Burden of potentially pathologic copy number variants is higher in children with isolated congenital heart disease and significantly impairs covariate-adjusted transplant-free survival.
Burden of potentially pathologic copy number variants is higher in children with isolated congenital heart disease and significantly impairs covariate-adjusted transplant-free survival.
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DOI：
10.1016/j.jtcvs.2015.09.136
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发表时间：
2016-04
期刊：
影响因子：
--
通讯作者：
Jarvik GP
中科院分区：
文献类型：
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作者：
Kim DS;Kim JH;Burt AA;Crosslin DR;Burnham N;Kim CE;McDonald-McGinn DM;Zackai EH;Nicolson SC;Spray TL;Stanaway IB;Nickerson DA;Heagerty PJ;Hakonarson H;Gaynor JW;Jarvik GP
拷贝数变异 (CNV) 是基因组区域的重复或缺失。大的 CNV 具有潜在致病性，并且在患有先天性心脏病 (CHD) 的儿童中比例过高。我们试图确定孤立性 CHD 儿童中大 CNV 的频率，并评估这些潜在致病性 CNV 与无移植生存的关系。这些病例来自于首次手术前确定的非综合征性 CHD 患者 (n=422) 的前瞻性队列。从电子病历和遗传流行病学 (eMERGE) 网络获得健康儿科对照 (n=500)，并将 CNV 频率与 CHD 病例和对照进行对比。通过算法确定 CNV，随后筛选两种方法之间 >95% 的重叠、大小 (>300kb)、质量评分、与基因的重叠和新颖性（已知良性 CNV 的数据库中不存在），并通过定量 PCR 分别进行验证。使用 Cox 比例风险模型计算病例的生存可能性，以评估 CNV 负担和已知混杂因素对无移植生存的联合影响。与儿科对照相比，非综合征性 CHD 儿童的潜在致病性 CNV 负担更高（12.1% vs. 5.0%，P=0.00016）。通过混杂因素调整，CNV 的存在与手术后显着降低的无移植生存率相关（HR=3.42，95% CI：1.66-7.09，P=0.00090）。我们证实，患有孤立性先心病的儿童具有更大的罕见/大型 CNV 负担。我们报告了一项新发现，即这些 CNV 与调整后的死亡或移植风险增加 2.55 倍相关。这些数据表明 CNV 负荷是 CHD 手术后生存的重要调节因素。
Copy number variants (CNVs) are duplications or deletions of genomic regions. Large CNVs are potentially pathogenic and over-represented in children with congenital heart disease (CHD). We sought to determine the frequency of large CNVs in children with isolated CHD and evaluate the relationship of these potentially pathogenic CNVs with transplant-free survival. These cases are derived from a prospective cohort of non-syndromic CHD patients (n=422) ascertained prior to their first surgery. Healthy pediatric controls (n=500) were obtained from the electronic Medical Records and Genetic Epidemiology (eMERGE) Network and CNV frequency was contrasted for CHD cases and controls. CNVs were algorithmically determined, subsequently screened for >95% overlap between two methods, size (>300kb), quality score, overlap with a gene, and novelty (absent from databases of known, benign CNVs), and separately validated with quantitative-PCR. Survival likelihoods were calculated for cases using Cox proportional hazards modeling to evaluate the joint effect of CNV burden and known confounders on transplant-free survival. Children with nonsyndromic CHD had a higher burden of potentially pathogenic CNVs compared to pediatric controls (12.1% vs. 5.0%, P=0.00016). Presence of a CNV was associated with significantly decreased transplant-free survival after surgery (HR=3.42, 95% CI: 1.66-7.09, P=0.00090) with confounder adjustment. We confirm that children with isolated CHD have a greater burden of rare/large CNVs. We report a novel finding that these CNVs are associated with an adjusted 2.55-fold increased risk of death or transplant. These data suggest that CNV burden is an important modifier of survival after surgery for CHD.