Jurgens Julie, Ling Hua, Hetrick Kurt, Pugh Elizabeth, Schiettecatte Francois, Doheny Kimberly, Hamosh Ada, Avramopoulos Dimitri, Valle David, Sobreira Nara
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Center for Inherited Disease Research, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Genet Med. 2015 Oct;17(10):782-8. doi: 10.1038/gim.2014.196. Epub 2015 Jan 8.
In March 2013 the American College of Medical Genetics and Genomics published a list of 56 genes with the recommendation that pathogenic and likely pathogenic variants detected incidentally by clinical sequencing be reported to patients. As an initial step in determining the practical consequences of this recommendation in the research setting, we searched for variants in these genes in 232 whole-exome sequences from the Baylor-Hopkins Center for Mendelian Genomics.
We identified rare, nonsynonymous, and splicing single-nucleotide variants and insertions/deletions and assessed variant classification using the Human Gene Mutation, Emory, and ClinVar databases. We analyzed the burden of mutation in each of the 56 genes and determined which variants should be reported to patients.
Our filtering resulted in 249 distinct variants, with a mean of 1.69 variants per individual. Half of these were novel missense mutations not classified by any of the three reference databases. Of 101 variants listed in the Human Gene Mutation Database, 48 were also in ClinVar and 3 were also in Emory; half of these shared variants were classified discordantly between databases. Some genes consistently had greater variation than others. In total, 0.86% of individuals had a reportable incidental variant.
These observations demonstrate some current challenges of assessing phenotypic consequences of incidental variants for counseling patients.
2013年3月，美国医学遗传学与基因组学学会公布了一份包含56个基因的清单，并建议将临床测序偶然检测到的致病和可能致病变异报告给患者。作为在研究环境中确定该建议实际影响的第一步，我们在贝勒-霍普金斯孟德尔基因组学中心的232个全外显子序列中搜索了这些基因中的变异。
我们鉴定了罕见的、非同义的和剪接单核苷酸变异以及插入/缺失，并使用人类基因突变数据库、埃默里数据库和临床变异数据库评估变异分类。我们分析了56个基因中每个基因的突变负担，并确定哪些变异应报告给患者。
我们的筛选产生了249个不同的变异，平均每人1.69个变异。其中一半是三个参考数据库均未分类的新错义突变。人类基因突变数据库中列出的101个变异中，48个也在临床变异数据库中，3个也在埃默里数据库中；这些共享变异中有一半在不同数据库之间的分类不一致。一些基因始终比其他基因具有更大的变异性。总共有0.86%的个体有可报告的偶然变异。
这些观察结果表明了目前在评估偶然变异的表型后果以指导患者咨询方面存在的一些挑战。
