Multilevel annotation of germline <em>MEN1</em> variants of synonymous, nonsynonymous, and uncertain significance in indian patients with sporadic primary hyperparathyroidism

Kaur, Gurjeet<sup>1</sup>; Bhadada, Sanjay Kumar<sup>1</sup>; Santra, Mithun<sup>1</sup>; Pal, Rimesh<sup>1</sup>; Sarma, Phulen<sup>2</sup>; Sachdeva, Naresh<sup>1</sup>; Dhiman, Vandana<sup>1</sup>; Dahiya, Divya<sup>3</sup>; Saikia, Uma Nahar<sup>4</sup>; Chakraborty, Anuradha<sup>5</sup>; Sood, Ashwani<sup>6</sup>; Prakash, Mahesh<sup>7</sup>; Behera, Arunanshu<sup>3</sup>; Rao, Sudhaker D.<sup>8</sup>

Affiliations

¹Department of Endocrinology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India

²Department of Pharmacology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India

³Department of General Surgery, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India

⁴Department of Histopathology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India

⁵Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India

⁶Department of Nuclear Medicine, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India

⁷Department of Radiodiagnosis, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India

⁸Bone and Mineral Research Laboratory, Henry Ford Hospital, Detroit, MI, USA

Abstract and keywords

Primary hyperparathyroidism (PHPT) is third most common endocrine disorder characterized by hypercalcemia with elevated or nonsuppressed parathyroid hormone levels by parathyroid tumors. Familial PHPT, as part of multiple endocrine type-1, occurs due to the germline mutation in the MEN1 gene. The involvement and the role of germline MEN1 variations in sporadic PHPT of Indian PHPT patients are unknown. Precise classifications of different types of MEN1 variations are fundamental for determining clinical relevance and diagnostic role. This prospective cohort study was performed on 82 patients with PHPT (with no clinical or history of MEN1) who underwent screening for MEN1 variations through Sanger sequencing. Multilevel computational analysis was performed to determine the structure–function relationship of synonymous, nonsynonymous, and variants of uncertain significance (VUS). Of the 82 PHPT patients, 42 (51%) had 26 germline MEN1 variants, including eight nonsynonymous, seven synonymous, nine VUS, one splice site, and one regulatory variation. Five most common germline variations (c.1838A>G, c.1817C>T, c.1525C>A, c.-35A>T, and c.250T>C) were observed in this study. c.-35A>T (5′ untranslated region [UTR]) was associated with recurrence of PHPT (odds ratio [OR] = 5.4; p = 0.04) and subsequent detection of other endocrine tumors (OR = 13.6, p = 0.035). c.1525C>A was associated with multi glandular parathyroid tumor (OR = 13.6, p = 0.035). Align–Grantham variation and Grantham deviation (Align-GVGD), functional analysis through hidden Markov MODEL (FATHMM), and MutationTaster analysis reported the disease-specific potential of VUS and synonymous variations. Significant linkage disequilibrium was observed in c.1785G>A and c.1817C>T (r² = 0.3859, p = 0.0001), c.1475C>G and c.1525C>A (r² = 0.385, p = 0.0004), and c.1569T>C and c.1838A>G (r² = 0.488, p = 0.0001). The detection of MEN1 variations, especially those with disease-specific potential, can prompt early screening for other MEN1-related tumors and disease recurrence.

Keywords: HYPERCALCEMIA; MULTIPLE ENDOCRINE NEOPLASIA TYPE 1 (MEN 1); PARATHYROIDECTOMY; PARATHYROID CARCINOMA; NEOPLASM; PARATHYROID GLAND; PRIMARY HYPERPARATHYROIDISM (PHPT); VARIANTS OF UNCERTAIN SIGNIFICANCE (VUS)

Links

DOI: 10.1002/jbmr.4653

PubMed: 35856247

WoS: 000851548200001

History

Received: 2022-02-01

Revised: 2022-07-12

Accepted: 2022-07-16

Cited Works (1)

Year

Entry

2015

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the american college of medical genetics and genomics and the association for molecular pathology. Genet Med. May 2015;17(5):405-424.