Whole-Exome sequencing identifies a Type 2 Diabetes candidate mutation in PTPRF

ObjectivesIdentification of genetic factors involved in Type 2 diabetes mellitus (T2DM) has been challenging. While genome-wide association studies (GWAS) have identified over 60 loci associated with T2DM, these variants only explain a small proportion of the total heritability of the disease. Whole-exome sequencing has become a powerful approach to identify genetic variants that are not captured by GWAS. We applied exome sequencing to identify causal genetic variants in a family with a 2-generation history of T2DM characterized by substantial insulin resistance, hypertension and isolated hypertriglyceridemia. Methods: Exome sequencing was performed on genomic DNA of two affected family members. Twenty-four identified variants that were present in both family members were further tested for segregation in all other family members by Sanger sequencing. Results: Three rare missense variants, located in the genes PTPRF, FUCA1 and FBXO30, were present in all affected family members but also in one unaffected family member. Protein-protein interaction analysis showed that PTPRF strongly interacts with several members of the insulin signaling pathway. Conclusions: Our results suggest that the variant in the PTPRF gene might be causal for an unusual T2DM subtype that is characterized by a severe insulin resistance and isolated hypertriglyceridemia.