Exploring the unique characteristics of genes with dual autosomal dominant and recessive inheritance: mechanisms, phenotypes and candidate identification.

IF 3.7 2区 医学 Q2 GENETICS & HEREDITY
Shlomit Ezer, Tal Sido, Jonathan Rips, Ronit Hoffman Lipschuetz, Adina Fuchs, Bassam Abu-Libdeh, Elena Chervinsky, Nadirah S Damseh, Nada Danial-Farran, Ilham Morani, Ann Saada, Mohammed Al-Raqad, Somaya Salah, Shira Yanovsky-Dagan, Nadra Samra, Hanna Mandel, Stavit A Shalev, Hagar Mor-Shaked, Joël Zlotogora, Tamar Harel
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引用次数: 0

Abstract

Background: Autosomal dominant (AD) inheritance often arises through haploinsufficiency, dominant-negative or gain of function (GoF) effects, while autosomal recessive (AR) inheritance generally results from partial or complete loss of function (LoF). Yet, a subset of genes demonstrates both inheritance patterns. We aimed to curate a list of such 'AD/AR' genes and to propose additional candidates.

Methods: AD/AR genes were subcategorised based on genotype-phenotype correlations and disease mechanisms. Using bioinformatic analyses, we compared genes with AD, AR and AD/AR inheritance across various metrics, including gnomAD constraint values, exon count, protein length, quaternary structure and gene ontology terms. A machine learning-based metric was used to account for interdependence among features.

Results: Pathogenic variants in AD/AR genes can lead to distinct or similar phenotypes, depending on the molecular mechanism. AD/AR genes exhibit unique bioinformatic properties such as intermediate constraint scores, a combination of gene ontology terms, a greater average number of exons and an elevated propensity to form homomeric/heteromeric proteins. We identified homozygous LoF or clinically reported variants in nine genes previously classified as AD only.

Conclusion: Collectively, the data suggest that AD/AR genes possess distinctive features that likely underpin their dual inheritance modes. We propose nine candidate AD/AR genes and emphasise caution in filtering by inheritance type alone.

探索具有双常染色体显性和隐性遗传的基因的独特特征:机制,表型和候选鉴定。
背景:常染色体显性遗传(AD)通常由单倍不全、显性阴性或功能获得(GoF)效应引起,而常染色体隐性遗传(AR)通常由部分或完全功能丧失(LoF)引起。然而,有一部分基因同时显示了这两种遗传模式。我们的目标是整理出这样的“AD/AR”基因列表,并提出其他候选基因。方法:根据基因型-表型相关性和发病机制对AD/AR基因进行亚分类。利用生物信息学分析,我们比较了AD、AR和AD/AR遗传基因的各种指标,包括gnomAD约束值、外显子数量、蛋白质长度、四级结构和基因本体术语。使用基于机器学习的度量来解释特征之间的相互依存关系。结果:AD/AR基因的致病变异可导致不同或相似的表型,这取决于分子机制。AD/AR基因表现出独特的生物信息学特性,如中等约束分数、基因本体术语的组合、更高的平均外显子数量以及形成同源/异源蛋白的更高倾向。我们鉴定了纯合子LoF或临床报告的9个基因变异,这些基因以前仅被归类为AD。结论:总的来说,数据表明AD/AR基因具有可能支持其双重遗传模式的独特特征。我们提出了9个候选AD/AR基因,并强调仅通过遗传类型筛选时要谨慎。
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来源期刊
Journal of Medical Genetics
Journal of Medical Genetics 医学-遗传学
CiteScore
7.60
自引率
2.50%
发文量
92
审稿时长
4-8 weeks
期刊介绍: Journal of Medical Genetics is a leading international peer-reviewed journal covering original research in human genetics, including reviews of and opinion on the latest developments. Articles cover the molecular basis of human disease including germline cancer genetics, clinical manifestations of genetic disorders, applications of molecular genetics to medical practice and the systematic evaluation of such applications worldwide.
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