Rare mendelian forms of obesity and diabetes and their implications for treatment outcomes

Abstract

Obesity and diabetes are becoming epidemic health issues worldwide. In recent decades, a considerable amount of work has been done to study the pathogenicity underlying those diseases, which has led to valuable insights into the genetic basis, treatment and prevention of obesity and diabetes. Nevertheless, despite our more detailed pathophysiological understanding of the rare forms of diabetes and obesity than of more common polygenic forms, we still know little about their prevalence and implications outside specialised genetics services. In the present work, I have explored the contribution of Mendelian forms of obesity in individuals with severe obesity. Initial segregation analyses of families with an obese proband, led to the identification of an oligogenic mode of inheritance for obesity. This was followed by re-analysis of pre-existing whole exome sequencing data from 91 individuals with extreme obesity, which revealed an additional 21 possible causative variants in known monogenic/syndromic obesity genes and three further cases of oligogenic inheritance. In addition, 11 candidate variants were identified in genes suggested by rodent models of obesity and/or diabetes, but not previously reported in humans. To further expand the analysis, a unique custom genotyping array focusing on, obesity and diabetes mellitus (T2D, and monogenic forms of diabetes) was designed to be applied to a larger number of samples (N=2068). Application of the array led to the identification of a total of 161 potential causative variants in 40 monogenic obesity/syndromic obesity genes, with a putative diagnostic yield of 11%. Initial analysis suggests that having one of these putative Mendelian forms of obesity resulted in no statistical difference in percentage weight loss at 2 years post-surgery and diabetes remission. Our first analysis on obesity indicates that the use of a custom-designed genotyping array for specific rare diseases may be an advantageous first level screening strategy in terms of cost and time. The work presented here also suggests that the true prevalence of Mendelian forms of obesity among bariatric surgery patients is likely to be high - this presents a significant unmet need for genetic analysis and follow-up.