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How to identify novel ID genes given the per generation mutation rate?
• Use gene specific mutation rates (GSMR)* which is based on gene size and local sequence context
• Based on tested cohort size, determine the expected number of de novo mutations per gene
• Determine the excesses in DNMs per gene for 2,104 ID trios
Expected DNMs Observed DNMs
*Samocha et al. Nat Gen. 2014
Gene A
1.2 1.0
Gene B
0.3 4.0
Gene C
... ...
 Significant?
(after correction for multiple testing)
De novo mutations in 10 novel candidate ID genes
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n = 2,419
n = 713
n = 30
28,1%
70,6%
~1.3% !
>200 patients per year in Europe alone!
ID trios @Radboudumc
(with consent for diagnostic innovation) Patients with a de novo mutation any
of the known ~1,000 ID genes
Patients with a de novo mutation in one of the novel genes
Lelieveld et al. Nature Neuroscience 2016
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