Abstract Background Pulmonary hypertension (PH) is characterized by increased blood pressure in the pulmonary arteries, resulting in damage to the right heart. A rare form of PH, known as chronic thromboembolic PH (CTEPH), is caused by persistent obstructive thrombi, and its genetic origins remain uncertain. Purpose This study aimed to investigate genetic variations in ion channel-encoding genes among patients diagnosed with chronic thromboembolic pulmonary hypertension (CTEPH). Methods DNA samples were isolated from peripheral blood obtained from 15 CTEPH patients, all of whom had a history of pulmonary embolism. Whole exome sequencing (WES) was conducted on the Illumina NovaSeqX platform using the SureSelect V6 kit. A total of 57 genes encoding sodium, potassium, calcium, and chloride ion channels were analyzed for genetic variations. Only exonic and splicing region variants were included, while intronic and intergenic variants were excluded. Rare variants (population frequency 1%) and variants with unknown population frequency were considered. Pathogenicity was assessed according to the REVEL score, which combines scores from 13 pathogenicity prediction tools. Results In 11 CTEPH patients, 19 distinct genetic variants were identified across 15 genes, including CACNA1A, CACNA1B, CACNA1E, GABRB1, GRIN2D, KCNA5, KCND3, KCNE3, RYR1, RYR2, SCN10A, SCN4B, SCN8A, SCN9A, and SCNN1B. Among these, 17 variants were missense, 2 variants were found in the splice region, and no nonsense or frameshift variants were detected. Two missense variants were classified as likely pathogenic in ClinVar database, while the others were categorized as variants of uncertain significance (VUS). Three VUS variants presented REVEL scores exceeding 0.6 and were deemed possibly pathogenic. The two splice region variants were predicted to potentially affect transcript splicing according to SpliceAI. Conclusion This study identified rare genetic variants in ion channel-encoding genes in CTEPH patients. These findings indicate that ion channel dysfunction may contribute to the genetic susceptibility of CTEPH. Ion channels are known to play crucial roles in vascular tone, platelet activation, cardiac rhythm, and coagulation processes, which may connect them to embolic risk and the development of CTEPH. Additional functional studies are necessary to elucidate the potential pathogenic roles of these variants in the development of CTEPH.
Ekici et al. (Sat,) studied this question.