De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies.
De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies.
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DOI：
10.1126/science.aac9396
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发表时间：
2015-12-04
期刊：
影响因子：
--
通讯作者：
Chung WK
中科院分区：
文献类型：
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作者：
Homsy J;Zaidi S;Shen Y;Ware JS;Samocha KE;Karczewski KJ;DePalma SR;McKean D;Wakimoto H;Gorham J;Jin SC;Deanfield J;Giardini A;Porter GA Jr;Kim R;Bilguvar K;López-Giráldez F;Tikhonova I;Mane S;Romano-Adesman A;Qi H;Vardarajan B;Ma L;Daly M;Roberts AE;Russell MW;Mital S;Newburger JW;Gaynor JW;Breitbart RE;Iossifov I;Ronemus M;Sanders SJ;Kaltman JR;Seidman JG;Brueckner M;Gelb BD;Goldmuntz E;Lifton RP;Seidman CE;Chung WK
先天性心脏病（CHD）患者心脏外先天性异常（CA）的患病率增加，且有神经发育障碍（NDD）的风险。对1213个先天性心脏病亲子三联体进行外显子组测序，发现了过多的蛋白质损伤性新生突变，尤其是在心脏和大脑发育过程中高表达的基因中。这些突变在患有先天性心脏病、神经发育障碍和心脏外先天性异常的患者中占20%，但在单纯先天性心脏病患者中仅占2%。突变改变了参与形态发生、染色质修饰和转录调控的基因，包括mRNA剪接调节因子RBFOX2的多个突变。在因神经发育障碍而确定的其他队列中发生突变的基因在先天性心脏病病例中富集，特别是那些同时存在神经发育障碍的病例。这些发现揭示了先天性心脏病、神经发育障碍和心脏外先天性异常的共同遗传因素，并为改善先天性心脏病患者的预后评估和早期治疗干预提供了机会。
Congenital heart disease (CHD) patients have increased prevalence of extra-cardiac congenital anomalies (CA) and risk of neurodevelopmental disabilities (NDD). Exome sequencing of 1,213 CHD parent-offspring trios identified an excess of protein-damaging de novo mutations, especially in genes highly expressed in developing heart and brain. These mutations accounted for 20% of patients with CHD, NDD and CA but only 2% with isolated CHD. Mutations altered genes involved in morphogenesis, chromatin modification, and transcriptional regulation, including multiple mutations in RBFOX2, an mRNA splice regulator. Genes mutated in other cohorts ascertained for NDD were enriched in CHD cases, particularly those with coexisting NDD. These findings reveal shared genetic contributions to CHD, NDD, and CA and provide opportunities for improved prognostic assessment and early therapeutic intervention in CHD patients.