对导致孟德尔病症的基因调控变体进行功能分类。

IF 3.8 2区 生物学 Q2 GENETICS & HEREDITY
Human Genetics Pub Date : 2024-04-01 Epub Date: 2024-03-04 DOI:10.1007/s00439-023-02639-w
Y H Hank Cheng, Stephanie C Bohaczuk, Andrew B Stergachis
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引用次数: 0

摘要

目前,我们对罕见人类疾病的了解大多来自编码基因变异。然而,非编码基因变异在众多罕见人类疾病中起着关键作用,导致基因调控、剪接和/或转录本稳定性改变等多种功能影响。随着基因组测序在临床实践中的应用越来越广泛,最重要的是要有一个清晰的框架来了解非编码基因变异是如何导致疾病的。为此,我们对数百种通过破坏基因调控模式导致罕见孟德尔病的非编码基因变异进行了文献综述,并提出了一种功能分类系统。具体来说,我们调整了用于编码变异的功能分类框架(即功能缺失、功能增益和显性阴性),以考虑非编码基因调控变异的独特特征。我们发现,非编码基因调控变异可按功能影响分为三类:(1) 非模块表达缺失(LOE)变异;(2) 模块表达缺失(mLOE)变异;(3) 异位表达增益(GOE)变异。LOE 变异与编码功能缺失变异有直接联系,而 mLOE 和 GOE 变异则代表了非编码变异所特有的疾病机制。这些功能分类的目的是提供一种统一的术语,用于对孟德尔条件下破坏基因调控模式的非编码变异的功能影响进行分类。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Functional categorization of gene regulatory variants that cause Mendelian conditions.

Functional categorization of gene regulatory variants that cause Mendelian conditions.

Much of our current understanding of rare human diseases is driven by coding genetic variants. However, non-coding genetic variants play a pivotal role in numerous rare human diseases, resulting in diverse functional impacts ranging from altered gene regulation, splicing, and/or transcript stability. With the increasing use of genome sequencing in clinical practice, it is paramount to have a clear framework for understanding how non-coding genetic variants cause disease. To this end, we have synthesized the literature on hundreds of non-coding genetic variants that cause rare Mendelian conditions via the disruption of gene regulatory patterns and propose a functional classification system. Specifically, we have adapted the functional classification framework used for coding variants (i.e., loss-of-function, gain-of-function, and dominant-negative) to account for features unique to non-coding gene regulatory variants. We identify that non-coding gene regulatory variants can be split into three distinct categories by functional impact: (1) non-modular loss-of-expression (LOE) variants; (2) modular loss-of-expression (mLOE) variants; and (3) gain-of-ectopic-expression (GOE) variants. Whereas LOE variants have a direct corollary with coding loss-of-function variants, mLOE and GOE variants represent disease mechanisms that are largely unique to non-coding variants. These functional classifications aim to provide a unified terminology for categorizing the functional impact of non-coding variants that disrupt gene regulatory patterns in Mendelian conditions.

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来源期刊
Human Genetics
Human Genetics 生物-遗传学
CiteScore
10.80
自引率
3.80%
发文量
94
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.
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