FRI157 Systematic Germline Genetic Analysis In A Cohort Of Adults With Primary Aldosteronism And Hypertension Onset ≤35 yo : Low Yield Of Genetic Pathogenic Variants
Authors: Parisien-La Salle Stefanie , Nadine Dumas , El-Haffaf Zaki , Lacroix André , Bourdeau Isabelle 
Published: October 2023

Disclosure: S. Parisien-La Salle: None. D. Nadine: None. Z. El-Haffaf: None. A. Lacroix: None. I. Bourdeau: None.

Introduction: Primary aldosteronism (PA) is a common but underdiagnosed cause of hypertension. Although most cases are sporadic, up to 5% of patients have a familial form of PA. Current guidelines recommend germline genetic analysis in patients who present PA &lt; 20 yo or have a family history of PA. As PA is underdiagnosed, we hypothesized that some patients with PA do not undergo germline genetic screening since familial history of PA is unrecognized. Objective: To evaluate the yield of systematic germline genetic analysis for familial PA in patients with PA, hypertension detection ≤ 35 yo and a family history of hypertension. Methods: From 2012-2022, patients diagnosed with PA (positive ARR and confirmatory testing), hypertension onset ≤ 35 yo and a family history of hypertension were offered genetic counselling for germline screening for known familial causes of PA. After informed consent, patients underwent germline analysis for the chimeric gene CYP11B2/CYP11B1 (Ruhr University Bochum, Germany) and a multigene panel including KCNJ5, CACNA1D, CACNA1H and CLCN2 genes (Fulgent, CA). Results: Twenty-five patients consented for genetic analysis. Thirteen patients (52%) were female. In regards to ethnic origin, 52% were French Canadians, 24% African-Americans and the other 24% was split between Asian, European and Middle Eastern descent. The mean age at diagnosis of hypertension was 28.3 yo and 39.7 yo at PA diagnosis. At PA diagnosis, 91.3% (21/23) had previous hypokalemia and 12% (3/25) a cortisol co-secretion (1 mg dexamethasone test&gt; 50 nmol/L). Approximately 13% were on one hypertension drug, 30% on two, 26% on three, 26% on four and 5% were on five medications. Comobordities included: 8% atrial fibrillation, 20% obstructive sleep apnea and 4% coronary heart disease. All patients had a family history of hypertension, 5 patients (20%) had a family history of stroke, and 1 patient (4%) had a family history of PA. Of the patients who had already undergone adrenal vein sampling (n=22), 68.2% (15/22) underwent an adrenalectomy for lateralised aldosterone secretion and 31.8% (7/22) were treated with medical therapy for bilateral disease. None of the 24 patients who underwent testing for glucocorticoid-remediable aldosteronism were found to have the chimeric gene CYP11B2/CYP11B1. Twenty-three patients underwent the multigene panel and no pathogenic variants were identified. However, 4/23 (17,4%) patients carried a variant of unknown significance (VUS) in CACNA1H or CLCN2 genes (CACNA1H c.1315C&gt;T(p.Arg439Cys),CACNA1H c.3868G&gt;A(p.Val1290Ile),CACNA1H c.1939G&gt;A (p.Gly647Ser), CLCN2 c.2402C&gt;T, (p.Thr801Ile)). Conclusion: Systematic germline genetic testing for familial PA in this cohort of patients with PA, hypertension diagnosis ≤ 35 yo and a family history of hypertension did not yield positive results. Although PA is an underdiagnosed disease, familial forms remain very rare.

Presentation: Friday, June 16, 2023