Prevalence of CNVs on the X chromosome in patients with neurodevelopmental disorders.

IF 1.3 4区生物学 Q4 GENETICS & HEREDITY

Molecular Cytogenetics Pub Date : 2025-02-21 DOI:10.1186/s13039-025-00703-w

Ekaterina N Tolmacheva, Anna A Kashevarova, Elizaveta A Fonova, Olga A Salyukova, Gulnara N Seitova, Lyudmila P Nazarenko, Anna A Agafonova, Larisa I Minaycheva, Ekaterina G Ravzhaeva, Valeria V Petrova, Maria E Lopatkina, Elena O Belyaeva, Svetlana L Vovk, Dmitry A Fedotov, Oksana Y Vasilyeva, Nikolay A Skryabin, Igor N Lebedev

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引用次数: 0

Abstract

Background: The X chromosome is enriched with genes related to brain development, and the hemizygous state of these genes in men causes some difficulties in the clinical interpretation of copy number variations (CNVs). In this study, we present data on the frequency and spectrum of CNVs on the X chromosome in a cohort of patients with neurodevelopmental disorders (NDDs).

Methods: Chromosomal microarray analysis was performed for 1175 patients with NDDs. CNVs were confirmed by real-time quantitative PCR. X chromosome inactivation was analysed by methyl-sensitive PCR. To determine the pathogenic significance of the CNVs, several criteria, including the origin (inherited or de novo), variant type (microdeletion or microduplication), and X chromosome inactivation pattern in asymptomatic and symptomatic carriers, were considered. Additionally, the spectrum, size and molecular bases of copy number changes in genes or gene regions involved in the development of the pathological phenotype in each patient were considered.

Results: CNVs on the X chromosome were identified in 33 patients (2.8%). Duplications and triplications (27 cases) were four times more common than deletions (6 cases). In 74% of patients, CNVs were of maternal origin; in 10% they were of paternal origin; and in 16% they arose de novo. The frequency of skewed X inactivation among family members who were healthy carriers of pathogenic and likely pathogenic CNVs and variants of uncertain significance (VUSs) on the X chromosome was 23%. For the first time, we reported several CNVs, including a pathogenic microdeletion at Xq26.1q26.2 involving the ARHGAP36 gene and a microduplication at Xp22.2 involving the OFD1 gene, CONCLUSIONS: This study expands on the frequency and spectrum of CNVs in patients with NDDs. Pathogenic variants on the X chromosome were present in 15% of cases, LP in 12%, VUS in 57%, and LB in 16% of cases. Previously unreported CNVs aid in the identification of new structural variants and genes associated with X-linked intellectual disability. We propose to consider the X-chromosome inactivation status when assessing the pathogenetic significance of CNVs using the ACMG algorithm (American College of Medical Genetics).

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神经发育障碍患者X染色体上CNVs的患病率

背景：X染色体富含与大脑发育相关的基因，这些基因在男性中的半合子状态给临床解释拷贝数变异（拷贝数变异，CNVs）带来了一些困难。在这项研究中，我们提供了一组神经发育障碍（ndd）患者X染色体上CNVs的频率和频谱数据。方法：对1175例ndd患者进行染色体微阵列分析。采用实时荧光定量PCR检测CNVs。用甲基敏感PCR分析X染色体失活。为了确定CNVs的致病意义，考虑了几种标准，包括起源（遗传或新生），变异类型（微缺失或微重复）以及无症状和有症状携带者的X染色体失活模式。此外，还考虑了每位患者病理表型发展中涉及的基因或基因区域拷贝数变化的谱、大小和分子基础。结果：33例（2.8%）患者在X染色体上发现CNVs。重复和重复（27例）是缺失（6例）的4倍。在74%的患者中，CNVs来自母体；10%是父系后代；16%的人是从头开始的。在X染色体上携带致病性和可能致病性CNVs和不确定意义变异（VUSs）的健康家庭成员中，歪斜X失活的频率为23%。我们首次报道了几个CNVs，包括涉及ARHGAP36基因的Xq26.1q26.2致病性微缺失和涉及OFD1基因的Xp22.2微重复。结论：本研究扩展了ndd患者CNVs的频率和频谱。致病性X染色体变异占15%，LP占12%，VUS占57%，LB占16%。以前未报道的CNVs有助于鉴定与x连锁智力残疾相关的新结构变异和基因。我们建议在使用ACMG算法（American College of Medical Genetics）评估CNVs的致病意义时考虑x染色体失活状态。

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来源期刊

Molecular Cytogenetics GENETICS & HEREDITY-

CiteScore

2.60

自引率

7.70%

发文量

审稿时长

>12 weeks

期刊介绍： Molecular Cytogenetics encompasses all aspects of chromosome biology and the application of molecular cytogenetic techniques in all areas of biology and medicine, including structural and functional organization of the chromosome and nucleus, genome variation, expression and evolution, chromosome abnormalities and genomic variations in medical genetics and tumor genetics. Molecular Cytogenetics primarily defines a large set of the techniques that operate either with the entire genome or with specific targeted DNA sequences. Topical areas include, but are not limited to: -Structural and functional organization of chromosome and nucleus- Genome variation, expression and evolution- Animal and plant molecular cytogenetics and genomics- Chromosome abnormalities and genomic variations in clinical genetics- Applications in preimplantation, pre- and post-natal diagnosis- Applications in the central nervous system, cancer and haematology research- Previously unreported applications of molecular cytogenetic techniques- Development of new techniques or significant enhancements to established techniques. This journal is a source for numerous scientists all over the world, who wish to improve or introduce molecular cytogenetic techniques into their practice.