Reply to Pisan et al.: Pathogenicity of inherited TRAF7 mutations in congenital heart disease.
Reply to Pisan et al.: Pathogenicity of inherited TRAF7 mutations in congenital heart disease.
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回复Pisan等人：遗传性TRAF7突变在先天性心脏病中的致病性。
DOI：
10.1073/pnas.2319578121
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发表时间：
2024
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
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作者：
Mishra-Gorur,Ketu;Barak,Tanyeri;Kaulen,LeonD;Henegariu,Octavian;Jin,ShengChih;Aguilera,StephanieMarie;Yalbir,Ezgi;Goles,Gizem;Nishimura,Sayoko;Miyagishima,Danielle;Djenoune,Lydia;Altinok,Selin;Rai,DevendraK;Viviano,Stephen;
我们收到了Pisan等人的来信。我们的论文(2)基于几个水平的数据报道了p. Val142Met、p. Val442Met和c. 1998+ 2T bbbbg TRAF7变异与先天性心脏病（CHD）的关联：实验上，p. Val442Met的过表达在爪蟾和斑马鱼中一致地表现了TRAF7的下调。具体来说，两者都通过破坏Sox10和Twist的表达来影响神经嵴发育；引起心脏和颅面缺损；扰乱ciliogenesis;与脑膜瘤相关的突变一样，Val442Met干扰TRAF7-CYLD和ift57的相互作用。一些计算机工具强烈支持这些变异的致病性。这两种错义突变都被AlphaMissense和MetaSVM预测为致病性突变，REVEL评分较高，而1998+ 2T> G被预测为破坏正常剪接。在一般人群中，这两种基因的等位基因频率都很低（分别为7.72 e−6和1.59 e−6），而特异的1998+ 2T >g变异在gnomAD-version4中没有发现（比version2高5倍）。TRAF7 WD40区域外的突变在综合征病例（3,4）和包括脑膜瘤在内的癌症(5)中具有致病性，它们与KLF4/ pik3k通路突变共同发生(6)。值得注意的是，cobioportal显示在大量癌症患者中广泛分布TRAF7突变（包括p. Val142和p. Val442） (https://bit。ly / 3 svbc5z)。低pLI评分本身并不能预测基因/变异的非致病状态。事实上，一些pLI评分较低的OMIM基因（< 0.1）可导致常染色体显性疾病（如COL4A2 7）。此外，杂合子Traf7缺失会导致表型（国际小鼠表型联盟，眼睛异常和心电图改变），支持Traf7单倍不足。
We are in receipt of Pisan et al.’s letter (1). Our manuscript (2) reported the association of p. Val142Met, p. Val442Met, and c. 1998+ 2T> G TRAF7 variants with congenital heart disease (CHD) based on several levels of data: Experimentally, overexpression of p. Val442Met consistently phenocopies TRAF7 knockdown in Xenopus and zebrafish. Specifically, both impact neural crest development with disruption of Sox10 and Twist expression; cause cardiac and craniofacial defects; disrupt ciliogenesis; and biochemically p. Val442Met, like meningioma-associated mutations, interferes with the TRAF7-CYLD and-IFT57 interactionsSeveral in silico tools strongly support the pathogenicity of these variants. Both missense mutations are predicted pathogenic by AlphaMissense and MetaSVM, with high REVEL scores, while 1998+ 2T> G is predicted to disrupt normal splicing. Both have low minor allele frequencies (7.72 e− 6 and 1.59 e− 6, respectively) in the general population, while the specific 1998+ 2T> G variant is not found in gnomAD-version4 (five times larger than version2). Mutations outside the TRAF7 WD40 region are pathogenic in syndromic cases (3, 4) and cancer (5) including meningiomas, where they co-occur with KLF4/PIK3K-pathway mutations (6). Notably, cbioportal shows a wide distribution of TRAF7 mutations (including p. Val142 and p. Val442) in a large cohort of cancer patients (https://bit. ly/3svbC5z). A low pLI score alone is not predictive of non-pathogenic status of genes/variants. Indeed, several OMIM genes with low pLI scores (< 0.1) cause autosomal dominant diseases (eg, COL4A2 7). Further, heterozygous Traf7 loss causes phenotypes (eye abnormalities and ECG changes, International Mouse Phenotyping Consortium), supporting haploinsufficiency of Traf7.