Molecular genetics of dystrophinopathy.

IF 2.6 3区 生物学 Q2 GENETICS & HEREDITY
Mariko Okubo
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引用次数: 0

Abstract

Dystrophinopathies, including Duchenne and Becker muscular dystrophies, are caused by pathogenic variants in the DMD gene, which spans 2.5 Mb and encodes multiple tissue-specific dystrophin isoforms. Advances in molecular diagnostic techniques have expanded our ability to detect a broad spectrum of DMD variants, including exonic deletions/duplications, small variants such as single-nucleotide variants and indels, and intronic rearrangements that disrupt splicing. Transcriptomic and long-read genomic analyses have revealed previously undetectable mechanisms of variation, including pseudoexon inclusion, intronic polyadenylation, and repeat expansions, underscoring the importance of integrating RNA-level data and in silico predictions into diagnostics. Genotype-phenotype correlations are influenced by the type and location of variants and by other factors, such as naturally occurring exon skipping and modifier genes. For instance, partial dystrophin expression caused by exon skipping in patients with certain nonsense variants can result in a milder Becker-like phenotype. These findings highlight the clinical significance of functional assays, such as minigene splicing reporters and immunostaining, in refining variant interpretation. This review summarizes the spectrum of DMD variants and outlines a stepwise diagnostic approach that integrates genetic, transcriptomic, and computational data. Special consideration is given to subgroups, such as female carriers and patients with mild phenotypes, in whom molecular diagnosis can be particularly challenging. Although therapeutic strategies are not the primary focus of this article, accurate molecular diagnosis forms the foundation for guiding individualized care. Together, these insights emphasize the value of integrated multi-omic variant assessment in improving diagnostic accuracy and patient management for dystrophinopathies.

肌营养不良症的分子遗传学。
肌营养不良症,包括杜氏肌营养不良症和贝克肌营养不良症,是由DMD基因的致病性变异引起的,该基因跨越2.5 Mb,编码多种组织特异性肌营养不良蛋白亚型。分子诊断技术的进步扩大了我们检测广谱DMD变异的能力,包括外显子缺失/重复,小变异,如单核苷酸变异和索引,以及破坏剪接的内含子重排。转录组学和长读基因组分析揭示了以前无法检测到的变异机制,包括假外显子包涵、内含子聚腺苷酸化和重复扩增,强调了将rna水平数据和计算机预测整合到诊断中的重要性。基因型-表型相关性受到变异的类型和位置以及其他因素的影响,例如自然发生的外显子跳变和修饰基因。例如,在某些无义变异的患者中,由外显子跳跃引起的部分肌营养不良蛋白表达可能导致较轻的贝克尔样表型。这些发现强调了功能分析的临床意义,如迷你基因剪接报告和免疫染色,在完善变异解释。这篇综述总结了DMD变异谱,并概述了一种整合遗传、转录组学和计算数据的逐步诊断方法。特别考虑到亚组,如女性携带者和轻度表型患者,其中分子诊断可能特别具有挑战性。虽然治疗策略不是本文的主要焦点,但准确的分子诊断是指导个体化治疗的基础。总之,这些见解强调了综合多组学变异评估在提高营养不良症的诊断准确性和患者管理方面的价值。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Human Genetics
Journal of Human Genetics 生物-遗传学
CiteScore
7.20
自引率
0.00%
发文量
101
审稿时长
4-8 weeks
期刊介绍: The Journal of Human Genetics is an international journal publishing articles on human genetics, including medical genetics and human genome analysis. It covers all aspects of human genetics, including molecular genetics, clinical genetics, behavioral genetics, immunogenetics, pharmacogenomics, population genetics, functional genomics, epigenetics, genetic counseling and gene therapy. Articles on the following areas are especially welcome: genetic factors of monogenic and complex disorders, genome-wide association studies, genetic epidemiology, cancer genetics, personal genomics, genotype-phenotype relationships and genome diversity.
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