Pan Yu, Liu Manli, Zhang Songsong, Mei Huaxian, Wu Jing
Intensive Care Unit, Guizhou Provincial People's Hospital, Guiyang, China.
J Thorac Dis. 2022 Aug;14(8):3008-3015. doi: 10.21037/jtd-22-970.
Tetralogy of Fallot (TOF) is the most common neonatal cyanotic heart defect, and genetic variation is an important risk factor for the etiology of TOF. Identifying TOF-associated genetic variants is critical to understanding susceptibility and outcome in patients with TOF and may help delineate pathological mechanisms.
Whole exome sequencing (WES) was performed 19 patients with sporadic TOF and 3 healthy controls. The dbSNP, GnomAD, Denovo-db, and ClinVar databases were used to annotate the mutations. PolyPhen, SIFT, MutationTaster, and FATHMM softwares were used for mutation pathogenicity analysis. Sanger sequencing was used to validate candidate variants.
We identified 21 genetic variants involving 16 genes were found in 12 patients with sporadic TOF. The types of mutations were missense and splicing variants. None of these genes were detected in samples from the 3 healthy controls. These variants include 9 pathogenic variants, 6 suspected pathogenic variants, and 6 variants of unknown significance (VUS). Further analysis showed that the patients with apolipoprotein B () and ring finger protein 135 () variants had more serious clinical symptoms. Sanger sequencing confirmed that the two variants were heterozygous in TOF patients.
We identified several genetic variants associated with TOF and confirmed that and variants were associated with TOF severity. These findings provide new evidence for exploring the genetic mechanism of TOF.
法洛四联症（TOF）是最常见的新生儿青紫型心脏缺陷，遗传变异是TOF病因的重要危险因素。识别与TOF相关的遗传变异对于理解TOF患者的易感性和预后至关重要，并且可能有助于阐明病理机制。
对19例散发性TOF患者和3例健康对照进行全外显子测序（WES）。使用dbSNP、GnomAD、Denovo-db和ClinVar数据库对突变进行注释。使用PolyPhen、SIFT、MutationTaster和FATHMM软件进行突变致病性分析。使用Sanger测序验证候选变异。
在12例散发性TOF患者中发现了涉及16个基因的21种遗传变异。突变类型为错义突变和剪接变异。在3例健康对照的样本中未检测到这些基因。这些变异包括9种致病性变异、6种疑似致病性变异和6种意义未明的变异（VUS）。进一步分析表明，载脂蛋白B（）和环指蛋白135（）变异的患者临床症状更严重。Sanger测序证实这两种变异在TOF患者中为杂合子。
我们识别了几种与TOF相关的遗传变异，并证实和变异与TOF严重程度相关。这些发现为探索TOF的遗传机制提供了新证据。
