Role of ZFX variants in parathyroid tumorigenesis

Somatic alterations in ZFX , a conserved zinc-finger transcription factor involved in stem cell maintenance and proliferation, have been reported across various malignancies including endometrioid carcinoma, melanoma, acute lymphoblastic leukemia, and diffuse large B cell lymphoma. Emerging evidence also links ZFX variants in zinc finger domains 12 and 13 to parathyroid tumorigenesis. Parathyroid gland tumors cause dysregulated calcium homeostasis and increased risk for bone fractures and kidney stones. While most people with parathyroid tumors have only one single gland affected (~85%), the remaining 15% have multigland disease (MGD). This condition, previously known as parathyroid hyperplasia, has distinct clinical implications including higher rates of recurrence and association with genetic syndromes, such as multiple endocrine neoplasia type 1, that may entail risk for family members. A few studies have reported germline variants in ZFX associated with MGD; however, the contribution of ZFX variants in MGD remains poorly understood.To assess the contribution of ZFX variants in MGD, we screened parathyroid tumor DNA from 26 patients with MGD for variants in zinc finger domains 12 and 13. We identified the variant p.Arg764Trp in one sample and confirmed it to be germline. This variant has been previously reported as both germline and somatic in parathyroid adenomas and as a somatic variant in other malignancies, but has not been reported in MGD. We subsequently screened germline DNA from an additional cohort of 47 patients with MGD and found no variants in the coding sequence of zinc finger domains 12 and 13. The finding of the p.Arg764Trp variant in this cohort further supports the contribution of ZFX variants to MGD. The mechanisms by which such variants predispose affected patients for MGD as opposed to solitary parathyroid tumors merit further investigation. Additionally, while we were unable to access family history in the patient with the p.Arg764Trp variant, a previously reported three-generation family with a different ZFX variant (p.Tyr774Cys) included four females diagnosed with hyperparathyroidism, with one proband having MGD. This familial pattern raises important considerations for genetic testing and counseling of family members of patients with ZFX variants.