Whole Exome Sequencing of Patients With Heritable and Idiopathic Pulmonary Arterial Hypertension in Central Taiwan

Kae-Woei Liang; Sheng-Kai Chang; Yu-Wei Chen; Wei-Wen Lin; Wan-Jane Tsai; Kuo-Yang Wang

doi:10.3389/fcvm.2022.911649

Whole Exome Sequencing of Patients With Heritable and Idiopathic Pulmonary Arterial Hypertension in Central Taiwan

Front Cardiovasc Med. 2022 Jun 22:9:911649. doi: 10.3389/fcvm.2022.911649. eCollection 2022.

Authors

Kae-Woei Liang^{1

2

3}, Sheng-Kai Chang⁴, Yu-Wei Chen^{1

2

3}, Wei-Wen Lin^{1

5}, Wan-Jane Tsai⁶, Kuo-Yang Wang⁶

Affiliations

¹ Cardiovascular Center, Taichung Veterans General Hospital, Taichung, Taiwan.
² Institute of Clinical Medicine and Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
³ School of Medicine and School of Life Science, National Chung Hsing University, Taichung, Taiwan.
⁴ Excelsior Biopharma Inc., Taipei, Taiwan.
⁵ Department of Life Science, Tunghai University, Taichung, Taiwan.
⁶ Center for Pulmonary Arterial Hypertension and Pulmonary Vascular Disease, China Medical University Hospital, Taichung, Taiwan.

Abstract

Background: Genetic variants could be identified in subjects with idiopathic and heritable pulmonary arterial hypertension (PAH). The 6th World Symposium on Pulmonary Hypertension (WSPH) provided a list of genes with evidence of association with PAH. However, reports using whole exome sequencing (WES) from southeastern Asian PAH cohorts were scarce.

Methods: Subjects with idiopathic and heritable PAH (N = 45) from two medical centers in central Taiwan were screened for PAH related gene variants. The genomic DNA was prepared from peripheral blood lymphocytes. We performed WES for all patients enrolled in this study. All identified gene variants were validated by polymerase-chain reaction and Sanger sequencing. The clinical and hemodynamic data were compared between bone morphogenetic protein receptor type-2 (BMPR2) gene variants carriers vs. non-carriers.

Results: Eight patients (8/45 = 17.8%) was identified carrying BMPR2 gene variants and 8 patients (8/45 = 17.8%) had other WSPH-listed PAH-related gene variants (1 with ACVRL1, 1 with ENG, 1 with SMAD9, 1 with SMAD1, 1 with ATP13A3 and 3 with AQP1). In addition, a total of 14 non-WSPH-listed PAH-related genetic variant sites (ABCC8, NOTCH1, NOTCH2, NOTCH3, JAG1, BMP10, GGCX, FBLN2, ABCA3 and PTGIS) were found in this PAH cohort. Subjects carrying BMPR2 gene variant (N = 8) were younger at diagnosis of PAH (30 ± 11 vs 49 ± 13 years, p = 0.001) than the non-carrier group (N = 37). BMPR2 variant carriers had a trend toward having higher mean pulmonary arterial pressure (PAP) (61 ± 19 vs. 51 ± 13 mmHg, p = 0.076) than the non-carriers upon initial diagnosis. Pulmonary vascular resistance, right atrial pressure, cardiac output, as well as functional class were similar between BMPR2 variant carriers and non-carriers at initial diagnosis.

Conclusions: We identified 17.8% of patients with BMPR2 gene variants and 17.8% subjects with other 6th WSPH-listed PAH-related gene variants in a Taiwanese idiopathic and heritable PAH cohort. PAH patients carrying BMPR2 variants presented at a younger age with a trend toward having higher mean PAP at initial diagnosis.

Keywords: activin receptor-like kinase 1 (ACVRL1); aquaporin 1 (AQP1); bone morphogenetic protein receptor type-2 (BMPR2); gene variants; pulmonary arterial hypertension (PAH); whole exome sequencing (WES).