Center for Congenital Heart Diseases, Department of Pediatric Cardiology, Beatrix Children's Hospital, University Medical Center Groningen, Groningen, the Netherlands.
Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
J Pediatr. 2020 Oct;225:65-73.e5. doi: 10.1016/j.jpeds.2020.05.051. Epub 2020 Jun 2.
To describe the prevalence of pulmonary arterial hypertension (PAH)-associated gene mutations, and other genetic characteristics in a national cohort of children with PAH from the Dutch National registry and to explore genotype-phenotype associations and outcomes.
Children (n = 70) diagnosed with idiopathic PAH, heritable PAH, PAH associated with congenital heart disease with coincidental shunt (PAH-congenital heart disease group 3), PAH after closure of a cardiac shunt (PAH-congenital heart disease group 4), or PAH associated with other noncardiac conditions were enrolled. Targeted next-generation sequencing was performed on PAH-associated genes (BMPR2, ACVRL1, EIF2AK4, CAV1, ENG, KCNK3, SMAD9, and TBX4). Also, children were tested for specific genetic disorders in case of clinical suspicion. Additionally, children were tested for copy number variations.
Nineteen children (27%) had a PAH-associated gene mutation/variant: BMPR2 n = 7, TBX4 n = 8, ACVRL1 n = 1, KCNK3 n = 1, and EIF2AK4 n = 2. Twelve children (17%) had a genetic disorder with an established association with PAH (including trisomy 21 and cobalamin C deficiency). In another 16 children (23%), genetic disorders without an established association with PAH were identified (including Noonan syndrome, Beals syndrome, and various copy number variations). Survival rates differed between groups and was most favorable in TBX4 variant carriers.
Children with PAH show a high prevalence of genetic disorders, not restricted to established PAH-associated genes. Genetic architecture could play a role in risk-stratified care management in pediatric PAH.
描述荷兰国家登记处一个全国性儿童肺动脉高压（PAH）队列中肺动脉高压相关基因突变及其他遗传特征，并探讨基因型-表型相关性和结局。
纳入诊断为特发性 PAH、遗传性 PAH、伴有偶然分流的先天性心脏病相关 PAH（PAH-先天性心脏病组 3）、心脏分流关闭后 PAH（PAH-先天性心脏病组 4）或伴有其他非心脏疾病的 PAH 的患儿。对肺动脉高压相关基因（BMPR2、ACVRL1、EIF2AK4、CAV1、ENG、KCNK3、SMAD9 和 TBX4）进行靶向下一代测序。此外，在有临床怀疑的情况下，对患儿进行特定的遗传疾病检测。此外，还对患儿进行拷贝数变异检测。
19 名患儿（27%）存在肺动脉高压相关基因突变/变异：BMPR2 n=7，TBX4 n=8，ACVRL1 n=1，KCNK3 n=1，EIF2AK4 n=2。12 名患儿（17%）存在与 PAH 有明确关联的遗传疾病（包括 21 三体和钴胺素 C 缺乏症）。在另外 16 名患儿（23%）中，发现了与 PAH 无明确关联的遗传疾病（包括 Noonan 综合征、Beals 综合征和各种拷贝数变异）。不同组间的生存率存在差异，TBX4 变异携带者的生存率最高。
PAH 患儿存在高遗传疾病患病率，且不限于已明确的 PAH 相关基因。遗传结构可能在儿科 PAH 的风险分层管理中发挥作用。
