The Genetic Epidemiology of Pediatric Pulmonary Arterial Hypertension

Haarman, M. G., Kerstjens-Frederikse, W. S., Vissia-Kazemier, T. R., Breeman, K. T. N., Timens, W., Vos, Y. J., Roofthooft, M. T. R., Hillege, H. L. & Berger, R. M. F., 2-Jun-2020, In : The Journal of Pediatrics. 44 p.

Research output: Contribution to journalArticleAcademicpeer-review

Copy link to clipboard


  • The genetic epidemiology of pediatric pulmonary arterial hypertension

    Final author's version, 2.89 MB, PDF document

    Embargo ends: 02/06/2021

    Request copy

  • The Genetic Epidemiology of Pediatric Pulmonary Arterial Hypertension

    Proof, 11 MB, PDF document

    Request copy


OBJECTIVE: 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.

STUDY DESIGN: Children (n = 70) diagnosed with idiopathic PAH (IPAH), heritable PAH (HPAH), PAH associated with congenital heart disease (CHD) with coincidental shunt (PAH-CHD group 3), PAH after closure of a cardiac shunt (PAH-CHD group 4), or PAH associated with other non-cardiac 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 (CNVs).

RESULTS: Nineteen children (27%) had a PAH-associated gene mutation/variant: BMPR2 n=7, TBX4 n=8, ACVRL1 n=1, KCNK3 n=1, 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 CNVs). Survival rates differed between groups and was most favorable in TBX4 variant carriers.

CONCLUSIONS: 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.

Original languageEnglish
Number of pages44
JournalThe Journal of Pediatrics
Publication statusE-pub ahead of print - 2-Jun-2020

ID: 126664716