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