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Expanding the genetic etiological and diagnostic spectrum of monogenic diabetes mellitus

Project description

In-depth genetic analysis of monogenic diabetes

Maturity onset diabetes of the young, a form of monogenic diabetes, is a Mendelian disorder referring to any of several hereditary forms of diabetes mellitus caused by mutations in an autosomal dominant gene disrupting insulin production. Genetic testing fails to show causal mutations in more than 50 % of known Mendelian disorders, highlighting an urgent need to establish the role of non-coding mutations in this disease. The EU-funded DecodeDiabetes project aims to develop a strategy for genetic analysis of regulatory variations in Mendelian diseases. The project created epigenomic resources to interpret the regulatory genome in embryonic pancreas and adult pancreatic islets. Importantly, researchers collected a large international patient cohort with a phenotype consistent with monogenic diabetes and with increased likelihood of harbouring non-coding mutations. Used alongside innovative technologies, these resources will uncover causal non-coding mutations.


Whole genome sequencing is quickly becoming a routine clinical instrument. However, our ability to decipher DNA variants 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 cause most cases of neonatal diabetes due to pancreas agenesis. This example raises major questions: (i) what is the overall impact of penetrant regulatory mutations in human diabetes? (ii) do regulatory mutations cause distinct forms of diabetes? (iii) more generally, can we develop a strategy to systematically tackle regulatory variation in Mendelian disease?
The current project will address these questions with unique resources. First, we have created epigenomic and functional perturbation resources to interpret the regulatory genome in embryonic pancreas and adult pancreatic islets. Second, we have collected an unprecedented international cohort of patients with a phenotype consistent with monogenic diabetes, yet lacking mutations in known gene culprits after genetic testing, and therefore with increased likelihood of harboring noncoding mutations. Third, we have developed a prototype platform to sequence regulatory mutations in a large number of patients.
These resources will be combined with innovative strategies to uncover causal enhancer mutations underlying Mendelian diabetes. If successful, this project will expand the diagnostic spectrum of diabetes, it will discover new genetic regulators of diabetes-relevant networks, and will provide a framework to understand regulatory variation in Mendelian disease.



Net EU contribution
€ 2 243 746,00
Carrer doctor aiguader 88
08003 Barcelona

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Este Cataluña Barcelona
Activity type
Research Organisations
Other funding
€ 0,00

Beneficiaries (1)