The Genetic Epidemiology of Pediatric Pulmonary Arterial Hypertension

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 correlations and outcome. Study design: Seventy children 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.

Genetics and Genomics of Pediatric Pulmonary Arterial Hypertension

“…BMPR1B , CAV1 , GDF2 , KCNK3 and KDR/BMP9 were identified in one to four cases each, accounting for <1% for each gene. In addition to autosomal dominant inheritance, recessively inherited EIF2AK4 variants have been identified in 1–3% of children in European and Chinese cohorts [ 31 , 45 , 46 ]. In addition, a rare occurrence of recessively inherited GDF2 variants has been reported for a 3-year-old boy with right heart failure [ 47 ].…”

Whole Exome Sequence Analysis Provides Novel Insights into the Genetic Framework of Childhood-Onset Pulmonary Arterial Hypertension

“…Clinical diagnoses were established by PAH specialists in accordance with the classification of the World Symposium on Pulmonary Hypertension [26]. All patients previously underwent conventional genetic screening for BMPR2, ACVRL1 and ENG, and were found to be mutation-negative [16,27]. Following pedigree analysis and clinical examination, patients were classified as having either idiopathic PAH (IPAH; n = 8), PAH associated with congenital heart disease (APAH-CHD; n = 7) or heritable PAH with one or more affected relatives (HPAH; n = 3).…”

Implication of Potassium Channels in the Pathophysiology of Pulmonary Arterial Hypertension

“…Best et al identified two additional mutations [ 52 ], and one additional mutation has been identified in Chinese pediatric PAH patients [ 53 ]. In 2020, a new mutation in KCNK3 was identified in a Dutch national cohort of children with PAH [ 54 ].…”

“…To date, 12 different KCNK3 mutations have been identified in 19 patients [ 11 , 50 , 51 , 52 , 53 , 54 , 55 ].…”

“…As indicated in Table 1 , all eight analyzed mutations (T8K, G97R, G106R, E182K, Y192C, G203D, L214R, and V221L) lead to KCNK3 LOF ( Table 1 ). To date, A114V, K145M, V206L, and A189T have not been evaluated [ 24 , 50 , 54 , 57 ]. In addition, the application of ONO-RS-082, which is a phospholipase A2 inhibitor previously shown to activate the KCNK3 channel [ 58 ], restores the function of T8K, E182K, and V221L to the same level as the non-mutated channel in basal conditions, while G203D, G106R, and L214R are insensitive to ONO-RS-082 [ 24 , 50 ].…”