Adaptation and validation of the ACMG/AMP variant classification framework for MYH7-associated inherited cardiomyopathies: recommendations by ClinGen's Inherited Cardiomyopathy Expert Panel.
Adaptation and validation of the ACMG/AMP variant classification framework for MYH7-associated inherited cardiomyopathies: recommendations by ClinGen's Inherited Cardiomyopathy Expert Panel.
复制标题
DOI：
10.1038/gim.2017.218
复制
发表时间：
2018-03
期刊：
影响因子：
--
通讯作者：
Funke B
中科院分区：
文献类型：
--
作者：
Kelly MA;Caleshu C;Morales A;Buchan J;Wolf Z;Harrison SM;Cook S;Dillon MW;Garcia J;Haverfield E;Jongbloed JDH;Macaya D;Manrai A;Orland K;Richard G;Spoonamore K;Thomas M;Thomson K;Vincent LM;Walsh R;Watkins H;Whiffin N;Ingles J;van Tintelen JP;Semsarian C;Ware JS;Hershberger R;Funke B
在临床护理中整合基因组测序需要变异解释实践的标准化。临床基因组资源建立了专家小组，以调整美国医学遗传学和基因组学学院/分子病理学协会的特定基因和疾病分类框架。心肌病专家小组选择MYH 7作为先导基因，以开发一种广泛适用的方法，MYH 7是遗传性心肌病的关键因素。通过临床和诊断实验室专家对60种变体进行结构化双重审查，对专家修订进行了测试。最终的共识规则是通过迭代讨论建立的。调整代表疾病/基因知情规范（12）或现有规则的强度调整（5）。九条规则被认为不适用。主要规范包括次要等位基因频率阈值的定量框架，分离数据的使用，以及在缺乏完全对照病例对照研究的情况下计算多个独立变异发生率的半定量方法。最初的专家间分类一致性为93%。来自参与的诊断实验室的内部数据改变了20%的变体（n = 12）的分类，突出了数据共享的至关重要性。这些适应性规则提供了增加的特异性，用于MYH 7相关疾病，结合专家评审和临床判断，并作为具有相似遗传和临床特征的基因和疾病的垫脚石。
Integrating genomic sequencing in clinical care requires standardization of variant interpretation practices. The Clinical Genome Resource has established expert panels to adapt the American College of Medical Genetics and Genomics/Association for Molecular Pathology classification framework for specific genes and diseases. The Cardiomyopathy Expert Panel selected MYH7, a key contributor to inherited cardiomyopathies, as a pilot gene to develop a broadly applicable approach. Expert revisions were tested with 60 variants using a structured double review by pairs of clinical and diagnostic laboratory experts. Final consensus rules were established via iterative discussions. Adjustments represented disease-/gene-informed specifications (12) or strength adjustments of existing rules (5). Nine rules were deemed not applicable. Key specifications included quantitative frameworks for minor allele frequency thresholds, the use of segregation data, and a semiquantitative approach to counting multiple independent variant occurrences where fully controlled case-control studies are lacking. Initial inter-expert classification concordance was 93%. Internal data from participating diagnostic laboratories changed the classification of 20% of the variants (n = 12), highlighting the critical importance of data sharing. These adapted rules provide increased specificity for use in MYH7-associated disorders in combination with expert review and clinical judgment and serve as a stepping stone for genes and disorders with similar genetic and clinical characteristics.
登录
查看更多内容
影响因子：
8.8
作者：
Alfares, Ahmed A.;Kelly, Melissa A.;Rehm, Heidi L.
通讯作者：
Rehm, Heidi L.
DOI：
10.1056/nejmsr1406261
发表时间：
2015-06-04
期刊：
The New England journal of medicine
影响因子：
--
作者：
Rehm HL;Berg JS;Brooks LD;Bustamante CD;Evans JP;Landrum MJ;Ledbetter DH;Maglott DR;Martin CL;Nussbaum RL;Plon SE;Ramos EM;Sherry ST;Watson MS;ClinGen
通讯作者：
ClinGen
影响因子：
9.8
作者：
Amendola, Laura M.;Jarvik, Gail P.;Rehm, Heidi L.
通讯作者：
Rehm, Heidi L.
影响因子：
8.8
作者：
Pugh, Trevor J.;Kelly, Melissa A.;Funke, Birgit H.
通讯作者：
Funke, Birgit H.
影响因子：
5.5
作者：
Gaba, Prakriti;Bos, J. Martijn;Ackerman, Michael J.
通讯作者：
Ackerman, Michael J.