The Genetic Epidemiology of Pediatric Pulmonary Arterial Hypertension

J Pediatr. 2020 Oct:225:65-73.e5. doi: 10.1016/j.jpeds.2020.05.051. Epub 2020 Jun 2.

Abstract

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, 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.

Results: 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.

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.

Keywords: genetics; outcome; pediatric pulmonary hypertension.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activin Receptors, Type II / genetics
  • Adolescent
  • Arachnodactyly / complications
  • Arachnodactyly / epidemiology
  • Arachnodactyly / genetics
  • Bone Morphogenetic Protein Receptors, Type II / genetics
  • Child
  • Child, Preschool
  • Contracture / complications
  • Contracture / epidemiology
  • Contracture / genetics
  • Down Syndrome / epidemiology
  • Down Syndrome / genetics
  • Female
  • Gene Dosage
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Genetic Variation
  • Heart Defects, Congenital / epidemiology*
  • Heart Defects, Congenital / genetics*
  • Humans
  • Infant
  • Male
  • Mutation*
  • Nerve Tissue Proteins / genetics
  • Netherlands / epidemiology
  • Noonan Syndrome / complications
  • Noonan Syndrome / epidemiology
  • Noonan Syndrome / genetics
  • Potassium Channels, Tandem Pore Domain / genetics
  • Prospective Studies
  • Protein Serine-Threonine Kinases / genetics
  • Pulmonary Arterial Hypertension / epidemiology*
  • Pulmonary Arterial Hypertension / genetics*
  • Registries
  • T-Box Domain Proteins / genetics
  • Vitamin B 12 / metabolism
  • Vitamin B 12 Deficiency / epidemiology
  • Vitamin B 12 Deficiency / genetics

Substances

  • Nerve Tissue Proteins
  • Potassium Channels, Tandem Pore Domain
  • T-Box Domain Proteins
  • TBX4 protein, human
  • potassium channel subfamily K member 3
  • EIF2AK4 protein, human
  • Protein Serine-Threonine Kinases
  • ACVRL1 protein, human
  • Activin Receptors, Type II
  • BMPR2 protein, human
  • Bone Morphogenetic Protein Receptors, Type II
  • Vitamin B 12

Supplementary concepts

  • Congenital contractural arachnodactyly