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

Abstract

BackgroundGenetic 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.MethodsSubjects 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.ResultsEight 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.ConclusionsWe 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.

A cluster of heritable pulmonary arterial hypertension cases in a family with all three siblings carrying the same novel AQP1 c.273C>G variant‐a case report

“…1 To date, no more than 30 cases have been reported at 10 additional variant sites in the AQP1 gene (Figure 2). [4][5][6][7] We recently reported a heterozygous missense variant site c.273C>G (p.Ile91-Met) in a young woman with heritable PAH. 7 Her other two younger siblings also wanted genetic tests, which revealed that they all carried the same variant site of AQP1 c.273C>G. Such test results prompted the middle brother, although initially feeling asymptomatic, to seek medical help and eventually confirmed his diagnosis of PAH.…”

“…(a) Location of variants of AQP1 cDNA and related amino acid change detected in subjects with PAH. [4][5][6][7] (b) Representation of the AQP1 protein and the amino acid changes detected in PAH cases. [4][5][6][7] The novel variant (c.273C>G, p.Ile91Met) described in this study was labeled in red font.…”

“…[4][5][6][7] (b) Representation of the AQP1 protein and the amino acid changes detected in PAH cases. [4][5][6][7] The novel variant (c.273C>G, p.Ile91Met) described in this study was labeled in red font. The variants were annotated with NM_198098.3.…”

“…Her symptoms were well controlled at functional class II. In 2021, she joined a clinical study 7 and received a genetic test (whole exome sequencing), confirming the presence of a new missense variant of AQP1 c.273C>G (p.Ile91Met) (Table 1). 7 She had two other siblings in the family, the youngest brother being the proband of PAH and the middle brother claiming to be asymptomatic for PAH without diagnosis (Figure 1).…”

“…In 2021, she joined a clinical study 7 and received a genetic test (whole exome sequencing), confirming the presence of a new missense variant of AQP1 c.273C>G (p.Ile91Met) (Table 1). 7 She had two other siblings in the family, the youngest brother being the proband of PAH and the middle brother claiming to be asymptomatic for PAH without diagnosis (Figure 1). The youngest brother was diagnosed with PAH at 31 years of age, at another medical center in northern Taiwan (Figure 1).…”