The use of proactive genetic screening for disease prevention and early detection is not yet widespread. Professional practice guidelines from the American College of Medical Genetics and Genomics (ACMG) have encouraged reporting pathogenic variants that confer personal risk for actionable monogenic hereditary disorders, but only as secondary findings from exome or genome sequencing. The Centers for Disease Control and Prevention (CDC) recognizes the potential public health impact of three Tier 1 actionable disorders. Here, we report results of a large multi-center cohort study to determine the yield and potential value of screening healthy individuals for variants associated with a broad range of actionable monogenic disorders, outside the context of secondary findings. Eligible adults were offered a proactive genetic screening test by health care providers in a variety of clinical settings. The screening panel based on next-generation sequencing contained up to 147 genes associated with monogenic disorders within cancer, cardiovascular, and other important clinical areas. Sequence and intragenic copy number variants classified as pathogenic, likely pathogenic, pathogenic (low penetrance), or increased risk allele were considered clinically significant and reported. Results were analyzed by clinical area and severity/burden of disease using chi-square tests without Yates’ correction. Among 10,478 unrelated adults screened, 1619 (15.5%) had results indicating personal risk for an actionable monogenic disorder. In contrast, only 3.1 to 5.2% had clinically reportable variants in genes suggested by the ACMG version 2 secondary findings list to be examined during exome or genome sequencing, and 2% had reportable variants related to CDC Tier 1 conditions. Among patients, 649 (6.2%) were positive for a genotype associated with a disease of high severity/burden, including hereditary cancer syndromes, cardiovascular disorders, or malignant hyperthermia susceptibility. This is one of the first real-world examples of specialists and primary care providers using genetic screening with a multi-gene panel to identify health risks in their patients. Nearly one in six individuals screened for variants associated with actionable monogenic disorders had clinically significant results. These findings provide a foundation for further studies to assess the role of genetic screening as part of regular medical care.

中文翻译：

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医生指导的基因筛查以评估可治疗疾病的个人风险：一项大型多中心队列研究

使用主动基因筛查进行疾病预防和早期检测尚未普及。美国医学遗传学和基因组学学院 (ACMG) 的专业实践指南鼓励报告赋予个人风险的可操作单基因遗传性疾病的致病变异，但仅作为外显子组或基因组测序的次要发现。疾病控制和预防中心 (CDC) 认识到三种一级可操作疾病的潜在公共卫生影响。在这里，我们报告了一项大型多中心队列研究的结果，以确定在次要发现的背景之外，筛查健康个体中与广泛的可操作单基因疾病相关的变异的产量和潜在价值。医疗保健提供者在各种临床环境中为符合条件的成年人提供了主动基因筛查测试。基于新一代测序的筛查面板包含多达 147 个与癌症、心血管和其他重要临床领域内的单基因疾病相关的基因。归类为致病性、可能致病性、致病性（低外显率）或风险增加的等位基因的序列和基因内拷贝数变异被认为具有临床意义并已报告。使用卡方检验按临床区域和疾病严重程度/负担分析结果，无需 Yates 校正。在筛查的 10,478 名不相关的成年人中，1619 名 (15.5%) 的结果表明存在可采取行动的单基因疾病的个人风险。相比之下，只有 3.1 到 5。2% 的基因中有 ACMG 第 2 版次要结果列表建议在外显子组或基因组测序期间检查的基因中的临床可报告变异，2% 具有与 CDC 第 1 级条件相关的可报告变异。在患者中，649 名 (6.2%) 对与高严重性/负担疾病相关的基因型呈阳性，包括遗传性癌症综合征、心血管疾病或恶性高热易感性。这是专家和初级保健提供者使用多基因面板进行基因筛查来识别患者健康风险的首批真实案例之一。近六分之一的人在筛查与可操作的单基因疾病相关的变异时获得了具有临床意义的结果。