Hotakainen Ronja, Järvinen Timo, Kettunen Kaisa, Anttonen Anna-Kaisa, Jakkula Eveliina
Laboratory of Genetics, HUS Diagnostic Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Laboratory of Genetics, HUS Diagnostic Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland; Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.
Genet Med. 2025 Jan;27(1):101304. doi: 10.1016/j.gim.2024.101304. Epub 2024 Nov 1.
Monogenic rare diseases contribute significantly to infant deaths and pediatric hospitalizations and cause burden to the patients and their families. The American College of Medical Genetics and Genomics recommended in 2021 that carrier screening of autosomal recessive and X-linked conditions with a carrier frequency of ≥1/200 and a severe or moderate phenotype should be offered when planning or during pregnancy. In November 2023 gnomAD v4.0 was released. It contains in total 807,162 individuals, being nearly 5× larger than previous versions, which have been used to estimate gene carrier frequencies (GCF).
We utilized gnomAD v4.0 (GRCh38) to calculate the GCFs for available genetic ancestry groups for variants having pathogenic or likely pathogenic classification (>80% of submissions) in ClinVar. We calculated GCF separately for exomes and genomes, combined data, and at-risk couple frequencies (ACF) per genetic ancestry group.
In total, 324 genes had a GCF ≥1/200 in at least 1 ancestry subgroup. The number of genes with GCF ≥1/200 varied greatly between subgroups. ACFs were more similar, Ashkenazi Jewish having the highest ACF of 6.11%.
Improved understanding of carrier risks and updated carrier screening content would allow patients to make more informed reproductive decisions.
单基因罕见病是婴儿死亡和儿科住院的重要原因，给患者及其家庭带来负担。美国医学遗传学与基因组学学会在2021年建议，在计划怀孕或怀孕期间，应对携带频率≥1/200且具有严重或中度表型的常染色体隐性和X连锁疾病进行携带者筛查。2023年11月发布了gnomAD v4.0。它总共包含807,162个个体，几乎是以前版本的5倍，以前的版本已用于估计基因携带者频率（GCF）。
我们利用gnomAD v4.0（GRCh38）计算ClinVar中具有致病性或可能致病性分类（>80%的提交数据）的变异在可用遗传血统组中的GCF。我们分别计算了外显子组和基因组、合并数据以及每个遗传血统组的高危夫妇频率（ACF）的GCF。
总共有324个基因在至少1个血统亚组中的GCF≥1/200。不同亚组中GCF≥1/200的基因数量差异很大。ACF更为相似，阿什肯纳兹犹太人的ACF最高，为6.11%。
更好地了解携带者风险和更新携带者筛查内容将使患者能够做出更明智的生育决策。
