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De novo mutations in a common disorder? Intellectual disability
• Intellectual disability is associated with reduced fitness
• Affects ~2‐3% of the population
o Significant limitation of intellectual functioning (IQ<70) o Significant limitation in adaptive behavior
o Onset before the age of 18
• Largest burden on health care budget in the Netherlands
Paradox in evolutionary theory:
Why are (and remain) reproductively lethal disorders, like intellectual disability, so frequent in our population?
Why would de novo mutations make sense?
Other factors that make de novo mutations at base pair level possible explanation for disease:
• Mostlysporadic
• Paternalage
• Lowrecurrencerisk
• Many genes involved
(asexpectedfordenovomutations) (increasedmutationrate) (arguesagainstrecessivedisease) (explains its high frequency)
Hypotheses
Each patient carries a de novo mutation in a different gene
Next Generation Sequencing in patient‐parent trios may find these mutations
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