Exome Sequencing in Children With Pulmonary Arterial Hypertension Demonstrates Differences Compared With Adults.
Exome Sequencing in Children With Pulmonary Arterial Hypertension Demonstrates Differences Compared With Adults.
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DOI：
10.1161/circgen.117.001887
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发表时间：
2018-04
期刊：
影响因子：
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通讯作者：
Chung WK
中科院分区：
文献类型：
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作者：
Zhu N;Gonzaga-Jauregui C;Welch CL;Ma L;Qi H;King AK;Krishnan U;Rosenzweig EB;Ivy DD;Austin ED;Hamid R;Nichols WC;Pauciulo MW;Lutz KA;Sawle A;Reid JG;Overton JD;Baras A;Dewey F;Shen Y;Chung WK
肺动脉高压（PAH）是一种罕见的疾病，其特征是肺小动脉重塑、动脉压和阻力升高以及随后的心力衰竭。与成人发病的疾病相比，儿童发病的肺动脉高压更具异质性，并且通常与较差的预后相关。虽然BMPR 2突变是约70%的成人家族性PAH（FPAH）病例的基础，但儿童PAH的遗传基础尚不清楚。我们对155名儿童和257名成人PAH患者进行了遗传分析，包括FPAH和散发性特发性PAH（IPAH）。在筛查两种常见PAH风险基因后，通过外显子组测序评估突变阴性FPAH和所有IPAH病例。我们在儿童和成人发病患者中观察到相似的罕见有害BMPR 2突变频率：两个年龄组的FPAH患者约为55%，IPAH患者约为10%。然而，与成人发病患者相比，TBX 4突变在儿童中显著富集（IPAH：10/130儿童- vs 0/178成人发病），并且TBX 4携带者的平均发病年龄比BMPR 2携带者更年轻。其他已知PAH风险基因的突变在两个年龄组中均不常见。值得注意的是，在已知风险基因中没有突变的儿科IPAH患者中，外显子组测序揭示了2倍的从头可能基因损伤（LGD）和预测的有害错义变体的富集。已知PAH风险基因的突变占两个年龄组FPAH的约70-80%，儿童发病IPAH的21%，成人发病IPAH的11%。TBX 4中罕见的、预测的有害变体在儿科患者中富集，新基因中的新生变体可以解释约19%的儿科发病的IPAH病例。
Pulmonary arterial hypertension (PAH) is a rare disease characterized by pulmonary arteriole remodeling, elevated arterial pressure and resistance, and subsequent heart failure. Compared to adult-onset disease, pediatric-onset PAH is more heterogeneous and often associated with worse prognosis. While BMPR2 mutations underlie ~70% of adult familial PAH (FPAH) cases, the genetic basis of PAH in children is less understood. We performed genetic analysis of 155 pediatric- and 257 adult-onset PAH patients, including both FPAH and sporadic, idiopathic PAH (IPAH). Following screening for two common PAH risk genes, mutation-negative FPAH and all IPAH cases were evaluated by exome sequencing. We observed similar frequencies of rare, deleterious BMPR2 mutations in pediatric- and adult-onset patients: ~55% in FPAH and 10% in IPAH patients in both age groups. However, there was significant enrichment of TBX4 mutations in pediatric-compared to adult-onset patients (IPAH: 10/130 pediatric- vs 0/178 adult-onset), and TBX4 carriers had younger mean age-of-onset compared to BMPR2 carriers. Mutations in other known PAH risk genes were infrequent in both age groups. Notably, among pediatric IPAH patients without mutations in known risk genes, exome sequencing revealed a 2-fold enrichment of de novo likely gene damaging (LGD) and predicted deleterious missense variants. Mutations in known PAH risk genes accounted for ~70–80% of FPAH in both age groups, 21% of pediatric-onset IPAH, and 11% of adult-onset IPAH. Rare, predicted deleterious variants in TBX4 are enriched in pediatric patients and de novo variants in novel genes may explain ~19% of pediatric-onset IPAH cases.