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.