Columbia University, New York, New York (H.M.R., E.E.G., R.H., D.A.F., A.M., R.W., L.B., C.W., Z.R., B.C., P.K., S.S.).
Columbia University Medical Center, New York, New York (W.K.C., D.B.G.).
Ann Intern Med. 2019 Jan 1;170(1):11-21. doi: 10.7326/M18-1241. Epub 2018 Nov 27.
Exome sequencing is increasingly being used for clinical diagnostics, with an impetus to expand reporting of incidental findings across a wide range of disorders. Analysis of population cohorts can help reduce risk for genetic variant misclassification and resultant unnecessary referrals to subspecialists.
To examine the burden of candidate pathogenic variants for kidney and genitourinary disorders emerging from exome sequencing.
Secondary analysis of genetic data.
A tertiary care academic medical center.
A convenience sample of exome sequence data from 7974 self-declared healthy adults.
Assessment of the prevalence of candidate pathogenic variants in 625 genes associated with Mendelian kidney and genitourinary disorders.
Of all participants, 23.3% carried a candidate pathogenic variant, most of which were attributable to previously reported variants that had implausibly high allele frequencies. In particular, 25 genes (discovered before the creation of the Exome Aggregation Consortium, a genetic database comprising data from a large control population) accounted for 67.7% of persons with candidate pathogenic variants. After stringent filtering based on allele frequency, 1.4% of persons still had a candidate pathogenic variant, an excessive rate given the prevalence of monogenic kidney and genitourinary disorders. Manual annotation of a subset of variants showed that the majority would be classified as nonbenign under current guidelines for clinical sequence interpretation and could prompt subspecialty referrals if returned.
Limited access to health record data prevented comprehensive assessment of the phenotypic concordance with genetic diagnoses.
Widespread reporting of incidental genetic findings related to kidney and genitourinary disorders will require stringent curation of clinical variant databases and detailed case-level review to avoid genetic misdiagnosis and unnecessary referrals. These findings motivate similar analyses for genes relevant to other medical subspecialties.
National Institute of Diabetes and Digestive and Kidney Diseases and National Human Genome Research Institute.
外显子组测序越来越多地用于临床诊断，推动了在广泛的疾病中报告偶然发现的结果。对人群队列的分析有助于减少遗传变异分类错误的风险，并避免不必要地向亚专科医生转诊。
检查外显子测序中出现的与肾脏和泌尿生殖系统疾病相关的候选致病性变异的负担。
遗传数据的二次分析。
三级保健学术医疗中心。
来自 7974 名自报健康成年人的外显子组序列数据的方便样本。
评估 625 个与孟德尔肾脏和泌尿生殖系统疾病相关的基因中候选致病性变异的患病率。
所有参与者中有 23.3%携带候选致病性变异，其中大多数归因于先前报道的变异，这些变异的等位基因频率高得不合理。特别是，25 个基因（在创建外显子聚集联盟之前发现，这是一个包含来自大型对照人群的数据的遗传数据库）占携带候选致病性变异的人的 67.7%。根据等位基因频率进行严格过滤后，仍有 1.4%的人携带候选致病性变异，鉴于单基因肾脏和泌尿生殖系统疾病的患病率，这一比例过高。对一部分变体进行手动注释表明，根据当前临床序列解释指南，大多数变体将被归类为非良性，并且如果返回，可能会促使进行亚专科转诊。
有限的获取健康记录数据，阻止了对遗传诊断的表型一致性的全面评估。
广泛报告与肾脏和泌尿生殖系统疾病相关的偶然遗传发现，将需要对临床变异数据库进行严格管理，并进行详细的病例级审查，以避免遗传误诊和不必要的转诊。这些发现促使对其他医学亚专科相关的基因进行类似的分析。
美国国立糖尿病、消化和肾脏疾病研究所和美国国家人类基因组研究所。
