Analysis of exome data from the latest release of the Genome Aggregation Database (gnomAD v.4.1.0) revealed a significant carrier burden of pathogenic/likely pathogenic (P/LP) variants in genes associated with autosomal-recessive conditions across diverse ancestral populations. Carrier screening panels are routinely offered to reproductive partners to inform their risk of having an affected child. Current guidelines from the American College of Medical Genetics and Genomics (ACMG) recommend screening for genes with a carrier frequency of at least 1/200 and associated with moderate/severe conditions. Here, we systematically analyzed >700,000 gnomAD v.4.1.0 exomes spanning eight ancestries to estimate the carrier frequency of P/LP variants in 2,987 genes associated with autosomal-recessive conditions. After expert curation for clinical severity, we identified 286 genes meeting the criteria for carrier screening. The number of genes exceeding the 1/200 threshold varied across populations, with 40 in the South Asian ancestry and up to 119 in the Ashkenazi Jewish population. Simulations showed that pan-ethnic screening panels offer advantages for individuals of diverse or admixed ancestry, while ancestry-specific panels may be preferable for genetically homogeneous populations. This study leveraged the most comprehensive genomic dataset to date to provide an updated candidate gene list for equitable carrier screening across diverse populations. Our findings highlight the need for continued expansion of genomic resources to better understand rare disease risk and inform screening efforts in underrepresented groups.

中文翻译：

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利用多样化的基因组数据来指导公平的携带者筛查：来自 gnomAD v.4.1.0 的见解。


对最新版本的基因组聚集数据库 （gnomAD v.4.1.0） 的外显子组数据分析显示，在不同祖先群体中，与常染色体隐性遗传病相关的基因中存在致病性/可能致病性 （P/LP） 变异的显著携带负担。定期向生殖伴侣提供携带者筛查小组，以告知他们生下患病孩子的风险。美国医学遗传学与基因组学学会 （ACMG） 的当前指南建议筛查携带频率至少为 1/200 且与中度/重度疾病相关的基因。在这里，我们系统地分析了跨越八个祖先的 >700,000 gnomAD v.4.1.0 外显子组，以估计与常染色体隐性遗传病相关的 2,987 个基因中 P/LP 变异的携带频率。在对临床严重程度进行专家管理后，我们确定了 286 个符合携带者筛查标准的基因。超过 1/200 阈值的基因数量因人群而异，南亚血统中有 40 个，德系犹太人多达 119 个。模拟表明，泛种族筛选面板为不同或混合血统的个体提供了优势，而血统特异性面板可能更适合遗传同质的人群。本研究利用迄今为止最全面的基因组数据集，为不同人群的公平携带者筛查提供了更新的候选基因列表。我们的研究结果强调了持续扩展基因组资源的必要性，以更好地了解罕见病风险并为代表性不足群体的筛查工作提供信息。