{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T05:14:19Z","timestamp":1763097259627,"version":"3.45.0"},"reference-count":36,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T00:00:00Z","timestamp":1763078400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p>\n                    Multiple endocrine neoplasia type 1 (MEN-1; OMIM 131100) is a rare, autosomal dominant syndrome caused by heterozygous inactivating mutations in the\n                    <jats:italic>MEN1<\/jats:italic>\n                    tumor suppressor gene (11q13; OMIM 613733). MEN-1 is characterized by polyglandular pathology, which typically involves the parathyroid glands (90%), pancreas (30-80%) and anterior pituitary (15-50%). To date, over 1,600 pathogenic\n                    <jats:italic>MEN1<\/jats:italic>\n                    variants have been documented, including nonsense, frameshift, and splice-site mutations, as well as rare large deletions. While germline mutation detection rates reach 70-90% in clinically diagnosed probands, approximately 10-30% of phenotypically confirmed MEN-1 families test negative by conventional sequencing, suggesting possible regulatory region defects, deep intronic mutations, or mosaic variants. In cases where\n                    <jats:italic>MEN1<\/jats:italic>\n                    germline testing is negative despite a clinical MEN-1 phenotype, somatic mosaicism should be considered. We investigated a familial cohort presenting with primary hyperparathyroidism, multifocal pancreatic and pituitary neuroendocrine neoplasms \u2013 a triad strongly suggestive of MEN-1. Using a multi-tissue sequencing approach, we analyzed DNA extracted from peripheral blood leukocytes and parathyroid adenomas tissue via both Sanger sequencing and next-generation sequencing (NGS) with high coverage. While conventional Sanger analysis failed to detect a mutation, targeted NGS revealed a novel, likely pathogenic\n                    <jats:italic>MEN1<\/jats:italic>\n                    variant present at low allele frequency (5-15%), consistent with postzygotic mosaicism. The variant was classified as pathogenic per ACMG\/AMP guidelines and correlated with disease manifestations in affected tissues. These findings demonstrate that high-coverage NGS of multiple tissues is critical for identifying low-level mosaic\n                    <jats:italic>MEN1<\/jats:italic>\n                    mutations missed by standard testing. Alternative screening methods are required for patients with strong clinical indications of MEN-1 and\/or a family history, but negative germline test results, one such method is NGS with high coverage.\n                  <\/jats:p>","DOI":"10.3389\/fendo.2025.1662871","type":"journal-article","created":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T05:10:26Z","timestamp":1763097026000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Case Report: Novel likely pathogenic MEN1 mosaic mutation in the family with MEN-1 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