Periodic Reporting for period 3 - DecodeDiabetes (Expanding the genetic etiological and diagnostic spectrum of monogenic diabetes mellitus)
Berichtszeitraum: 2021-11-01 bis 2023-04-30
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.
Recent examples have highlighted that mutations in enhancers can cause human diseases. Based on these studies, we have tried to address the following 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?
Our project addresses 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 are being combined with innovative strategies to uncover causal enhancer mutations underlying Mendelian diabetes. This project has the potential to expand the diagnostic spectrum of diabetes, and to discover new genetic regulators of diabetes-relevant networks, providing a framework to understand regulatory variation in Mendelian disease.
Recent examples have highlighted that mutations in enhancers can cause human diseases. Based on these studies, we have tried to address the following 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?
Our project addresses 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 are being combined with innovative strategies to uncover causal enhancer mutations underlying Mendelian diabetes. This project has the potential to expand the diagnostic spectrum of diabetes, and to discover new genetic regulators of diabetes-relevant networks, providing a framework to understand regulatory variation in Mendelian disease.
So far this project has succeeded in sequencing a large cohort of patients as planned, and developed computational and experimental pipelines to define new causal mutations.
The expansion of defects underlying human Mendelian diseases from coding to noncoding genomic space represents a major milestone in human genetics. This project is expected to make major contributions to this endeavour.