William Harvey Research Institute, Queen Mary University of London, London, United Kingdom.
ITS Research, Queen Mary University of London, London, United Kingdom.
Genet Med. 2024 Jul;26(7):101141. doi: 10.1016/j.gim.2024.101141. Epub 2024 Apr 15.
Existing resources that characterize the essentiality status of genes are based on either proliferation assessment in human cell lines, viability evaluation in mouse knockouts, or constraint metrics derived from human population sequencing studies. Several repositories document phenotypic annotations for rare disorders; however, there is a lack of comprehensive reporting on lethal phenotypes.
We queried Online Mendelian Inheritance in Man for terms related to lethality and classified all Mendelian genes according to the earliest age of death recorded for the associated disorders, from prenatal death to no reports of premature death. We characterized the genes across these lethality categories, examined the evidence on viability from mouse models and explored how this information could be used for novel gene discovery.
We developed the Lethal Phenotypes Portal to showcase this curated catalog of human essential genes. Differences in the mode of inheritance, physiological systems affected, and disease class were found for genes in different lethality categories, as well as discrepancies between the lethal phenotypes observed in mouse and human.
We anticipate that this resource will aid clinicians in the diagnosis of early lethal conditions and assist researchers in investigating the properties that make these genes essential for human development.
现有的基因必需性评估资源主要基于人类细胞系的增殖评估、小鼠敲除的生存能力评估，或者基于人类群体测序研究的约束指标。有几个存储库记录了罕见疾病的表型注释；但是，缺乏对致死表型的全面报告。
我们通过在线孟德尔遗传数据库查询与致死性相关的术语，并根据相关疾病记录的最早死亡年龄（从产前死亡到无早逝报告）对所有孟德尔基因进行分类。我们对这些致死性类别中的基因进行了特征描述，检查了来自小鼠模型的生存能力证据，并探讨了如何利用这些信息进行新基因发现。
我们开发了致死表型门户，以展示这个经过精心整理的人类必需基因目录。在不同致死性类别中的基因中，发现了遗传模式、受影响的生理系统和疾病类别之间的差异，以及在小鼠和人类中观察到的致死表型之间的差异。
我们预计该资源将有助于临床医生诊断早期致死情况，并帮助研究人员研究使这些基因对人类发育至关重要的特性。
