Purpose

To evaluate the effectiveness and specificity of population-based genomic screening in Alabama.

Methods

The Alabama Genomic Health Initiative (AGHI) has enrolled and evaluated 5369 participants for the presence of pathogenic/likely pathogenic (P/LP) variants using the Illumina Global Screening Array (GSA), with validation of all P/LP variants via Sanger sequencing in a CLIA-certified laboratory before return of results.

Results

Among 131 variants identified by the GSA that were evaluated by Sanger sequencing, 67 (51%) were false positives (FP). For 39 of the 67 FP variants, a benign/likely benign variant was present at or near the targeted P/LP variant. Variants detected within African American individuals were significantly enriched for FPs, likely due to a higher rate of nontargeted alternative alleles close to array-targeted P/LP variants.

Conclusion

In AGHI, we have implemented an array-based process to screen for highly penetrant genetic variants in actionable disease genes. We demonstrate the need for clinical validation of array-identified variants in direct-to-consumer or population testing, especially for diverse populations.

中文翻译：

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在阿拉巴马州通过基于人群的基因组筛查识别罕见的医学相关变异：机遇和陷阱

目的

评估阿拉巴马州基于人群的基因组筛查的有效性和特异性。

方法

阿拉巴马州基因组健康计划 (AGHI) 使用 Illumina 全球筛查阵列 (GSA) 招募并评估了 5369 名参与者是否存在致病/可能致病 (P/LP) 变异，并通过 Sanger 测序验证所有 P/LP 变异CLIA 认证的实验室在返回结果之前。

结果

在通过 Sanger 测序评估的 GSA 鉴定的 131 个变体中，67 个（51%）为假阳性（FP）。对于 67 个 FP 变体中的 39 个，在目标 P/LP 变体处或附近存在良性/可能良性变体。在非裔美国人个体中检测到的变异显着富集了 FP，这可能是由于接近阵列靶向 P/LP 变异的非靶向替代等位基因的比率更高。

结论

在 AGHI 中，我们实施了一个基于阵列的流程来筛选可操作疾病基因中的高渗透性遗传变异。我们证明了在直接面向消费者或人群测试中对阵列识别变体进行临床验证的必要性，特别是对于不同人群。