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With the development of highly specific human aldosterone synthase (CYP11B2) antibodies for immunohistochemistry (IHC), the presence of microscopic subcapsular foci of CYP11B2-postive cells \u2013 now termed aldosterone-producing micronodules (APM) \u2013 has been documented in normal and PA adrenal glands, however, there continues to be debate regarding the role of APM in the pathogenesis of PA. In this study, CYP11B2 IHC-guided targeted next-generation sequencing (NGS) was utilized to characterize the frequency and spectrum of somatic aldosterone-driver mutations in APM identified within adrenal glands from deceased renal donors and patients with primary aldosteronism (PA). 59 subjects were enrolled (31 deceased renal donors and 28 PA patients), 173 APM were collected using CYP11B2-guided IHC (65 APM from 31 deceased renal donors and 108 APM from 28 PA patients), and NGS data was successfully obtained for 131 APM (51 APM from 31 deceased renal donors and 80 APM from 28 PA patients). Importantly, NGS identified aldosterone-driver mutations in a significantly higher proportion of APM from PA patients relative to deceased renal donors (71.3% compared to 45.1%; P-value &lt; 0.05) \u2013 with the vast majority in either group being missense mutations in the L-type calcium channel gene\n                    <jats:italic>CACNA1D<\/jats:italic>\n                    . Interestingly, in PA patients, the presence of APA\/APN harboring\n                    <jats:italic>CACNA1D<\/jats:italic>\n                    or\n                    <jats:italic>ATP1A1<\/jats:italic>\n                    mutations was significantly associated with an increased frequency of APM with\n                    <jats:italic>CACNA1D<\/jats:italic>\n                    mutations, while APM from adrenal glands with KCNJ5 mutation-bearing APA\/APN were more likely to be mutation-negative (\n                    <jats:italic>P<\/jats:italic>\n                    -values &lt; 0.001 and &lt; 0.05, respectively). Finally, clinical outcomes for PA patients were significantly associated with APM genotype, with post-surgical cure showing higher frequencies of\n                    <jats:italic>KCNJ5<\/jats:italic>\n                    -mutant and mutation-negative APM and a lower frequency of\n                    <jats:italic>CACNA1D<\/jats:italic>\n                    -mutant APM. Overall, our data support a link between the acquisition of somatic aldosterone-driver mutations in APM and PA pathogenesis and suggest the possibility of diverse genetic mechanisms underlying APM development in normal and PA adrenal glands. Furthermore, these results suggest that molecular diagnostic testing of CYP11B2-positive adrenal cortical lesions may help risk stratify patients in clinical practice.\n                  <\/jats:p>","DOI":"10.1007\/s12022-026-09912-4","type":"journal-article","created":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T03:26:17Z","timestamp":1773977177000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Increased Frequency and Distinct Genotypic Patterns of Somatic Aldosterone-Driver Mutations in Aldosterone-Producing Micronodules from Primary Aldosteronism Patients"],"prefix":"10.1007","volume":"37","author":[{"given":"Jung Soo","family":"Lim","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun-Yi","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaoping","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia-Jen","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Desmar\u00e9","family":"van Rooyen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dina R.","family":"Sapiro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas J.","family":"Giordano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adina F.","family":"Turcu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William E.","family":"Rainey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron M.","family":"Udager","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,20]]},"reference":[{"issue":"1","key":"9912_CR1","doi-asserted-by":"publisher","first-page":"10","DOI":"10.7326\/M20-0065","volume":"173","author":"JM Brown","year":"2020","unstructured":"Brown JM, Siddiqui M, Calhoun DA, Carey RM, Hopkins PN, Williams GH, et al. 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Giordano is an Editorial Board member of Endocrine Pathology.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Disclosure"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"16"}}