Using Whole Exome Sequencing (WES) to identify genes underlying unexplained Maturity Onset Diabetes of the Young (MODY-X)

Some rare forms of diabetes are purely inherited and are unaffected by the environment, that is they are only due to damaging changes in the DNA sequence of a gene that is passed down through a family. One type of this rare form is called maturity-onset diabetes of the young (MODY), because it resembles common type 2 diabetes (T2D), which is usually seen in people over 40 years, but occurs at a young age, below about 20 years. Seven genes so far have been shown to give rise to MODY but many MODY cases are still of unknown cause. With new advances in DNA sequencing technologies, it is possible to examine all of the DNA in a person?s genome that is translated into the products that go to make up a healthy person. Using this technology, this proposal will aim to identify the changes in the DNA sequence that are responsible for MODY in six unrelated families. This is likely to improve the diagnosis of further MODY families and may affect their treatment as previous findings have enabled MODY patients to be successfully treated with sulfonylureas rather than daily insulin injection. Previous research into MODY has also helped make a significant contribution to the understanding of the genetics of common T2D and there is every reason to believe that the current proposal will also contribute something significant to the T2D field.

Monogenic forms of early-onset non-autoimmune diabetes typically occur before the age of twenty and are characterized by primary pancreatic beta-cell dysfunction, generally resulting in severe defects in insulin secretion. This is called Maturity-Onset Diabetes of the Young, or MODY, and where the underlying gene defect is unknown it is referred to as MODY-X. Currently, MODY prevalence is estimated to be 1-2% of all European T2D cases. A recent estimate of the population prevalence in the UK reported a minimum prevalence of 108 cases per million, giving an estimated 6500 MODY patients in the UK alone. In spite of many successes, in the majority of cases the underlying genetic defect remains unknown. With the ability to sequence all the coding regions in a genome, whole exome sequencing (WES), in a timely and efficient manner, it is now possible to explore characterisation of MODY of unknown cause (MODY-X). The current proposal utilises WES of four subjects form each of six multi-generational MODY-X) families followed by identification of strong candidate SNPs by using a filtering system. Initial filtering will be based on bioinformatics information, prioritising SNPs that are missense, nonsense or frameshift. Predictions of possible effects on protein structure and function will also be examined. Segregation analysis of the remaining candidate variants will then be carried out to confirm clear transmission of the variant together with MODY. Absence of the variant from unaffected individuals will be confirmed in a set of 760 unrelated French Caucasian adults. Genes containing variants that pass all criteria will then be investigated in a further 15-20 MODY-X families for the presence of the novel variant, or other variants, which may be responsible for their MODY-X. Novel variants will also be examined for their presence in a set of ~200 type 2 diabetes patients with evidence of monogenic transmission in their family. Overall, this strategy will lead to the identification of multiple MODY-X gene variants, which may lead to the identification of additional genes that are involved in MODY and possibly have wider implications for our current understanding of the genetics of type 2 diabetes.