Genetic characterization of selected probands with atypical/ multigenerational non autoimmune diabetes

Abstract

The genetic aetiology of diabetes mellitus (DM) and morbid obesity is heterogenous, thus exhibit differences in disease severity. Due to this genotypic and phenotypic variation, atypical forms of DM can be misdiagnosed as type 1 DM or type 2 DM. Consequently, affected patients are not given the optimal treatment and this reduces their quality of life. Diagnosis of DM presents several challenges which may be solved by means of genetic testing. Scientific efforts have been made in order to determine variants which contribute to the pathophysiology of DM. Sanger sequencing, which targets single genes, has been employed, however, this has been replaced by next-generation sequencing (NGS) where multiple genes are sequenced together. In this study, a number of selected probands presenting either atypical diabetes and/or morbid were investigated. A panel of 383 genes implicated in diabetes, insulin resistance and obesity were analysed using whole exome sequencing. A filtering and prioritisation strategy was applied in order to identify variants which may be of clinical significance and scored using the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) classification guidelines. Eight variants of interests were identified: one is likely benign, four are of uncertain significance, one is VUS-leaning pathogenic, and one is likely pathogenic according to the ACMG/AMP criteria. The impact of the variant on the pathophysiology of DM was not determined with confidence and thus further studies such as segregation analysis and in vivo or in vitro assays should be employed to establish their effect. Genetic characterisation of atypical forms of DM and morbid obesity provides an insight into an underlying monogenic aetiology in the Maltese population.