Secondary findings and carrier test frequencies in a large multiethnic sample
Secondary findings and carrier test frequencies in a large multiethnic sample
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DOI：
10.1186/s13073-015-0171-1
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发表时间：
2015-06-13
期刊：
影响因子：
12.3
通讯作者：
Boerwinkle, Eric
中科院分区：
文献类型：
--
作者：
Gambin, Tomasz;Jhangiani, Shalini N.;Boerwinkle, Eric
背景：全外显子组测序 (WES) 除了在临床诊断和了解孟德尔及复杂疾病的遗传基础方面日益重要之外，它还是对医生、患者及其家属具有潜在临床实用性的附加信息的丰富来源。我们分析了来自一项大型随机抽样队列研究的 8554 名个体和来自一项假定孟德尔病研究的 2514 名接受过 WES 的患者的外显子组中的单核苷酸变异 (SNV) 的频率和性质，这些患者被认为是次要发现和隐性疾病等位基因携带者状态。方法：我们使用相同的测序平台和数据处理流程来分析所有样本，并表征报告的致病性分布（ClinVar，人类基因突变数据库 (HGMD)）并预测结果：在56个ACMG二次发现基因中，每个个体预测的有害变异的平均数量为0.74，ClinVar报告的致病变异的平均数量为0.06。我们在 1423 个常染色体隐性遗传病基因中观察到，每个个体平均有 10 个有害变异和 0.78 个 ClinVar 报告的致病变异。通过重复对外显子组进行采样，根据 ClinVar 变异，随机生成的夫妇中 0.5% 的后代患常染色体隐性遗传病的风险为 25%。结论：通过调查报告的致病变异和新颖的、预测的有害变异，我们估计了外显子组测序可能揭示其他医学相关信息的群体比例的下限和上限。我们建议，由于分类数据库和预测算法的改进，这些频率数的下限和上限的观测范围将逐渐缩小。
Background: Besides its growing importance in clinical diagnostics and understanding the genetic basis of Mendelian and complex diseases, whole exome sequencing (WES) is a rich source of additional information of potential clinical utility for physicians, patients and their families. We analyzed the frequency and nature of single nucleotide variants (SNVs) considered secondary findings and recessive disease allele carrier status in the exomes of 8554 individuals from a large, randomly sampled cohort study and 2514 patients from a study of presumed Mendelian disease having undergone WES.Methods: We used the same sequencing platform and data processing pipeline to analyze all samples and characterized the distributions of reported pathogenic (ClinVar, Human Gene Mutation Database (HGMD)) and predicted deleterious variants in the pre-specified American College of Medical Genetics and Genomics (ACMG) secondary findings and recessive disease genes in different ethnic groups.Results: In the 56 ACMG secondary findings genes, the average number of predicted deleterious variants per individual was 0.74, and the mean number of ClinVar reported pathogenic variants was 0.06. We observed an average of 10 deleterious and 0.78 ClinVar reported pathogenic variants per individual in 1423 autosomal recessive disease genes. By repeatedly sampling pairs of exomes, 0.5 % of the randomly generated couples were at 25 % risk of having an affected offspring for an autosomal recessive disorder based on the ClinVar variants.Conclusions: By investigating reported pathogenic and novel, predicted deleterious variants we estimated the lower and upper limits of the population fraction for which exome sequencing may reveal additional medically relevant information. We suggest that the observed wide range for the lower and upper limits of these frequency numbers will be gradually reduced due to improvement in classification databases and prediction algorithms.