Background:De novo genic and copy number variants are enriched in patients with congenital heart disease, particularly those with extra-cardiac anomalies. The impact of de novo damaging variants on outcomes following cardiac repair is unknown.Methods:We studied 2517 patients with congenital heart disease who had undergone whole-exome sequencing as part of the CHD GENES study (Congenital Heart Disease Genetic Network).Results:Two hundred ninety-four patients (11.7%) had clinically significant de novo variants. Patients with de novo damaging variants were 2.4 times more likely to have extra-cardiac anomalies (P=5.63×10⁻¹²). In 1268 patients (50.4%) who had surgical data available and underwent open-heart surgery exclusive of heart transplantation as their first operation, we analyzed transplant-free survival following the first operation. Median follow-up was 2.65 years. De novo variants were associated with worse transplant-free survival (hazard ratio, 3.51; P=5.33×10⁻⁰⁴) and longer times to final extubation (hazard ratio, 0.74; P=0.005). As de novo variants had a significant interaction with extra-cardiac anomalies for transplant-free survival (P=0.003), de novo variants conveyed no additional risk for transplant-free survival for patients with these anomalies (adjusted hazard ratio, 1.96; P=0.06). By contrast, de novo variants in patients without extra-cardiac anomalies were associated with worse transplant-free survival during follow-up (hazard ratio, 11.21; P=1.61×10⁻⁰⁵) than that of patients with no de novo variants. Using agnostic machine-learning algorithms, we identified de novo copy number variants at 15q25.2 and 15q11.2 as being associated with worse transplant-free survival and 15q25.2, 22q11.21, and 3p25.2 as being associated with prolonged time to final extubation.Conclusions:In patients with congenital heart disease undergoing open-heart surgery, de novo variants were associated with worse transplant-free survival and longer times on the ventilator. De novo variants were most strongly associated with adverse outcomes among patients without extra-cardiac anomalies, suggesting a benefit for preoperative genetic testing even when genetic abnormalities are not suspected during routine clinical practice.Registration:URL: https://www.clinicaltrials.gov. Unique identifier: NCT01196182.

中文翻译：

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先天性心脏病的从头损伤变异、临床表型和术后结果。

背景：从头基因和拷贝数变异在先天性心脏病患者中富集，尤其是那些有心脏外异常的患者。从头损伤变异对心脏修复后结果的影响尚不清楚。 方法：我们研究了 2517 名接受全外显子测序的先天性心脏病患者，作为 CHD GENES 研究（先天性心脏病遗传网络）的一部分。结果：两个194 名患者 (11.7%) 具有临床上显着的 de novo 变异。具有新发破坏性变异的患者发生心外异常的可能性高 2.4 倍（P =5.63×10 ^-12）。在 1268 名有手术数据并接受心脏直视手术（不包括心脏移植手术）的患者（50.4%）中，我们分析了首次手术后的无移植生存率。中位随访时间为 2.65 年。从头变异与较差的无移植存活率（风险比，3.51；P =5.33×10 ^-04）和更长的最终拔管时间（风险比，0.74；P = 0.005）相关。由于 de novo 变异与心脏外异常对无移植存活率有显着的相互作用（P = 0.003），因此 de novo 变异不会为有这些异常的患者带来无移植存活的额外风险（调整后的风险比，1.96；P=0.06）。相比之下，没有心脏外异常的患者的新发变异与随访期间较差的无移植生存率相关（风险比，11.21；P =1.61×10 ^-05) 比没有 de novo 变异的患者。使用不可知的机器学习算法，我们发现 15q25.2 和 15q11.2 的从头拷贝数变异与较差的无移植生存相关，而 15q25.2、22q11.21 和 3p25.2 与延长时间相关最终拔管。结论：在接受心脏直视手术的先天性心脏病患者中，de novo 变异与更差的无移植生存率和更长的呼吸机时间相关。在没有心脏外异常的患者中，从头变异与不良结果的相关性最强，这表明即使在常规临床实践中没有怀疑遗传异常的情况下，术前基因检测也是有益的。注册：URL：https://www.clinicaltrials.gov . 唯一标识符：NCT01196182。