Miscarriage risk assessment: a bioinformatic approach to identifying candidate lethal genes and variants

IF 3.8 2区生物学 Q2 GENETICS & HEREDITY Human Genetics Pub Date : 2024-02-01 DOI:10.1007/s00439-023-02637-y

Mona Aminbeidokhti, Jia-Hua Qu, Shweta Belur, Hakan Cakmak, Eleni Jaswa, Ruth B. Lathi, Marina Sirota, Michael P. Snyder, Svetlana A. Yatsenko, Aleksandar Rajkovic

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Abstract

Purpose

Miscarriage, often resulting from a variety of genetic factors, is a common pregnancy outcome. Preconception genetic carrier screening (PGCS) identifies at-risk partners for newborn genetic disorders; however, PGCS panels currently lack miscarriage-related genes. In this study, we evaluated the potential impact of both known and candidate genes on prenatal lethality and the effectiveness of PGCS in diverse populations.

Methods

We analyzed 125,748 human exome sequences and mouse and human gene function databases. Our goals were to identify genes crucial for human fetal survival (lethal genes), to find variants not present in a homozygous state in healthy humans, and to estimate carrier rates of known and candidate lethal genes in various populations and ethnic groups.

Results

This study identified 138 genes in which heterozygous lethal variants are present in the general population with a frequency of 0.5% or greater. Screening for these 138 genes could identify 4.6% (in the Finnish population) to 39.8% (in the East Asian population) of couples at risk of miscarriage. This explains the cause of pregnancy loss in approximately 1.1–10% of cases affected by biallelic lethal variants.

Conclusion

This study has identified a set of genes and variants potentially associated with lethality across different ethnic backgrounds. The variation of these genes across ethnic groups underscores the need for a comprehensive, pan-ethnic PGCS panel that includes genes related to miscarriage.

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流产风险评估：确定候选致死基因和变体的生物信息学方法

目的流产通常由各种遗传因素造成，是一种常见的妊娠结局。孕前遗传携带者筛查（PGCS）可识别新生儿遗传疾病的高风险伴侣；然而，PGCS 面板目前缺乏与流产相关的基因。在这项研究中，我们评估了已知基因和候选基因对产前致死率的潜在影响以及 PGCS 在不同人群中的有效性。方法我们分析了 125,748 个人类外显子组序列以及小鼠和人类基因功能数据库。我们的目标是找出对人类胎儿存活至关重要的基因（致死基因），找到健康人类中同源状态下不存在的变异基因，并估算已知和候选致死基因在不同人群和族群中的携带率。结果这项研究发现了 138 个基因，这些基因中的杂合致死变异出现在普通人群中的频率达到或超过 0.5%。对这138个基因进行筛查，可发现4.6%（芬兰人群）至39.8%（东亚人群）的夫妇有流产风险。这就解释了大约 1.1-10%受双拷贝致死变异影响的病例的妊娠失败原因。这些基因在不同种族群体中的差异突出表明，有必要建立一个包括流产相关基因在内的全面、泛种族 PGCS 面板。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Human Genetics 生物-遗传学

CiteScore

10.80

自引率

3.80%

发文量

审稿时长

1 months

期刊介绍： Human Genetics is a monthly journal publishing original and timely articles on all aspects of human genetics. The Journal particularly welcomes articles in the areas of Behavioral genetics, Bioinformatics, Cancer genetics and genomics, Cytogenetics, Developmental genetics, Disease association studies, Dysmorphology, ELSI (ethical, legal and social issues), Evolutionary genetics, Gene expression, Gene structure and organization, Genetics of complex diseases and epistatic interactions, Genetic epidemiology, Genome biology, Genome structure and organization, Genotype-phenotype relationships, Human Genomics, Immunogenetics and genomics, Linkage analysis and genetic mapping, Methods in Statistical Genetics, Molecular diagnostics, Mutation detection and analysis, Neurogenetics, Physical mapping and Population Genetics. Articles reporting animal models relevant to human biology or disease are also welcome. Preference will be given to those articles which address clinically relevant questions or which provide new insights into human biology. Unless reporting entirely novel and unusual aspects of a topic, clinical case reports, cytogenetic case reports, papers on descriptive population genetics, articles dealing with the frequency of polymorphisms or additional mutations within genes in which numerous lesions have already been described, and papers that report meta-analyses of previously published datasets will normally not be accepted. The Journal typically will not consider for publication manuscripts that report merely the isolation, map position, structure, and tissue expression profile of a gene of unknown function unless the gene is of particular interest or is a candidate gene involved in a human trait or disorder.