SUN-239 Molecular Investigation of Primary Aldosteronism: Exploring Genetic Heterogeneity in Understudied Populations.

Abstract Disclosure: L.K. Maeda: None. M. De Castro: None. S.R. Rauber Antonini: None. A.C. Moreira: None. F.L. Fernandes Rosa: None. L.M. Mermejo: None. Introduction: Primary Hyperaldosteronism (PA), characterized by elevated plasma aldosterone and suppressed plasma renin, has been one of the most common causes of secondary hypertension. Several genetic abnormalities in ion channels that regulate the depolarization potential of glomerular cell plasma membranes and, consequently, aldosterone secretion, have been identified in aldosterone-producing adenoma (APA). Objective: To evaluate somatic mutations in the KCNJ5, CACNA1D, CLCN2, ATP1A1, ATP2B3, GNAQ, GNA11 and CTNNB1 genes in patients with APA and assessed the genotype-phenotype correlation, including patient clinical outcome after adrenalectomy. Patients and Methods: Our cohort consisted of 32 patients with APA. Clinical and laboratory data were collected from the medical records of patients. Tumor samples were collected during surgery and microdissected to isolate tumoral tissue for molecular studies. The amplified products were automated sequenced. Results: Pathogenic variants (PV) were found in 43.6% (14/32) of the patients. The most frequent PV were found in KCNJ5, with a prevalence of 31.2% (10/32 patients): p.L168R (15.6%), p.G151R (9.3%), Glu145Gln (3.2%) and a novel PV, the p.Tyr152_Arg155del (3.2%). Two PV were identified in CLCN2 gene (6.25%): p.Pro48Arg (3.2%) and p.Ala195Thr (3.2%). In the APA of the later patient, the p.Glu145Gln in the KCNJ5 gene was also found. In the ATP1A1 gene, the p.Leu104Arg PV (3.2%) and in the ATP2B3 gene the p.Leu425_Val426del PV (3.2%) were found. No PVs were found in the genes CACNA1D, GNAQ, GNA11, and CTNNB1. Patients with KCNJ5 PVs were mainly females (90% vs. 45.5%; p=0.01), with an early age of the PA diagnosis (38 vs 54 years; p=0.04), and had lower prevalence of electrocardiogram abnormalities (20% vs. 59%; p=0.04), with no differences in the other clinical and biochemical parameters. The same finding was observed in the group of patients with PVs in any of the studied genes. PASO score showed that 37.5% of the patients met clinical and laboratory cure criteria, 12.5% partial improvement in both aspects, while 50% showed complete laboratory marker remission but still had some clinical symptoms. Patients carrying PVs in genes related-APA pathogenesis presented higher rate of complete clinical and laboratory cure (66.7% vs 33.3%, p = 0.05). Conclusion: Our findings reveal PVs in genes responsible for intracellular ionic homeostasis and cellular membrane potential, particularly in KCNJ5. Additionally, we identified novel PVs in genes related-APA pathogenesis specific to the Brazilian population. The study also confirms an association with the presence of PVs and female patients and earlier onset of hypertension. Presentation: Sunday, July 13, 2025