Investigating the contribution of rare variants in monogenic diabetes genes to early onset type 2 diabetes in the Maltese population

Abstract

Diabetes Mellitus (DM) along with some of its clinical characteristics have been vastly researched and identified to have a highly heterogenic genetic aetiology. This thus results in high genotypic and phenotypic variability, hence atypical forms of DM tend to be misdiagnosed, particularly monogenic subtypes of diabetes being misdiagnosed more commonly as Type 2 DM. Misdiagnosis could consequently lead to these patients not being given the optimal treatment, resulting in a decline of quality of life. The misdiagnosis of DM may be solved through means of genetic testing whereby scientists have continuously attempted at identifying variants contributing towards the pathophysiology of DM. Previously, genomic studies on single targeted genes were performed via Sanger sequencing, which has nowadays been replaced by the next generation sequencing (NGS) which enables the sequencing of multiple genes at one time. In this study 293 selected probands presenting with early-onset atypical diabetes were investigated. 'A panel of 18 genes implicated in monogenic diabetes or monogenic forms of the metabolic syndrome were analysed using low-pass whole exome sequencing. Filtering and prioritisation strategies were implemented to identify variants which might have clinical significance whilst also being scored in accordance with the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) classification guidelines. Twelve variants of interest were identified: one being Likely Pathogenic and eleven being Variants of Uncertain Significance (VUS) according to ACMG/AMP criteria. This work demonstrates that approximately 5% of Maltese adults with a diagnosis of early-onset type 2 diabetes , defined by age of onset before 45 years carry deleterious variation in monogenic diabetes genes. It also reinforces the etiological overlap between monogenic and polygenic forms of the disease.