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. 2013 Sep 12;501(7466):217-21.
doi: 10.1038/nature12439. Epub 2013 Aug 11.

De novo mutations in epileptic encephalopathies

Epi4K Consortium; Epilepsy Phenome/Genome Project; Andrew S Allen, Samuel F Berkovic, Patrick Cossette, Norman Delanty, Dennis Dlugos, Evan E Eichler, Michael P Epstein, Tracy Glauser, David B Goldstein, Yujun Han, Erin L Heinzen, Yuki Hitomi, Katherine B Howell, Michael R Johnson, Ruben Kuzniecky, Daniel H Lowenstein, Yi-Fan Lu, Maura R Z Madou, Anthony G Marson, Heather C Mefford, Sahar Esmaeeli Nieh, Terence J O'Brien, Ruth Ottman, Slavé Petrovski, Annapurna Poduri, Elizabeth K Ruzzo, Ingrid E Scheffer, Elliott H Sherr, Christopher J Yuskaitis, Bassel Abou-Khalil, Brian K Alldredge, Jocelyn F Bautista, Samuel F Berkovic, Alex Boro, Gregory D Cascino, Damian Consalvo, Patricia Crumrine, Orrin Devinsky, Dennis Dlugos, Michael P Epstein, Miguel Fiol, Nathan B Fountain, Jacqueline French, Daniel Friedman, Eric B Geller, Tracy Glauser, Simon Glynn, Sheryl R Haut, Jean Hayward, Sandra L Helmers, Sucheta Joshi, Andres Kanner, Heidi E Kirsch, Robert C Knowlton, Eric H Kossoff, Rachel Kuperman, Ruben Kuzniecky, Daniel H Lowenstein, Shannon M McGuire, Paul V Motika, Edward J Novotny, Ruth Ottman, Juliann M Paolicchi, Jack M Parent, Kristen Park, Annapurna Poduri, Ingrid E Scheffer, Renée A Shellhaas, Elliott H Sherr, Jerry J Shih, Rani Singh, Joseph Sirven, Michael C Smith, Joseph Sullivan, Liu Lin Thio, Anu Venkat, Eileen P G Vining, Gretchen K Von Allmen, Judith L Weisenberg, Peter Widdess-Walsh, Melodie R Winawer

De novo mutations in epileptic encephalopathies

Epi4K Consortium et al. Nature. .

Abstract

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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Conflict of interest statement

The authors declare no competing financial interests.

Figures

Figure 1
Figure 1. Heat map illustrating the probability of observing the number of de novo mutations in genes with an estimated gene mutation rate
The number of de novo mutations required to achieve significance is indicated by the solid red line. The superimposed black dots reflect positions of all genes found to harbor multiple de novo mutations in our study. GABRB3, SCN1A, CDKL5, STXBP1 have significantly more de novo mutations than expected. The positions indicated for ALG13 and SCN2A reflect only the fact that there are two mutations observed, not that there are two mutations affecting the same site (Additional Methods).
Figure 2
Figure 2. A protein-protein interaction network of genes with de novo mutations found in IS and LGS patients studied
Six of the genes found to harbor de novo mutations in an IS or LGS patient are known MIM EE genes (shaded circles). Five additional known MIM EE genes that were not found to be mutated in the 264 EE patients, but are involved in this network, are also shown (shaded circles with the gene underlined). The previously identified severe infantile epilepsy gene TNK2 is superimposed into this network (red circle).
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