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Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1



Epileptic encephalopathies are a devastating group of epilepsies with poor prognosis, of which the majority are of unknown etiology. We perform targeted massively parallel resequencing of 19 known and 46 candidate genes for epileptic encephalopathy in 500 affected individuals (cases) to identify new genes involved and to investigate the phenotypic spectrum associated with mutations in known genes. Overall, we identified pathogenic mutations in 10% of our cohort. Six of the 46 candidate genes had 1 or more pathogenic variants, collectively accounting for 3% of our cohort. We show that de novo CHD2 and SYNGAP1 mutations are new causes of epileptic encephalopathies, accounting for 1.2% and 1% of cases, respectively. We also expand the phenotypic spectra explained by SCN1A, SCN2A and SCN8A mutations. To our knowledge, this is the largest cohort of cases with epileptic encephalopathies to undergo targeted resequencing. Implementation of this rapid and efficient method will change diagnosis and understanding of the molecular etiologies of these disorders.

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Figure 1
Figure 2: Protein alterations encoded by de novo mutations in new genes for epileptic encephalopathies.

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We thank the individuals with epileptic encephalopathies and their families for participating in our research. H.C.M. is supported by a grant from the US National Institutes of Health (NIH; National Institute of Neurological Disorders and Stroke (NINDS) 1R01NS069605) and is a recipient of a Burroughs Wellcome Fund Career Award for Medical Scientists. This work was supported by the National Health and Medical Research Council of Australia (program grant 628952 to S.F.B. and I.E.S., practitioner fellowship 1006110 to I.E.S.) and a Health Research Council of New Zealand project grant to L.G.S.

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Authors and Affiliations



G.L.C., H.C.M. and I.E.S. designed the study and wrote the manuscript. H.C.M. and I.E.S. supervised the study. G.L.C. constructed libraries, developed the variant calling pipeline (with assistance from J.C.) and analyzed the sequence data. B.J.O. and J.S. developed the molecular inversion probe (MIP) methodology and analysis pipeline. S.B.H., S.C.Y., J.M.M., S.C., S.M., G.W., T.S., A.M.E.B., A.B., K.B.H., S.K., M.T.M., V.R.-C., R.W., A. Korczyn, Z.A., N.Z., T.L.-S., D.L., R.S.M., D.G., D.M.A., J.L.F., L.G.S., S.F.B. and I.E.S. performed phenotypic analysis. S.B.H., J.M.M., S.F.B. and I.E.S. critically reviewed the manuscript. G.L.C. and A. Khan performed segregation analysis experiments. M.O.D. and M.W. performed Illumina HiSeq sequencing.

Corresponding authors

Correspondence to Ingrid E Scheffer or Heather C Mefford.

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The authors declare no competing financial interests.

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Carvill, G., Heavin, S., Yendle, S. et al. Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nat Genet 45, 825–830 (2013).

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