Causes and consequences of de novo mutations in intellectual disability and male infertility


General Background
De novo germline mutations can cause disease when they affect functionally relevant bases in the genome. Our studies using exome and genome sequencing have shown for the first time that these mutations may be the major cause of early-onset disorders such as severe intellectual disability. In spite of this we still know very little of the causes and consequences of these important mutations in health and disease. What is the effect of de novo non-coding mutations? How many de novo mutations does a child “inherit” from her 50 year old father, with or without the use of assisted reproductive technology? Can de novo mutations be the cause of other conditions with reduced fecundity such as male infertility?

Objective
In this VICI application we will try to answer the questions raised above, using well-characterized patient/control cohorts, making use of high quality genome sequencing in combination with state-of-the-art bioinformatics. This ultimate genetic test allows us to reliably determine all de novo mutations throughout the genome. This provides the basis for our genetic disease studies in intellectual disability and male infertility, and for studying the impact of increased paternal age and the use of assisted reproductive technology on the genome of children.

Project description
In this VICI application we will try to answer the questions raised above, using well-characterized patient/control cohorts, making use of high quality genome sequencing in combination with state-of-the-art bioinformatics. This ultimate genetic test allows us to reliably determine all de novo mutations throughout the genome. This provides the basis for our genetic disease studies in intellectual disability and male infertility, and for studying the impact of increased paternal age and the use of assisted reproductive technology on the genome of children.

Anticipated results
This project contributes significantly to our understanding of the genetics underlying both intellectual disability and male infertility, and provides important insight into increased paternal age and assisted reproductive technologies as risk factors for these and other disorders.

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