Exome Sequencing and Multigene Panel Testing in 1,411 Patients With Adult-Onset Neurologic Disorders.

IF 3 3区医学 Q2 CLINICAL NEUROLOGY

Neurology-Genetics Pub Date : 2023-06-01 DOI:10.1212/NXG.0000000000200071

Nika Schuermans, Hannah Verdin, Jody Ghijsels, Madeleine Hellemans, Elke Debackere, Elke Bogaert, Sofie Symoens, Leslie Naesens, Elien Lecomte, David Crosiers, Bruno Bergmans, Kristof Verhoeven, Bruce Poppe, Guy Laureys, Sarah Herdewyn, Tim Van Langenhove, Patrick Santens, Jan L De Bleecker, Dimitri Hemelsoet, Bart Dermaut

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引用次数: 1

Abstract

Background and objectives: Owing to their extensive clinical and molecular heterogeneity, hereditary neurologic diseases in adults are difficult to diagnose. The current knowledge about the diagnostic yield and clinical utility of exome sequencing (ES) for neurologic diseases in adults is limited. This observational study assesses the diagnostic value of ES and multigene panel analysis in adult-onset neurologic disorders.

Methods: From January 2019 through April 2022, ES-based multigene panel testing was conducted in 1,411 patients with molecularly unexplained neurologic phenotypes at the Ghent University Hospital. Gene panels were developed for ataxia and spasticity, leukoencephalopathy, movement disorders, paroxysmal episodic disorders, neurodegeneration with brain iron accumulation, progressive myoclonic epilepsy, and amyotrophic lateral sclerosis. Single nucleotide variants, small indels, and copy number variants were analyzed. Across all panels, our analysis covered a total of 725 genes associated with Mendelian inheritance.

Results: A molecular diagnosis was established in 10% of the cases (144 of 1,411) representing 71 different monogenic disorders. The diagnostic yield depended significantly on the presenting phenotype with the highest yield seen in patients with ataxia or spastic paraparesis (19%). Most of the established diagnoses comprised disorders with an autosomal dominant inheritance (62%), and the most frequently mutated genes were NOTCH3 (13 patients), SPG7 (11 patients), and RFC1 (8 patients). 34% of the disease-causing variants were novel, including a unique likely pathogenic variant in APP (Ghent mutation, p.[Asn698Asp]) in a family presenting with stroke and severe cerebral white matter disease. 7% of the pathogenic variants comprised copy number variants detected in the ES data and confirmed by an independent technique.

Discussion: ES and multigene panel testing is a powerful and efficient tool to diagnose patients with unexplained, adult-onset neurologic disorders.

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1411例成人发病神经疾病患者的外显子组测序和多基因面板检测

背景和目的:由于其广泛的临床和分子异质性，成人遗传性神经系统疾病难以诊断。目前关于外显子组测序(ES)对成人神经系统疾病的诊断率和临床应用的知识是有限的。本观察性研究评估了ES和多基因面板分析在成人发病神经系统疾病中的诊断价值。方法:从2019年1月到2022年4月，在根特大学医院对1411名分子无法解释的神经表型患者进行了基于es的多基因面板检测。开发了针对共济失调和痉挛、脑白质病、运动障碍、阵发性发作性疾病、伴有脑铁积累的神经变性、进行性肌阵挛性癫痫和肌萎缩性侧索硬化症的基因面板。分析了单核苷酸变异、小索引和拷贝数变异。在所有小组中，我们的分析涵盖了与孟德尔遗传相关的总共725个基因。结果:在71种不同的单基因疾病中，10%的病例(1411例中的144例)进行了分子诊断。诊断率显著依赖于呈现的表型，在共济失调或痉挛性截瘫患者中诊断率最高(19%)。大多数已确定的诊断包括常染色体显性遗传疾病(62%)，最常见的突变基因是NOTCH3(13例)，SPG7(11例)和RFC1(8例)。34%的致病变异是新发现的，包括一种独特的可能致病的APP变异(根特突变，p.[Asn698Asp])，出现在一个中风和严重脑白质疾病的家庭中。7%的致病变异包括ES数据中检测到的拷贝数变异，并经独立技术证实。讨论:ES和多基因面板检测是一种强大而有效的工具，用于诊断不明原因的成人发病神经系统疾病。

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

Neurology-Genetics Medicine-Neurology (clinical)

CiteScore

6.30

自引率

3.20%

发文量

107

审稿时长

15 weeks

期刊介绍： Neurology: Genetics is an online open access journal publishing peer-reviewed reports in the field of neurogenetics. Original articles in all areas of neurogenetics will be published including rare and common genetic variation, genotype-phenotype correlations, outlier phenotypes as a result of mutations in known disease-genes, and genetic variations with a putative link to diseases. This will include studies reporting on genetic disease risk and pharmacogenomics. In addition, Neurology: Genetics will publish results of gene-based clinical trials (viral, ASO, etc.). Genetically engineered model systems are not a primary focus of Neurology: Genetics, but studies using model systems for treatment trials are welcome, including well-powered studies reporting negative results.