Targeted Next-Generation Sequencing of MEN 1, RET, CDC 73, and CDKNIB Genes in Familial Primary Hyperparathyroidism: A Study from Northern India.

Introduction: Limited data exist on the genetic profile of Familial primary hyperparathyroidism (FPHPT) in the Indian population. This study was conducted to determine the prevalence of targeted gene mutations in high-risk patients with PHPT. Methods: This prospective cross-sectional study was conducted in the Department of Endocrinology at our University Hospital from February 2021 to February 2023, in which 103 patients diagnosed with PHPT were taken. A customised gene panel (MEN1, RET, CDKNIB, and CDC73) using next-generation sequencing (NGS) was performed in 39 patients with a strong suspicion of FPHPT based on age <35 years, family history of PHPT, multiglandular disease, hyperparathyroidism jaw tumour, cystic parathyroid adenoma (PA), parathyroid carcinoma (PC) and suspicion of MEN 1/2A/4 syndrome. Results: Germline variants were observed in 11/39 (28.2%). MEN1 mutations were found in 7 patients (17.9%) and CDC73 mutations in 4 (10.2%). MENI mutations included c. 1351-2A>G, c. 249_252del (p.Ile85fs), c. 1763C>T(p.S588L) and c. 415C>T(p.H139Y). Clinical features in MEN1-positive patients included microprolactinomas (n = 2), multiglandular disease (n = 5), recurrent PHPT (n = 1), persistent PHPT (n = 1), and gastric neuroendocrine tumour (n = 1). Among CDC73 mutation patients, 2 (50%) had familial PHPT, 2 (50%) had hyperparathyroidism jaw tumour syndrome (one had multiple bilateral renal cysts and one had multiple uterine leiomyomas); however, none had either ossifying fibroma of the jaw. Identified CDC73 mutations included c. 664C>T(p.R222X), c. 415C>T(p.R139X), c. 687_688dellAG(p.Arg229Serfs37), and c76delA(p.Ile26SerfsX11). The mutations were statistically associated with age, higher serum calcium levels, elevated ALP, and greater skeletal involvement. Conclusion: For optimal management, PHPT patients with high-risk features should be subjected to customised genetic testing in resource-limited settings.