SAT-770 Pathogenic Variant Analysis of ZFX in Sporadic Parathyroid Adenomas

Abstract Disclosure: S. Halili: None. L. Iommazzo: None. C. Burke: None. J. Bellizzi: None. J. Costa-Guda: None. A. Arnold: None. Primary hyperparathyroidism (PHPT) is a common disorder defined by PTH oversecretion and calcium dysregulation. Most cases are caused by parathyroid adenomas, with smaller proportions attributed to multigland hyperplasia and carcinoma. In addition to established genetic drivers like CCND1, MEN1, and CDC73, several candidate genes have been implicated in parathyroid adenoma development. Of particular interest is ZFX, which encodes a conserved zinc-finger transcription factor known to play a role in tumor development and stem cell renewal. We first linked ZFX to PHPT when specific, recurring somatic missense variants in adjacent arginine residues in critical zinc finger domain 13 (codons 786 and 787) were identified in a subset of parathyroid adenomas. Recently, germline missense ZFX variants (in zinc finger domains 12 and 13) were identified in 11 probands with an X-linked neurodevelopmental disorder, and 3 of the 7 probands for whom data were available had PHPT. Several neurodevelopmentally unaffected female carriers of these variants also had PHPT requiring parathyroidectomy. Additionally, a separate case report described a female patient with learning disability and a parathyroid adenoma, who carried a similar heterozygous germline ZFX variant R764W. These strong links between PHPT and missense variants within the crucial DNA-binding region of ZFX carry potentially important clinical and mechanistic implications. To further investigate the role of ZFX variants in causing or contributing to PHPT, we performed Sanger sequencing of zinc finger domains 12 and 13 of ZFX in 231 sporadic parathyroid adenoma DNA samples. Three variants, one in each of three tumors, were identified and interestingly, each was represented in the highly restricted set of codons previously implicated. One male-derived adenoma had the R787T variant, with indeterminate germline/somatic status. One female-derived adenoma was heterozygous for R764W and was somatic, in contrast to its previously reported role as a germline variant. Further, the identical heterozygous R764W was identified in an additional female-derived sample (germline/somatic status currently not determined). These findings suggest that domain 12/13 ZFX missense variants are relatively rare in otherwise typically presenting sporadic parathyroid adenomas. Our results also reinforce the emerging concept in parathyroid neoplasia that these exquisitely specific variants appear to be strongly pathogenic when present, whether as germline predisposition alleles or as somatically mutated tumor drivers, and their downstream mechanistic consequences in parathyroid cells merit investigation. Presentation: Saturday, July 12, 2025