Genetic Analysis of Patients with Chronic Thromboembolic Pulmonary Hypertension (CTEPH): A Single-Center Observational Study

<b>Background/Objectives</b>: Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare disease, in which multiple genetic and environmental factors may contribute. This study aimed to identify potential genetic determinants in patients with CTEPH and to compare their occurrence to a control group, which included patients with pulmonary embolism who had not developed CTEPH. <b>Methods</b>: Tier 1 and 2 genes related to coagulation, fibrinolysis and platelet disorders-as recommended by the International Society on Thrombosis and Haemostasis-and genes associated with vascular conditions were analyzed in n = 15 patients with CTEPH and n = 17 controls using next-generation sequencing. Non-synonymous, rare variants were collected and interpreted. <b>Results</b>: As expected, no single gene or variant was consistently present among CTEPH patients. Instead, individuals carried different mutations and combinations of variants. We identified several variants that were not found in the control group. Candidate variants were detected in <i>F12</i>, <i>F13A1</i>, <i>F13B</i>, <i>F5</i>, <i>KNG1</i>, <i>SERPIND1</i>, <i>THBD</i>, <i>ADAMTS13</i>, <i>VWF</i>, <i>STIM1</i>, <i>ETV6</i>, <i>THPO</i>, <i>MPL</i>, <i>SERPINA1</i>, <i>ENG</i>, <i>RASA1</i>, <i>ACVRL1</i>, <i>GDF2</i>, <i>NFE2</i>, <i>SOX17</i> and <i>RNF213.</i> We did not detect exclusive variants in <i>FGA</i>, <i>CPB2</i>, and <i>BMPR2</i> although they were suggested as candidates in previous studies. Elevated factor VIII and von Willebrand factor in CTEPH could not be explained by mutations in <i>VWF</i> and <i>F8</i>. <b>Conclusions</b>: Our study supports the hypothesis of heterogeneous genetic background in CTEPH, involving multiple pathways such as coagulation, altered fibrinolysis and impaired angiogenesis. These results provide a basis for more detailed investigations into specific genes and variants potentially associated with CTEPH in larger cohorts.