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DecodeDiabetes: Expanding the genetic etiological and diagnostic spectrum of monogenic diabetes mellitus

Jorge Ferrer

Whole genome sequencing is quickly becoming a routine clinical instrument. However, our ability to decipher the role of DNA variants in human disease is still largely limited to protein-coding exons, which comprise 1% of the genome. Most known Mendelian mutations are in exons, yet genetic testing still fails to show causal coding mutations in more than 50% of well-characterized Mendelian disorders. This defines a pressing need to interpret noncoding genome sequences, and to establish the role of noncoding mutations in Mendelian disease.

A recent case study harnessed whole genome sequencing, epigenomics, and functional genomics to show that mutations in an enhancer explains most cases of neonatal diabetes due to pancreas agenesis. In addition we and others have extensively reported that T2D associated variants are enriched in pancreatic islet enhancers and we show that variants which fall within islet hubs impact the heritability of insulin secretion.

Our goal is to assess the role of the complete allele-frequency spectrum of non-coding variants in rare forms of human diabetes, and the potential to deliver more improved disease definitions to pave the way to precision medicine.