Journal Article

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

Chervinsky, Elena, Hoffman Lipschuetz, Ronit, Fuchs, Adina, Salah, Somaya, Samra, Nadra, Sido, Tal, Zlotogora, Joël, Danial-Farran, Nada, Yanovsky-Dagan, Shira, Rips, Jonathan, Shalev, Stavit A, Harel, Tamar, Abu-Libdeh, Bassam, Morani, Ilham, Al-Raqad, Mohammed, Damseh, Nadirah S, Saada, Ann, Ezer, Shlomit, Mandel, Hanna, Mor-Shaked, Hagar

2025

Overview

BackgroundAutosomal 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.MethodsAD/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.ResultsPathogenic 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.ConclusionCollectively, 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.

• Publisher: BMJ Publishing Group Ltd,BMJ Publishing Group LTD
• Subject: Computational Biology - methods / Disease / exome sequencing / Exons / Gene Ontology / Genes / Genes, Dominant - genetics / Genes, Recessive - genetics / Genetic Association Studies / Genetic Predisposition to Disease / genetic variation / genetics, medical / genotype / Genotype & phenotype / Genotype-phenotype correlations / Genotypes / Haploinsufficiency / Haploinsufficiency - genetics / Heredity / Humans / Machine learning / Molecular modelling / Phenotype / Phenotypes / Protein structure / Proteins / Quaternary structure