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High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies
- Source :
- American Journal of Human Genetics, 101, 664-685, American Journal of Human Genetics, American Journal of Human Genetics, Elsevier (Cell Press), 2017, 101 (5), pp.664-685. 〈10.1016/j.ajhg.2017.09.008〉, American Journal of Human Genetics, 2017, 101 (5), pp.664-685. ⟨10.1016/j.ajhg.2017.09.008⟩, American Journal of Human Genetics, Elsevier (Cell Press), 2017, 101 (5), pp.664-685. ⟨10.1016/j.ajhg.2017.09.008⟩, American Journal of Human Genetics, 101(5), 664-685. CELL PRESS, Hamdan, F F, Myers, C T, Cossette, P, Lemay, P, Spiegelman, D, Laporte, A D, Nassif, C, Diallo, O, Monlong, J, Cadieux-Dion, M, Dobrzeniecka, S, Meloche, C, Retterer, K, Cho, M T, Rosenfeld, J A, Bi, W, Massicotte, C, Miguet, M, Brunga, L, Regan, B M, Mo, K, Tam, C, Schneider, A, Hollingsworth, G, FitzPatrick, D R, Donaldson, A, Canham, N, Blair, E, Kerr, B, Fry, A E, Thomas, R H, Shelagh, J, Hurst, J A, Brittain, H, Blyth, M, Lebel, R R, Gerkes, E H, Davis-Keppen, L, Stein, Q, Chung, W K, Dorison, S J, Benke, P J, Fassi, E, Corsten-Janssen, N, Kamsteeg, E-J, Mau-Them, F T, Bruel, A-L, Verloes, A & Õunap, K & Wojcik, M H 2017, ' High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies ', American Journal of Human Genetics, vol. 101, no. 5, pp. 664-685 . https://doi.org/10.1016/j.ajhg.2017.09.008, American Journal of Human Genetics, 101, 5, pp. 664-685, Kerr, B & et al 2017, ' High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies ', American Journal of Human Genetics . https://doi.org/10.1016/j.ajhg.2017.09.008
- Publication Year :
- 2017
-
Abstract
- Item does not contain fulltext Developmental and epileptic encephalopathy (DEE) is a group of conditions characterized by the co-occurrence of epilepsy and intellectual disability (ID), typically with developmental plateauing or regression associated with frequent epileptiform activity. The cause of DEE remains unknown in the majority of cases. We performed whole-genome sequencing (WGS) in 197 individuals with unexplained DEE and pharmaco-resistant seizures and in their unaffected parents. We focused our attention on de novo mutations (DNMs) and identified candidate genes containing such variants. We sought to identify additional subjects with DNMs in these genes by performing targeted sequencing in another series of individuals with DEE and by mining various sequencing datasets. We also performed meta-analyses to document enrichment of DNMs in candidate genes by leveraging our WGS dataset with those of several DEE and ID series. By combining these strategies, we were able to provide a causal link between DEE and the following genes: NTRK2, GABRB2, CLTC, DHDDS, NUS1, RAB11A, GABBR2, and SNAP25. Overall, we established a molecular diagnosis in 63/197 (32%) individuals in our WGS series. The main cause of DEE in these individuals was de novo point mutations (53/63 solved cases), followed by inherited mutations (6/63 solved cases) and de novo CNVs (4/63 solved cases). De novo missense variants explained a larger proportion of individuals in our series than in other series that were primarily ascertained because of ID. Moreover, these DNMs were more frequently recurrent than those identified in ID series. These observations indicate that the genetic landscape of DEE might be different from that of ID without epilepsy.
- Subjects :
- Male
0301 basic medicine
Candidate gene
medicine.medical_specialty
medical genetics
glycosylation
Nonsense mutation
Genome-wide association study
Gene mutation
Biology
Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12]
Article
severe intellectual disability
03 medical and health sciences
Epilepsy
0302 clinical medicine
children
Recurrence
Seizures
Genetic linkage
Intellectual Disability
[ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology
Journal Article
Genetics
medicine
Humans
Child
disorders
Genetics (clinical)
Genetic association
Brain Diseases
disease
cis-prenyltransferase
Genome, Human
structural basis
medicine.disease
diphosphate synthase
030104 developmental biology
Child, Preschool
Mutation
Medical genetics
Female
nogo-b receptor
030217 neurology & neurosurgery
[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Genome-Wide Association Study
Meta-Analysis
Subjects
Details
- ISSN :
- 00029297 and 15376605
- Database :
- OpenAIRE
- Journal :
- American Journal of Human Genetics, 101, 664-685, American Journal of Human Genetics, American Journal of Human Genetics, Elsevier (Cell Press), 2017, 101 (5), pp.664-685. 〈10.1016/j.ajhg.2017.09.008〉, American Journal of Human Genetics, 2017, 101 (5), pp.664-685. ⟨10.1016/j.ajhg.2017.09.008⟩, American Journal of Human Genetics, Elsevier (Cell Press), 2017, 101 (5), pp.664-685. ⟨10.1016/j.ajhg.2017.09.008⟩, American Journal of Human Genetics, 101(5), 664-685. CELL PRESS, Hamdan, F F, Myers, C T, Cossette, P, Lemay, P, Spiegelman, D, Laporte, A D, Nassif, C, Diallo, O, Monlong, J, Cadieux-Dion, M, Dobrzeniecka, S, Meloche, C, Retterer, K, Cho, M T, Rosenfeld, J A, Bi, W, Massicotte, C, Miguet, M, Brunga, L, Regan, B M, Mo, K, Tam, C, Schneider, A, Hollingsworth, G, FitzPatrick, D R, Donaldson, A, Canham, N, Blair, E, Kerr, B, Fry, A E, Thomas, R H, Shelagh, J, Hurst, J A, Brittain, H, Blyth, M, Lebel, R R, Gerkes, E H, Davis-Keppen, L, Stein, Q, Chung, W K, Dorison, S J, Benke, P J, Fassi, E, Corsten-Janssen, N, Kamsteeg, E-J, Mau-Them, F T, Bruel, A-L, Verloes, A & Õunap, K & Wojcik, M H 2017, ' High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies ', American Journal of Human Genetics, vol. 101, no. 5, pp. 664-685 . https://doi.org/10.1016/j.ajhg.2017.09.008, American Journal of Human Genetics, 101, 5, pp. 664-685, Kerr, B & et al 2017, ' High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies ', American Journal of Human Genetics . https://doi.org/10.1016/j.ajhg.2017.09.008
- Accession number :
- edsair.doi.dedup.....1e6b43223d1c8b9217763bad5e995f37