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对被诊断患有心脏通道病的家族进行全基因组测序揭示了全外显子组测序错过的结构变异。

Whole genome sequencing of families diagnosed with cardiac channelopathies reveals structural variants missed by whole exome sequencing.

机构信息

CSIR- Institute of Genomics and Integrative Biology, Mathura Road, Sukhdev Vihar, New Delhi, 110025, India.

Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.

出版信息

J Hum Genet. 2024 Sep;69(9):455-465. doi: 10.1038/s10038-024-01265-2. Epub 2024 Jun 18.

Abstract

Cardiac channelopathies are a group of heritable disorders that affect the heart's electrical activity due to genetic variations present in genes coding for ion channels. With the advent of new sequencing technologies, molecular diagnosis of these disorders in patients has paved the way for early identification, therapeutic management and family screening. The objective of this retrospective study was to understand the efficacy of whole-genome sequencing in diagnosing patients with suspected cardiac channelopathies who were reported negative after whole exome sequencing and analysis. We employed a 3-tier analysis approach to identify nonsynonymous variations and loss-of-function variations missed by exome sequencing, and structural variations that are better resolved only by sequencing whole genomes. By performing whole genome sequencing and analyzing 25 exome-negative cardiac channelopathy patients, we identified 3 pathogenic variations. These include a heterozygous likely pathogenic nonsynonymous variation, CACNA1C:NM_000719:exon19:c.C2570G:p. P857R, which causes autosomal dominant long QT syndrome in the absence of Timothy syndrome, a heterozygous loss-of-function variation CASQ2:NM_001232.4:c.420+2T>C classified as pathogenic, and a 9.2 kb structural variation that spans exon 2 of the KCNQ1 gene, which is likely to cause Jervell-Lange-Nielssen syndrome. In addition, we also identified a loss-of-function variation and 16 structural variations of unknown significance (VUS). Further studies are required to elucidate the role of these identified VUS in gene regulation and decipher the underlying genetic and molecular mechanisms of these disorders. Our present study serves as a pilot for understanding the utility of WGS over clinical exomes in diagnosing cardiac channelopathy disorders.

摘要

心脏通道病是一组遗传性疾病,由于编码离子通道的基因中的遗传变异,会影响心脏的电活动。随着新测序技术的出现,对这些疾病患者进行分子诊断为早期识别、治疗管理和家族筛查铺平了道路。本回顾性研究的目的是了解全基因组测序在诊断全外显子组测序和分析报告为阴性的疑似心脏通道病患者中的疗效。我们采用了 3 级分析方法来识别外显子组测序遗漏的非同义变异和功能丧失变异,以及仅通过全基因组测序才能更好地解析的结构变异。通过对 25 例外显子阴性心脏通道病患者进行全基因组测序和分析,我们鉴定出 3 种致病性变异。这些变异包括杂合性可能致病性非同义变异 CACNA1C:NM_000719:exon19:c.C2570G:p. P857R,它在没有 Timothy 综合征的情况下导致常染色体显性长 QT 综合征;杂合性功能丧失变异 CASQ2:NM_001232.4:c.420+2T>C 归类为致病性;以及跨越 KCNQ1 基因外显子 2 的 9.2 kb 结构变异,可能导致 Jervell-Lange-Nielssen 综合征。此外,我们还鉴定出 1 种功能丧失变异和 16 种意义不明的结构变异(VUS)。需要进一步研究来阐明这些鉴定的 VUS 在基因调控中的作用,并阐明这些疾病的潜在遗传和分子机制。我们目前的研究为理解 WGS 在诊断心脏通道病中的优于临床外显子组的作用提供了一个试点。

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