Rare germline variants in canonical and candidate genes in apparently sporadic bilateral primary aldosteronism

The germline genetic basis of bilateral primary aldosteronism (PA) remains poorly understood, particularly in apparently sporadic disease. We investigated rare germline variants in canonical and candidate genes in patients with bilateral PA associated with resistant hypertension and/or hypertension diagnosed before 40 years of age.

We studied 53 individuals with bilateral PA after exclusion of familial PA types 1 and 3. Whole-exome sequencing was performed in 52 probands and 1 affected relative. Variant prioritization was restricted to genes with direct or indirect evidence linking them to PA using a virtual panel approach. Clinical, biochemical, and imaging data were compared between carriers and noncarriers.

Nine of 53 patients (17%) harbored at least one rare germline candidate variant. Variants in canonical PA genes were identified in 5 patients (9.6%), including CACNA1H (n = 4) and CACNA1D (n = 1). In 4 patients (7.5%), rare variants were identified in plausible candidate genes (ANO1, KCNK3, CASZ1, and STRN). All prioritized variants were classified as variants of uncertain significance. Compared with noncarriers, carriers showed a lower frequency of hypokalemia (P < .0001), higher prevalence of family history of hypertension (P < .0001), higher frequency of resistant hypertension (P < .0001), required more antihypertensives (P = .0264), and had more frequent adrenal computed tomography abnormalities, particularly bilateral involvement (P < .0001).

Rare germline variants in canonical and candidate genes were identified in a subset of patients with apparently sporadic bilateral PA. Variants in established genes, particularly CACNA1H, were relatively frequent, with additional variants in biologically plausible candidates.