Genetics and Genomics of Pediatric Pulmonary Arterial Hypertension

Overview

Journal Genes (Basel)

Publisher MDPI

Date 2020 Oct 21

PMID 33081265

Citations 19

Authors

Carrie L Welch

Wendy K Chung

Affiliations

Soon will be listed here.

Abstract

Pulmonary arterial hypertension (PAH) is a rare disease with high mortality despite recent therapeutic advances. The disease is caused by both genetic and environmental factors and likely gene-environment interactions. While PAH can manifest across the lifespan, pediatric-onset disease is particularly challenging because it is frequently associated with a more severe clinical course and comorbidities including lung/heart developmental anomalies. In light of these differences, it is perhaps not surprising that emerging data from genetic studies of pediatric-onset PAH indicate that the genetic basis is different than that of adults. There is a greater genetic burden in children, with rare genetic factors contributing to ~42% of pediatric-onset PAH compared to ~12.5% of adult-onset PAH. De novo variants are frequently associated with PAH in children and contribute to at least 15% of all pediatric cases. The standard of medical care for pediatric PAH patients is based on extrapolations from adult data. However, increased etiologic heterogeneity, poorer prognosis, and increased genetic burden for pediatric-onset PAH calls for a dedicated pediatric research agenda to improve molecular diagnosis and clinical management. A genomics-first approach will improve the understanding of pediatric PAH and how it is related to other rare pediatric genetic disorders.

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References

Zhu N, Pauciulo M, Welch C, Lutz K, Coleman A, Gonzaga-Jauregui C . Novel risk genes and mechanisms implicated by exome sequencing of 2572 individuals with pulmonary arterial hypertension. Genome Med. 2019; 11(1):69. PMC: 6857288. DOI: 10.1186/s13073-019-0685-z. View

Levy M, Eyries M, Szezepanski I, Ladouceur M, Nadaud S, Bonnet D . Genetic analyses in a cohort of children with pulmonary hypertension. Eur Respir J. 2016; 48(4):1118-1126. DOI: 10.1183/13993003.00211-2016. View

Reuter M, Jobling R, Chaturvedi R, Manshaei R, Costain G, Heung T . Haploinsufficiency of vascular endothelial growth factor related signaling genes is associated with tetralogy of Fallot. Genet Med. 2018; 21(4):1001-1007. PMC: 6752294. DOI: 10.1038/s41436-018-0260-9. View

Qi H, Yu L, Zhou X, Wynn J, Zhao H, Guo Y . De novo variants in congenital diaphragmatic hernia identify MYRF as a new syndrome and reveal genetic overlaps with other developmental disorders. PLoS Genet. 2018; 14(12):e1007822. PMC: 6301721. DOI: 10.1371/journal.pgen.1007822. View

Hemnes A, Beck G, Newman J, Abidov A, Aldred M, Barnard J . PVDOMICS: A Multi-Center Study to Improve Understanding of Pulmonary Vascular Disease Through Phenomics. Circ Res. 2017; 121(10):1136-1139. PMC: 5685561. DOI: 10.1161/CIRCRESAHA.117.311737. View

West J, Cogan J, Geraci M, Robinson L, Newman J, Phillips J . Gene expression in BMPR2 mutation carriers with and without evidence of pulmonary arterial hypertension suggests pathways relevant to disease penetrance. BMC Med Genomics. 2008; 1:45. PMC: 2561034. DOI: 10.1186/1755-8794-1-45. View

Nimmakayalu M, Major H, Sheffield V, Solomon D, Smith R, Patil S . Microdeletion of 17q22q23.2 encompassing TBX2 and TBX4 in a patient with congenital microcephaly, thyroid duct cyst, sensorineural hearing loss, and pulmonary hypertension. Am J Med Genet A. 2011; 155A(2):418-23. DOI: 10.1002/ajmg.a.33827. View

Saji T . Update on pediatric pulmonary arterial hypertension. Differences and similarities to adult disease. Circ J. 2013; 77(11):2639-50. DOI: 10.1253/circj.cj-13-1180. View

Allen A, Cossette P, Delanty N, Eichler E, Goldstein D, Han Y . De novo mutations in epileptic encephalopathies. Nature. 2013; 501(7466):217-21. PMC: 3773011. DOI: 10.1038/nature12439. View

10.

Zhu N, Gonzaga-Jauregui C, Welch C, Ma L, Qi H, King A . Exome Sequencing in Children With Pulmonary Arterial Hypertension Demonstrates Differences Compared With Adults. Circ Genom Precis Med. 2018; 11(4):e001887. PMC: 5896781. DOI: 10.1161/CIRCGEN.117.001887. View

11.

Byers H, Dagle J, Klein J, Ryckman K, McDonald E, Murray J . Variations in CRHR1 are associated with persistent pulmonary hypertension of the newborn. Pediatr Res. 2012; 71(2):162-7. PMC: 3718388. DOI: 10.1038/pr.2011.24. View

12.

Lange A, Haitchi H, LeCras T, Sridharan A, Xu Y, Wert S . Sox17 is required for normal pulmonary vascular morphogenesis. Dev Biol. 2014; 387(1):109-20. PMC: 4422074. DOI: 10.1016/j.ydbio.2013.11.018. View

13.

Zhu N, Swietlik E, Welch C, Pauciulo M, Hagen J, Zhou X . Rare variant analysis of 4241 pulmonary arterial hypertension cases from an international consortium implicates FBLN2, PDGFD, and rare de novo variants in PAH. Genome Med. 2021; 13(1):80. PMC: 8112021. DOI: 10.1186/s13073-021-00891-1. View

14.

Rhodes C, Ghataorhe P, Wharton J, Rue-Albrecht K, Hadinnapola C, Watson G . Plasma Metabolomics Implicates Modified Transfer RNAs and Altered Bioenergetics in the Outcomes of Pulmonary Arterial Hypertension. Circulation. 2016; 135(5):460-475. PMC: 5287439. DOI: 10.1161/CIRCULATIONAHA.116.024602. View

15.

Kanai-Azuma M, Kanai Y, Gad J, Tajima Y, Taya C, Kurohmaru M . Depletion of definitive gut endoderm in Sox17-null mutant mice. Development. 2002; 129(10):2367-79. DOI: 10.1242/dev.129.10.2367. View

16.

Del Cerro M, Abman S, Diaz G, Freudenthal A, Freudenthal F, Harikrishnan S . A consensus approach to the classification of pediatric pulmonary hypertensive vascular disease: Report from the PVRI Pediatric Taskforce, Panama 2011. Pulm Circ. 2011; 1(2):286-298. PMC: 3161725. DOI: 10.4103/2045-8932.83456. View

17.

Wei Y, Gong J, Thimmulappa R, Kosmider B, Biswal S, Duh E . Nrf2 acts cell-autonomously in endothelium to regulate tip cell formation and vascular branching. Proc Natl Acad Sci U S A. 2013; 110(41):E3910-8. PMC: 3799376. DOI: 10.1073/pnas.1309276110. View

18.

Harbaum L, Rhodes C, Otero-Nunez P, Wharton J, Wilkins M . The application of 'omics' to pulmonary arterial hypertension. Br J Pharmacol. 2020; 178(1):108-120. DOI: 10.1111/bph.15056. View

19.

Samocha K, Robinson E, Sanders S, Stevens C, Sabo A, McGrath L . A framework for the interpretation of de novo mutation in human disease. Nat Genet. 2014; 46(9):944-50. PMC: 4222185. DOI: 10.1038/ng.3050. View

20.

Tinker A, Uren N, Schofield J . Severe pulmonary hypertension in Ullrich-Noonan syndrome. Br Heart J. 1989; 62(1):74-7. PMC: 1216735. DOI: 10.1136/hrt.62.1.74. View