Observational Study
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Diabetes. Nov 15, 2021; 12(11): 1957-1966
Published online Nov 15, 2021. doi: 10.4239/wjd.v12.i11.1957
Comprehensive genetic screening reveals wide spectrum of genetic variants in monogenic forms of diabetes among Pakistani population
Ibrar Rafique, Asif Mir, Shajee Siddiqui, Muhammad Arif Nadeem Saqib, Asher Fawwad, Luc Marchand, Muhammad Adnan, Muhammad Naeem, Abdul Basit, Constantin Polychronakos
Ibrar Rafique, Asif Mir, Department of Biological Sciences, International Islamic University, Islamabad 44000, Pakistan
Ibrar Rafique, Luc Marchand, Constantin Polychronakos, Departments of Pediatrics and Human Genetics, McGill University Health Centre Research Institute, Montreal H4A 3J1, Canada
Ibrar Rafique, Research Development and Coordination, Pakistan Health Research Council, Islamabad 44000, Pakistan
Shajee Siddiqui, Department of Medicine, Pakistan Institute of Medical Sciences, Islamabad 44000, Pakistan, Pakistan
Muhammad Arif Nadeem Saqib, Department of Medical Laboratory Technology, National Skills University, Islamabad, 44000, Pakistan
Asher Fawwad, Department of Biochemistry, Baqai Institute of Diabetology and Endocrinology, Baqai Medical University, Karachi 74600, Sindh, Pakistan
Muhammad Adnan, PHRC Research Centre, FJMU, Pakistan Health Research Council, Lahore 54000, Pakistan
Muhammad Naeem, Department of Biotechnology, Quaid-I-Azam University, Islamabad 44000, Pakistan
Abdul Basit, Department of Medicine, Baqai Institute of Diabetology and Endocrinology, Baqai Medical University, Karachi 74600, Sindh, Pakistan
Author contributions: Rafique I, Mir A, Saqib MAN, and Naeem M designed the research study; Siddiqui S, Fawwad A, Adnan M, and Basit A conducted and supervised the data collection; Marchand L analyzed the data. Polychronakos C supervised the exome analysis, revised the draft, and added intellectual content to the study; All authors critically reviewed and approved the final manuscript as submitted.
Supported by Canadian Institutes of Health Research, No. PJT-159715.
Institutional review board statement: The study was approved by the Institutional Bioethics Committee of Pakistan Health Research Council (4-87-1/16/IBC/RDC/3231) and Ethical Review Board of Pakistan Institute of Medical Sciences (1-1/2015/ERB/SZABMU).
Informed consent statement: All study participants or their legal guardian provided consent for participation in this study
Conflict-of-interest statement: The authors declare conflict of interest as none.
Data sharing statement: No additional data are available.
STROBE statement: The authors have read the STROBE statement – checklist of items, and the manuscript was prepared and revised according to the STROBE statement – checklist of items.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Constantin Polychronakos, MD, Professor, Departments of Pediatrics and Human Genetics, McGill University Health Centre Research Institute, 1001 Decarie Boulevard, Montreal H4A 3J1, Canada. constantin.polychronakos@mcgill.ca
Received: May 18, 2021
Peer-review started: May 18, 2021
First decision: July 4, 2021
Revised: July 14, 2021
Accepted: October 27, 2021
Article in press: October 27, 2021
Published online: November 15, 2021
Processing time: 180 Days and 22.8 Hours
Abstract
BACKGROUND

Monogenic forms of diabetes (MFD) are single gene disorders. Their diagnosis is challenging, and symptoms overlap with type 1 and type 2 diabetes.

AIM

To identify the genetic variants responsible for MFD in the Pakistani population and their frequencies.

METHODS

A total of 184 patients suspected of having MFD were enrolled. The inclusion criterion was diabetes with onset below 25 years of age. Brief demographic and clinical information were taken from the participants. The maturity-onset diabetes of the young (MODY) probability score was calculated, and glutamate decarboxylase ELISA was performed. Antibody negative patients and features resembling MODY were selected (n = 28) for exome sequencing to identify the pathogenic variants.

RESULTS

A total of eight missense novel or very low-frequency variants were identified in 7 patients. Three variants were found in genes for MODY, i.e. HNF1A (c.169C>A, p.Leu57Met), KLF11 (c.401G>C, p.Gly134Ala), and HNF1B (c.1058C>T, p.Ser353Leu). Five variants were found in genes other than the 14 known MODY genes, i.e. RFX6 (c.919G>A, p.Glu307Lys), WFS1 (c.478G>A, p.Glu160Lys) and WFS1 (c.517G>A, p.Glu173Lys), RFX6 (c.1212T>A, p.His404Gln) and ZBTB20 (c.1049G>A, p.Arg350His).

CONCLUSION

The study showed wide spectrum of genetic variants potentially causing MFD in the Pakistani population. The MODY genes prevalent in European population (GCK, HNF1A, and HNF4a) were not found to be common in our population. Identification of novel variants will further help to understand the role of different genes causing the pathogenicity in MODY patient and their proper management and diagnosis.

Keywords: MODY; Diabetes; Genetics; Monogenic diabetes; Monogenic forms of diabetes

Core Tip: There was a lack of data on monogenic forms of diabetes (MFD) from Pakistan, therefore this study was designed to determine the genetic variants responsible for MFD in the country. The study identified wide spectrum of genetic variants potentially causing MFD. The identification of novel variants paved the way for better understanding of genetic landscape and risk factors of MFD in the country.