Purpose

Expanded preconception carrier screening (ECS) identifies at-risk couples (ARCs) for multiple diseases. ECS reports currently include only pathogenic/likely pathogenic variants (P/LPVs). Variants of unknown significance (VUS) are not reported, unlike genomic or chromosomal array test results in other post/prenatal settings. Couples who are P/LP and VUS carriers (P/LP*VUS) may be at risk, particularly in genes with high P/LP carrier rates. We examined the possible contribution of P/LP*cVUS (coding, nonsynonymous VUS) matings to ECS yield in an Ashkenazi Jewish cohort, a population with well-established preconception screening.

Methods

We analyzed 672 Ashkenazi Jewish genome sequences (225,456 virtual matings) for variants in three different gene sets and calculated the rates of P/LP*P/LP and P/LP*cVUS matings.

Results

Across 180 genes, we identified 4671 variants: 144 (3.1%) P/LP and 1963 (42%) VUS. Across gene sets, the proportion of P/LP*P/LP and P/LP*cVUS ARCs was 2.7–3.8% and 6.8–7.5%, respectively.

Conclusion

Disregarding VUS in ECS may miss ARCs. Even if only 10% of couples currently classified as P/LP*cVUS are ultimately reclassified as P/LP*P/LP, ECS yield would increase by ≈20%. While current understanding of VUS precludes VUS reporting in ECS, these findings underscore the importance of VUS reclassification. This will crucially depend on enlarging population frequency databases, especially of affected individuals.

中文翻译：

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孕前携带者筛查率：具有临床显着变异的携带者伴侣中未知意义的变异的影响。

目的

扩大的孕前携带者筛查 (ECS) 可识别多种疾病的高危夫妇 (ARC)。ECS 报告目前仅包括致病/可能致病变异 (P/LPV)。与其他产后/产前环境中的基因组或染色体阵列检测结果不同，未报告意义不明的变异 (VUS)。P/LP 和 VUS 携带者 (P/LP*VUS) 的夫妇可能处于危险之中，尤其是在具有高 P/LP 携带率的基因中。我们检查了 P/LP*cVUS（编码，非同义 VUS）交配对德系犹太人队列中 ECS 产量的可能贡献，该队列具有完善的孕前筛查。

方法

我们分析了 672 个德系犹太人基因组序列（225,456 个虚拟交配）的三个不同基因集中的变体，并计算了 P/LP*P/LP 和 P/LP*cVUS 交配的比率。

结果

在 180 个基因中，我们确定了 4671 个变体：144 个 (3.1%) P/LP 和 1963 个 (42%) VUS。在基因组中，P/LP*P/LP 和 P/LP*cVUS ARC 的比例分别为 2.7-3.8% 和 6.8-7.5%。

结论

在 ECS 中忽略 VUS 可能会错过 ARC。即使目前归类为 P/LP*cVUS 的夫妇中只有 10% 最终被重新归类为 P/LP*P/LP，ECS 的产量也会增加约 20%。虽然目前对 VUS 的理解排除了 ECS 中的 VUS 报告，但这些发现强调了 VUS 重新分类的重要性。这将关键取决于扩大人口频率数据库，尤其是受影响的个人。