De Novo Damaging Variants, Clinical Phenotypes, and Post-Operative Outcomes in Congenital Heart Disease
De Novo Damaging Variants, Clinical Phenotypes, and Post-Operative Outcomes in Congenital Heart Disease
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DOI：
10.1161/circgen.119.002836
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发表时间：
2020-08-01
影响因子：
7.4
通讯作者：
Seidman, Christine E.
中科院分区：
文献类型：
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作者：
Boskovski, Marko T.;Homsy, Jason;Seidman, Christine E.
背景：先天性心脏病患者，尤其是伴有心外异常的患者，新生基因变异和拷贝数变异更为富集。新生有害变异对心脏修复后预后的影响尚不明确。
方法：我们研究了2517例先天性心脏病患者，这些患者作为先天性心脏病基因网络（CHD GENES）研究的一部分接受了全外显子组测序。
结果：294例患者（11.7%）具有临床显著的新生变异。具有新生有害变异的患者出现心外异常的可能性高2.4倍（P = 5.63×10⁻¹²）。在1268例（50.4%）有手术数据且首次手术为非心脏移植的开胸手术患者中，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。新生变异与较差的无移植生存率相关（风险比，3.51；P = 5.33×10⁻⁴）以及最终拔管时间延长相关（风险比，0.74；P = 0.005）。由于新生变异与心外异常在无移植生存率方面存在显著交互作用（P = 0.003），对于有这些异常的患者，新生变异并未带来额外的无移植生存风险（校正风险比，1.96；P = 0.06）。相比之下，无心脏外异常患者中的新生变异与随访期间较差的无移植生存率相关（风险比，11.21；P = 1.61×10⁻⁵），比无新生变异的患者更差。利用不可知论的机器学习算法，我们确定15q25.2和15q11.2处的新生拷贝数变异与较差的无移植生存率相关，15q25.2、22q11.21和3p25.2与最终拔管时间延长相关。
结论：在接受开胸手术的先天性心脏病患者中，新生变异与较差的无移植生存率和更长的呼吸机使用时间相关。在无心脏外异常的患者中，新生变异与不良预后的相关性最强，这表明即使在常规临床实践中未怀疑有遗传异常，术前基因检测也是有益的。
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 CH D 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=5.63x 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=5.33x10(-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=1.61x10(-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 15811.2 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.