Whole exome sequencing identifies novel inherited genetic variants in tetralogy of Fallot.
Whole exome sequencing identifies novel inherited genetic variants in tetralogy of Fallot.
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全外显子组测序鉴定出法洛四联症中新的遗传变异
DOI：
10.21037/jtd-22-970
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发表时间：
2022-08
影响因子：
2.5
通讯作者：
中科院分区：
文献类型：
--
作者：
法洛四联症（TOF）是最常见的新生儿紫绀型心脏缺陷，遗传变异是TOF病因的重要危险因素。识别 TOF 相关的遗传变异对于了解 TOF 患者的易感性和结果至关重要，并可能有助于描述病理机制。对 19 名散发性 TOF 患者和 3 名健康对照者进行了全外显子组测序 (WES)。 dbSNP、GnomAD、Denovo-db 和 ClinVar 数据库用于注释突变。使用PolyPhen、SIFT、MutationTaster和FATHMM软件进行突变致病性分析。桑格测序用于验证候选变体。我们在 12 名散发性 TOF 患者中发现了涉及 16 个基因的 21 个遗传变异。突变类型为错义突变和剪接突变。在 3 名健康对照的样本中没有检测到这些基因。这些变异包括9个致病变异、6个疑似致病变异和6个意义不明的变异（VUS）。进一步分析显示，载脂蛋白B（APOB）和环指蛋白135（RNF135）变异的患者临床症状更为严重。桑格测序证实这两种变异在 TOF 患者中是杂合的。我们鉴定了与 TOF 相关的几种遗传变异，并确认 RNF135 和 ABOB 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的证据。
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 (APOB) and ring finger protein 135 (RNF135) 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 RNF135 and ABOB variants were associated with TOF severity. These findings provide new evidence for exploring the genetic mechanism of TOF.
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影响因子：
6.5
作者：
Futema M;Taylor-Beadling A;Williams M;Humphries SE
通讯作者：
Humphries SE
影响因子：
3.7
作者：
Manshaei R;Merico D;Reuter MS;Engchuan W;Mojarad BA;Chaturvedi R;Heung T;Pellecchia G;Zarrei M;Nalpathamkalam T;Khan R;Okello JBA;Liston E;Curtis M;Yuen RKC;Marshall CR;Jobling RK;Oechslin E;Wald RM;Silversides CK;Scherer SW;Kim RH;Bassett AS
通讯作者：
Bassett AS
影响因子：
4.4
作者：
Nagahara, Keiko;Nishibukuro, Tsuyoshi;Ogiwara, Yasuko;Ikegawa, Kento;Tada, Hayato;Yamagishi, Masakazu;Kawashiri, Masa-aki;Ochi, Ayako;Toyoda, Junya;Nakano, Yuya;Adachi, Masanori;Mizuno, Katsumi;Hasegawa, Yukihiro;Dobashi, Kazushige
通讯作者：
Dobashi, Kazushige
影响因子：
2.7
作者：
Sun H;Zhang S;Wang J;Zhou X;Zhang H;Yang H;He Y
通讯作者：
He Y
影响因子：
6.2
作者：
Blais, Samuel;Marelli, Ariane;Dallaire, Frederic
通讯作者：
Dallaire, Frederic