Whole exome sequencing for investigation of novel genetic causes of primary aldosteronism caused by bilateral adrenal hyperplasia

• Grant number: 25/06660-0
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: August 01, 2025
• End date: April 30, 2026
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Madson Queiroz Almeida
• Grantee: Débora Kristina Alves Fernandes
• Host Institution: Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
• Associated research grant: 19/15873-6 - Investigation of new genetic, clinical and pathological aspects of endocrine arterial hypertension, AP.TEM

Abstract

Primary aldosteronism (PA) is the most common form of endocrine arterial hypertension with an estimated prevalence of approximately 4% in hypertensives treated in primary care services and 10% among those referenced to tertiary hospitals. The most frequent causes of PA are bilateral adrenal hyperplasia (BH) and aldosteronomas. In the past few years considerable advances have been made towards in elucidating the pathogenesis of primary aldosteronism (PA). Somatic pathogenic variants in KCNJ5, CACNA1D, ATP1A1, ATP2B3 and CTNNB1 genes were identified in aldosteronomas. Among familial PA, germlines defects in KCNJ5, CACNA1D, CACNA1H and CLCN2 were identified in early onset PA patients. Despite the advances made towards the better understanding of PA pathogenesis, genetic factors involved in PA caused by BH remain poorly elucidated in most cases. Recently, we performed whole exome sequencing in 11 patients with PA caused by BH. Rare germline variants in the phosphodiesterase 2A (PDE2A) e 3B (PDE3B) genes were identified in 3 out of 11 of them. In addition, PDE2A was a marker of zona glomerulosa and aldosterone-producing hyperplastic areas. In vitro functional studies supported the involvement of PDE2A and PDE3B in the pathogenesis of PA caused by BH. The aim of this project is to investigate novel genetic causes of PA caused by BH. The specific aims are: 1) To perform whole exome sequencing (germline DNA) of an expanded cohort of 30 patients with PA caused by BH without pathogenic variants in genes previously associated with this phenotype; 2) To correlate genetic findings with clinical and follow-up data; 3) To perform in vitro functional studies to evaluate the pathogenicity of rare germline variants in new candidate genes.