Mutations in genes related to myocyte contraction and ventricular septum development in non-syndromic tetralogy of Fallot.
Mutations in genes related to myocyte contraction and ventricular septum development in non-syndromic tetralogy of Fallot.
复制标题
DOI：
10.3389/fcvm.2023.1249605
复制
发表时间：
2023
影响因子：
3.6
通讯作者：
Kumar, S. Ram
中科院分区：
文献类型：
--
作者：
Harvey, Drayton C.;Verma, Riya;Sedaghat, Brandon;Hjelm, Brooke E.;Morton, Sarah U.;Seidman, Jon G.;Kumar, S. Ram
80%的法洛四联症（TOF）患者没有已知的遗传病因或综合征。我们试图确定非综合征性TOF的关键分子途径和生物学过程，而不是单一的驱动基因来阐明这种疾病的发病机制，TOF是青紫型先天性心脏病最常见的形式。我们在儿科心脏基因组学联盟（PCGC）中对362名非综合征性TOF先显子及其父母进行了外显子组测序。我们鉴定了罕见的（小等位基因频率<1 × 10−4）从头变异，以确定该人群中受影响的途径和过程，从而更好地了解TOF的发病机制。将PCGC TOF队列中富集的通路和生物学过程与来自西蒙斯基金会自闭症研究计划（SFARI）的317名无心脏缺陷的对照组（及其父母）进行比较。117个基因中的120个变异被鉴定为最可能有害的，CHD7、CLUH、UNC13C和WASHC5分别在两个先证中被鉴定出来。使用多种生物信息学工具对这些变异进行的基因本体学分析表明，在细胞周期进程、染色质重塑、肌细胞收缩和钙转运以及室间隔和心室发育等过程中都有显著的富集。SOX9靶基因也显著富集，SOX9靶基因在第二心野发育中至关重要，其缺失导致膜性室间隔缺损，与近端出室间隔破裂有关。在SFARI对照组中，这些过程都没有显著增加。心脏祖细胞的先天分子缺陷以及与其活力和收缩功能相关的基因似乎是非综合征性TOF发病机制的核心。利用我们的结果的未来研究可能对TOF患者的分层和个性化临床护理的提供具有重要意义。
Eighty percent of patients with a diagnosis of tetralogy of Fallot (TOF) do not have a known genetic etiology or syndrome. We sought to identify key molecular pathways and biological processes that are enriched in non-syndromic TOF, the most common form of cyanotic congenital heart disease, rather than single driver genes to elucidate the pathogenesis of this disease. We undertook exome sequencing of 362 probands with non-syndromic TOF and their parents within the Pediatric Cardiac Genomics Consortium (PCGC). We identified rare (minor allele frequency <1 × 10−4), de novo variants to ascertain pathways and processes affected in this population to better understand TOF pathogenesis. Pathways and biological processes enriched in the PCGC TOF cohort were compared to 317 controls without heart defects (and their parents) from the Simons Foundation Autism Research Initiative (SFARI). A total of 120 variants in 117 genes were identified as most likely to be deleterious, with CHD7, CLUH, UNC13C, and WASHC5 identified in two probands each. Gene ontology analyses of these variants using multiple bioinformatic tools demonstrated significant enrichment in processes including cell cycle progression, chromatin remodeling, myocyte contraction and calcium transport, and development of the ventricular septum and ventricle. There was also a significant enrichment of target genes of SOX9, which is critical in second heart field development and whose loss results in membranous ventricular septal defects related to disruption of the proximal outlet septum. None of these processes was significantly enriched in the SFARI control cohort. Innate molecular defects in cardiac progenitor cells and genes related to their viability and contractile function appear central to non-syndromic TOF pathogenesis. Future research utilizing our results is likely to have significant implications in stratification of TOF patients and delivery of personalized clinical care.
登录
查看更多内容
影响因子：
5.5
作者：
Azbazdar Y;Karabicici M;Erdal E;Ozhan G
通讯作者：
Ozhan G
影响因子：
4.4
作者：
Briot A;Bouloumié A;Iruela-Arispe ML
通讯作者：
Iruela-Arispe ML
影响因子：
1.2
作者：
Cingolani, Pablo;Platts, Adrian;Ruden, Douglas M.
通讯作者：
Ruden, Douglas M.
影响因子：
2
作者：
Munabi, Naikhoba C. O.;Mikhail, Shady;Toubat, Omar;Webb, Michelle;Auslander, Allyn;Sanchez-Lara, Pedro A.;Manojlovic, Zarko;Schmidt, Ryan J.;Craig, David;Magee, William P.;Kumar, Subramanyan Ram
通讯作者：
Kumar, Subramanyan Ram
影响因子：
3.5
作者：
Chelu A;Williams SG;Keavney BD;Talavera D
通讯作者：
Talavera D