De novo mutations in epileptic encephalopathies.

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Nature 2013 Sep 11;501(7466):217-21. Epub 2013 Aug 11.

Epileptic encephalopathies are a devastating group of severe childhood epilepsy disorders for which the cause is often unknown. Here we report a screen for de novo mutations in patients with two classical epileptic encephalopathies: infantile spasms (n = 149) and Lennox-Gastaut syndrome (n = 115). We sequenced the exomes of 264 probands, and their parents, and confirmed 329 de novo mutations. A likelihood analysis showed a significant excess of de novo mutations in the ∼4,000 genes that are the most intolerant to functional genetic variation in the human population (P = 2.9 × 10(-3)). Among these are GABRB3, with de novo mutations in four patients, and ALG13, with the same de novo mutation in two patients; both genes show clear statistical evidence of association with epileptic encephalopathy. Given the relevant site-specific mutation rates, the probabilities of these outcomes occurring by chance are P = 4.1 × 10(-10) and P = 7.8 × 10(-12), respectively. Other genes with de novo mutations in this cohort include CACNA1A, CHD2, FLNA, GABRA1, GRIN1, GRIN2B, HNRNPU, IQSEC2, MTOR and NEDD4L. Finally, we show that the de novo mutations observed are enriched in specific gene sets including genes regulated by the fragile X protein (P < 10(-8)), as has been reported previously for autism spectrum disorders.

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http://dx.doi.org/10.1038/nature12439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3773011PMC
September 2013
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References

(Supplied by CrossRef)

AT Berg et al.
Epilepsia 2010

I Iossifov et al.
Neuron 2012

EL Heinzen et al.
Am. J. Hum. Genet. 2012

JC Mulley et al.
Epilepsia 2011

D Kasperaviciute et al.
Brain 2010

LE Vissers et al.
Nature Genet. 2010

BM Neale et al.
Nature 2012

VM Kalscheuer et al.
Am. J. Hum. Genet. 2003

L Claes et al.
Am. J. Hum. Genet. 2001

H Saitsu et al.
Nature Genet. 2008

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