应用高分辨率变异分类的心律失常基因检测在人口统计学不同队列的突然不明原因死亡。

Ying Lin, Nori Williams, Dawei Wang, William Coetzee, Bo Zhou, Lucy S Eng, Sung Yon Um, Ruijun Bao, Orrin Devinsky, Thomas V McDonald, Barbara A Sampson, Yingying Tang
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引用次数: 31

摘要

背景:遗传变异解释有助于检测报告的不明原因猝死的产率差异。采用高分辨率变异解释框架,考虑疾病患病率、降低外显率、遗传异质性和等位基因贡献,以确定gnomAD中最大耐受等位基因计数,我们报告了在美国最大的法医办公室进行彻底调查的大型人口统计学多样化的突然原因死亡队列中对心脏通道病和心肌病基因的评估。方法和结果:该队列有296名死者:147名黑人,64名西班牙裔,49名白人,22名亚洲人和14名混合种族;142名婴儿(1至11个月),39名儿童(1至17岁),74名年轻人(18至34岁),41名成年人(35至55岁)。89个心脏病基因被评估。使用高分辨率的变异解释工作流程,我们将17个变异分类为致病或可能致病(其中2个是偶然发现的,在测试产率分析中被排除在外),46个不确定意义的新变异,以及130个不确定意义的变异。ClinVar的9个致病性或可能致病性变异被重新分类为可能的良性变异,并被排除在测试产率分析之外。按种族和年龄划分的阳性病例率在混合种族中为21.4%,白人10.2%,亚洲人4.5%,西班牙裔3.1%,黑人2%;7.7%为儿童,7.3%为成人,5.4%为年轻人,2.8%为婴儿。不同种族具有不确定意义变异的不确定病例在亚洲人中占45.5%,在西班牙人中占45.3%,在黑人中占44.20%,在白人中占36.7%,在混合种族中占14.3%。结论:高分辨率变异解释提供了诊断准确性和医疗效率。在未来的研究中应更多地纳入代表性不足的人群。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Applying High-Resolution Variant Classification to Cardiac Arrhythmogenic Gene Testing in a Demographically Diverse Cohort of Sudden Unexplained Deaths.

Background: Genetic variant interpretation contributes to testing yield differences reported for sudden unexplained death. Adapting a high-resolution variant interpretation framework, which considers disease prevalence, reduced penetrance, genetic heterogeneity, and allelic contribution to determine the maximum tolerated allele count in gnomAD, we report an evaluation of cardiac channelopathy and cardiomyopathy genes in a large, demographically diverse sudden unexplained death cohort that underwent thorough investigation in the United States' largest medical examiner's office.

Methods and results: The cohort has 296 decedents: 147 Blacks, 64 Hispanics, 49 Whites, 22 Asians, and 14 mixed ethnicities; 142 infants (1 to 11 months), 39 children (1 to 17 years), 74 young adults (18 to 34 years), and 41 adults (35 to 55 years). Eighty-nine cardiac disease genes were evaluated. Using a high-resolution variant interpretation workflow, we classified 17 variants as pathogenic or likely pathogenic (2 of which were incidental findings and excluded in testing yield analysis), 46 novel variants of uncertain significance, and 130 variants of uncertain significance. Nine pathogenic or likely pathogenic variants in ClinVar were reclassified to likely benign and excluded in testing yield analysis. The yields of positive cases by ethnicity and age were 21.4% in mixed ethnicities, 10.2% Whites, 4.5% Asians, 3.1% Hispanics, and 2% Blacks; 7.7% children, 7.3% in adults, 5.4% young adults, and 2.8% infants. The percentages of uncertain cases with variants of uncertain significance by ethnicity were 45.5% in Asians, 45.3% Hispanics, 44.20% Blacks, 36.7% Whites, and 14.3% in mixed ethnicities.

Conclusions: High-resolution variant interpretation provides diagnostic accuracy and healthcare efficiency. Under-represented populations warrant greater inclusion in future studies.

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来源期刊
Circulation: Cardiovascular Genetics
Circulation: Cardiovascular Genetics CARDIAC & CARDIOVASCULAR SYSTEMS-GENETICS & HEREDITY
自引率
0.00%
发文量
0
审稿时长
6-12 weeks
期刊介绍: Circulation: Genomic and Precision Medicine considers all types of original research articles, including studies conducted in human subjects, laboratory animals, in vitro, and in silico. Articles may include investigations of: clinical genetics as applied to the diagnosis and management of monogenic or oligogenic cardiovascular disorders; the molecular basis of complex cardiovascular disorders, including genome-wide association studies, exome and genome sequencing-based association studies, coding variant association studies, genetic linkage studies, epigenomics, transcriptomics, proteomics, metabolomics, and metagenomics; integration of electronic health record data or patient-generated data with any of the aforementioned approaches, including phenome-wide association studies, or with environmental or lifestyle factors; pharmacogenomics; regulation of gene expression; gene therapy and therapeutic genomic editing; systems biology approaches to the diagnosis and management of cardiovascular disorders; novel methods to perform any of the aforementioned studies; and novel applications of precision medicine. Above all, we seek studies with relevance to human cardiovascular biology and disease.
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