{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T09:00:34Z","timestamp":1784883634985,"version":"3.55.0"},"reference-count":42,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T00:00:00Z","timestamp":1784851200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T00:00:00Z","timestamp":1784851200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Glucocorticoid resistance syndrome (GRS) is a rare hereditary disorder caused by pathogenic variants in\n                    <jats:italic>NR3C1<\/jats:italic>\n                    , characterized by marked phenotypic heterogeneity and frequent misdiagnosis as primary aldosteronism or subclinical Cushing's syndrome. We report a family harboring a novel\n                    <jats:italic>NR3C1<\/jats:italic>\n                    frameshift variant and provide an integrated characterization of its clinical and biochemical features. By combining structural prediction, tissue\u2010 and single\u2010cell\u2010level expression analyses, in silico virtual gene perturbation, and systematic literature review, we evaluated the potential functional impact and clinical relevance of this variant. Comprehensive clinical phenotyping, steroid metabolomic profiling, adrenal CT imaging, and segregation analysis were performed in the proband and his father. AlphaFold3 was used to predict the structures of wild\u2010type and mutant GR\u03b1 proteins. Variant pathogenicity was assessed following ACMG\/AMP criteria. Cross\u2010tissue and single\u2010cell expression patterns of\n                    <jats:italic>NR3C1<\/jats:italic>\n                    were analyzed, and in silico virtual knockout analysis was performed to generate exploratory hypotheses regarding potentially affected biological pathways. A systematic review was conducted to summarize previously reported GRS cases, their variants, and associated phenotypes. Two affected males across successive generations presented with refractory hypertension without Cushingoid features. Steroid profiling demonstrated mild hypercortisolemia with elevated ACTH, marked increases in 11\u2010deoxycorticosterone and 11\u2010deoxycortisol, suppressed renin, and low\u2010to\u2010normal aldosterone, consistent with ACTH\u2010driven accumulation of mineralocorticoid precursors. Sequencing identified a novel\n                    <jats:italic>NR3C1<\/jats:italic>\n                    frameshift variant, c.923dupG (p.Ala309Serfs*6), absent from population databases and co\u2010segregating with the familial phenotype. Structural prediction indicated premature termination within the N\u2010terminal transactivation domain, supporting loss of the downstream DNA\u2010binding and ligand\u2010binding domains. According to ACMG\/AMP criteria, the variant was classified as pathogenic. In silico virtual perturbation analysis suggested that\n                    <jats:italic>NR3C1<\/jats:italic>\n                    dysfunction may extend beyond a linear defect in glucocorticoid signaling, potentially influencing neuroendocrine communication, extracellular matrix regulation, protein translation, and developmental pathways. Literature review identified 66 reported GRS cases encompassing substantial phenotypic variability, with cardiovascular events documented in some carriers of N\u2010terminal or truncating variants. We describe a novel exon 2\n                    <jats:italic>NR3C1<\/jats:italic>\n                    frameshift variant that co\u2010segregates with a characteristic GRS hormonal profile and is supported by clinical, genetic, and structural evidence. This case expands the genotype\u2013phenotype spectrum of\n                    <jats:italic>NR3C1<\/jats:italic>\n                    \u2010related GRS. The potential relationship between N\u2010terminal truncating variants and cardiovascular complications remains hypothesis\u2010generating and requires validation in larger cohorts and functional studies. Our findings underscore the importance of considering\n                    <jats:italic>NR3C1<\/jats:italic>\n                    \u2010related GRS in patients presenting with resistant hypertension accompanied by a distinctive steroid profile.\n                  <\/jats:p>","DOI":"10.1002\/ajmg.a.70230","type":"journal-article","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T08:01:22Z","timestamp":1784880082000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Novel\n                    <scp>\n                      <i>NR3C1<\/i>\n                    <\/scp>\n                    Frameshift Variant Associated With Familial Glucocorticoid Resistance Syndrome: An Integrated Analysis of Steroid Profiling and Structural Modeling"],"prefix":"10.1002","author":[{"given":"Sufang","family":"Yun","sequence":"first","affiliation":[{"name":"Department of Endocrinology Affiliated Hospital of Inner Mongolia 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