a FBN1-specific flowchart for PVS1, defining functional domains of the protein, developing a point-based system of counting probands and instances of de novo occurrences, recommending a points-based method of accounting for family segregation data, and clarifying the applicable functional assays that should be considered. To date, this VCEP has curated 120 variants which have been deposited to ClinVar with the 3-star review status.

Conclusions: Establishing specific adaptations for FBN1 has provided a framework to foster greater classification concordance among clinical laboratories, ultimately improving clinical care for patients with Marfan syndrome.

与马凡氏综合征相关的FBN1变异的解释和分类:来自临床基因组资源的FBN1变异管理专家组的共识建议。
背景:2015年,美国医学遗传学与基因组学学院(ACMG)和分子病理学协会(AMP)制定了孟德尔疾病的标准化变异管理指南。尽管这些指导方针已被广泛采用,但它们并非针对特定基因或疾病。为了减轻分类差异,2018年成立了临床基因组资源FBN1变异管理专家小组(VCEP),以开发与马凡综合征相关的FBN1的ACMG/AMP标准的适应性。方法:通过文献综述、调查、在线专家小组讨论和60种不同变体的试点测试,制定具体建议。如果至少75%的成员同意给定的规则规范,则认为专家达成了共识。最终的一套规则得到了ClinGen序列变体解释工作组的批准。结果:制定的规范对28个ACMG/AMP证据标准中的14个进行了修改,并认为6个标准不适用。其中一些规范包括细化次要等位基因频率阈值,为PVS1创建fbn1特异性流程图,定义蛋白质的功能域,开发基于点的先证计数系统和新生病例发生的实例,推荐基于点的家庭分离数据计算方法,并澄清应考虑的适用功能分析。到目前为止,该VCEP已经收集了120个变体,这些变体已被提交给ClinVar,并获得了3星评审状态。结论:建立FBN1特异性适应提供了一个框架,以促进临床实验室之间的分类一致性,最终改善马凡氏综合征患者的临床护理。
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来源期刊
Genome Medicine
Genome Medicine GENETICS & HEREDITY-
CiteScore
20.80
自引率
0.80%
发文量
128
审稿时长
6-12 weeks
期刊介绍: Genome Medicine is an open access journal that publishes outstanding research applying genetics, genomics, and multi-omics to understand, diagnose, and treat disease. Bridging basic science and clinical research, it covers areas such as cancer genomics, immuno-oncology, immunogenomics, infectious disease, microbiome, neurogenomics, systems medicine, clinical genomics, gene therapies, precision medicine, and clinical trials. The journal publishes original research, methods, software, and reviews to serve authors and promote broad interest and importance in the field.
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