DENOVO: Detection and interpretation of de novo mutations and structural genomic variations in mental retardation

General Background
Previous work from Veltman's group using microarrays has already demonstrated de novo genomic copy number variations in intellectual disability and in schizophrenia. However, microarrays do not allow us to capture the most common form of de novo mutations, those occurring at the nucleotide level. Technological innovations now for the first time allow us to comprehensively study the entire genome of an individual for genomic variations at all levels. In a recent pilot study Veltman's group used whole exome sequencing to obtain first evidence that de novo point mutations may indeed be a major cause of intellectual disability.

This project DENOVO will contribute significantly to resolving the genetic causes of reproductively lethal disorders such as intellectual disability, provide critical knowledge on the frequency and consequences of de novo mutations in our genome and help to establish medical genome sequencing as a routine diagnostic approach.

Project description
In this ERC project Veltman will further explore the de novo mutation hypothesis in whole exome and whole genome sequence data, using intellectual disability as a model disorder. This study will reveal many novel disease genes and help to identify the biological pathways involved in intellectual disability. In addition, Veltman will use these datasets to answer basic questions about de novo mutations; What is the frequency and distribution of the different types of de novo mutations in our genome? What are the genomic mechanisms involved in the generation of de novo mutations and are there genomic or environmental risk factors that can enhance the mutation rate?
Joris Veltman will use this grant during the next five years to investigate the role of de novo mutations in intellectual disability. Intellectual disability, like most common neurodevelopmental and psychiatric diseases, shows a strong genetic component, but the underlying genetic causes remain largely unknown. Clearly, these causes cannot lie in inherited variation with reduced penetrance, as very large genetic association studies have been performed which failed to explain more than a few percent of the genetic variability. Veltman hypothesizes that a large proportion of this so-called “missing heritability” lies in de novo genetic variation. These de novo mutations do not increase the genetic load, because they are rapidly eliminated from the population since individuals with such diseases have severely compromised fecundity.

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