Role of TBX20 Truncating Variants in Dilated Cardiomyopathy and Left Ventricular Noncompaction.

IF 6 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Circulation: Genomic and Precision Medicine Pub Date : 2024-04-01 Epub Date: 2024-02-14 DOI:10.1161/CIRCGEN.123.004404

Almudena Amor-Salamanca, Alfredo Santana Rodríguez, Hazhee Rasoul, José F Rodríguez-Palomares, Oana Moldovan, Thomas Morris Hey, María Gallego Delgado, David López Cuenca, Daniel de Castro Campos, María Teresa Basurte-Elorz, Rosa Macías-Ruiz, María Eugenia Fuentes Cañamero, Joseph Galvin, Raquel Bilbao Quesada, Luis de la Higuera Romero, Juan Pablo Trujillo-Quintero, Loida María García-Cruz, Ivonne Cárdenas-Reyes, Juan Jiménez-Jáimez, Soledad García-Hernández, María Valverde-Gómez, Iria Gómez-Díaz, Javier Limeres Freire, José M García-Pinilla, Juan R Gimeno-Blanes, Konstantinos Savattis, Pablo García-Pavía, Juan Pablo Ochoa

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引用次数: 0

Abstract

Background: Less than 40% of patients with dilated cardiomyopathy (DCM) have a pathogenic/likely pathogenic genetic variant identified. TBX20 has been linked to congenital heart defects; although an association with left ventricular noncompaction (LVNC) and DCM has been proposed, it is still considered a gene with limited evidence for these phenotypes. This study sought to investigate the association between the TBX20 truncating variant (TBX20tv) and DCM/LVNC.

Methods: TBX20 was sequenced by next-generation sequencing in 7463 unrelated probands with a diagnosis of DCM or LVNC, 22 773 probands of an internal comparison group (hypertrophic cardiomyopathy, channelopathies, or aortic diseases), and 124 098 external controls (individuals from the gnomAD database). Enrichment of TBX20tv in DCM/LVNC was calculated, cosegregation was determined in selected families, and clinical characteristics and outcomes were analyzed in carriers.

Results: TBX20tv was enriched in DCM/LVNC (24/7463; 0.32%) compared with internal (1/22 773; 0.004%) and external comparison groups (4/124 098; 0.003%), with odds ratios of 73.23 (95% CI, 9.90-541.45; P<0.0001) and 99.76 (95% CI, 34.60-287.62; P<0.0001), respectively. TBX20tv was cosegregated with DCM/LVNC phenotype in 21 families for a combined logarythm of the odds score of 4.53 (strong linkage). Among 57 individuals with TBX20tv (49.1% men; mean age, 35.9±20.8 years), 41 (71.9%) exhibited DCM/LVNC, of whom 14 (34.1%) had also congenital heart defects. After a median follow-up of 6.9 (95% CI, 25-75:3.6-14.5) years, 9.7% of patients with DCM/LVNC had end-stage heart failure events and 4.8% experienced malignant ventricular arrhythmias.

Conclusions: TBX20tv is associated with DCM/LVNC; congenital heart defect is also present in around one-third of cases. TBX20tv-associated DCM/LVNC is characterized by a nonaggressive phenotype, with a low incidence of major cardiovascular events. TBX20 should be considered a definitive gene for DCM and LVNC and routinely included in genetic testing panels for these phenotypes.

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TBX20 截断变体在扩张型心肌病和左心室不充盈中的作用

背景：在扩张型心肌病（DCM）患者中，只有不到 40% 发现了致病/可能致病的基因变异。TBX20 与先天性心脏缺陷有关；尽管有人提出它与左心室不充盈（LVNC）和 DCM 有关，但它仍被认为是一个与这些表型有关的证据有限的基因。本研究试图调查 TBX20 截短变异体（TBX20tv）与 DCM/LVNC 之间的关联：方法：通过新一代测序对 7463 例诊断为 DCM 或 LVNC 的非亲缘关系探查者、22 773 例内部对比组（肥厚型心肌病、通道病或主动脉疾病）探查者和 124 098 例外部对照（gnomAD 数据库中的个体）进行了 TBX20 测序。计算了TBX20tv在DCM/LVNC中的富集程度，确定了选定家系中的共分离情况，并分析了携带者的临床特征和预后：与内部组（1/22 773；0.004%）和外部对比组（4/124 098；0.003%）相比，TBX20tv在DCM/LVNC中富集（24/7463；0.32%），几率比为73.23（95% CI，9.90-541.45）；PPTBX20tv与21个家系的DCM/LVNC表型共分离，LOD综合评分为4.53（强关联）。在 57 名 TBX20tv 患者（49.1% 为男性；平均年龄为 35.9±20.8 岁）中，41 人（71.9%）表现为 DCM/LVNC，其中 14 人（34.1%）还伴有先天性心脏缺陷。中位随访 6.9 年（95% CI，25-75:3.6-14.5）后，9.7% 的 DCM/LVNC 患者出现终末期心力衰竭，4.8% 的患者出现恶性室性心律失常：结论：TBX20tv 与 DCM/LVNC 相关；约三分之一的病例存在先天性心脏缺陷。与 TBX20tv 相关的 DCM/LVNC 具有非侵袭性表型的特点，重大心血管事件的发生率较低。TBX20 应被视为 DCM 和 LVNC 的确定基因，并被常规纳入这些表型的基因检测中。

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

Circulation: Genomic and Precision Medicine Biochemistry, Genetics and Molecular Biology-Genetics

CiteScore

9.20

自引率

5.40%

发文量

144

期刊介绍： Circulation: Genomic and Precision Medicine is a distinguished journal dedicated to advancing the frontiers of cardiovascular genomics and precision medicine. It publishes a diverse array of original research articles that delve into the genetic and molecular underpinnings of cardiovascular diseases. The journal's scope is broad, encompassing studies from human subjects to laboratory models, and from in vitro experiments to computational simulations. Circulation: Genomic and Precision Medicine is committed to publishing studies that have direct relevance to human cardiovascular biology and disease, with the ultimate goal of improving patient care and outcomes. The journal serves as a platform for researchers to share their groundbreaking work, fostering collaboration and innovation in the field of cardiovascular genomics and precision medicine.