Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 664-685 |
| Number of pages | 22 |
| Journal | American Journal of Human Genetics |
| Volume | 101 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 2017 |
Keywords
- CLTC
- DHDDS
- epileptic encephalopathy
- GABBR2
- GABRB2
- NTRK2
- NUS1
- RAB11
- SNAP25
- adolescent
- adult
- Article
- Canada
- child
- CLTC gene
- data mining
- developmental and epileptic encephalopathy
- developmental delay
- DHDDS gene
- epilepsy
- female
- frameshift mutation
- GABBR2 gene
- GABRB2 gene
- gene
- gene deletion
- gene duplication
- gene identification
- gene mutation
- gene sequence
- gene targeting
- genetic association
- genetic linkage
- genetic variability
- human
- intellectual impairment
- major clinical study
- male
- missense mutation
- molecular diagnosis
- mutational analysis
- nonsense mutation
- NTRK2 gene
- NUS1 gene
- preschool child
- priority journal
- RAB11A gene
- school child
- SNAP25 gene
- whole genome sequencing
- young adult
- brain disease
- genetics
- genome-wide association study
- human genome
- meta analysis
- mutation
- procedures
- recurrent disease
- seizure
- Brain Diseases
- Child
- Child, Preschool
- Epilepsy
- Female
- Genome, Human
- Genome-Wide Association Study
- Humans
- Intellectual Disability
- Male
- Mutation
- Recurrence
- Seizures
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High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies. / 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.; Martinelli, S.; Dallapiccola, B.; Tartaglia, M.; Nava, C.
In: American Journal of Human Genetics, Vol. 101, No. 5, 2017, p. 664-685.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies
AU - Hamdan, F.F.
AU - Myers, C.T.
AU - Cossette, P.
AU - Lemay, P.
AU - Spiegelman, D.
AU - Laporte, A.D.
AU - Nassif, C.
AU - Diallo, O.
AU - Monlong, J.
AU - Cadieux-Dion, M.
AU - Dobrzeniecka, S.
AU - Meloche, C.
AU - Retterer, K.
AU - Cho, M.T.
AU - Rosenfeld, J.A.
AU - Bi, W.
AU - Massicotte, C.
AU - Miguet, M.
AU - Brunga, L.
AU - Regan, B.M.
AU - Mo, K.
AU - Tam, C.
AU - Schneider, A.
AU - Hollingsworth, G.
AU - FitzPatrick, D.R.
AU - Donaldson, A.
AU - Canham, N.
AU - Blair, E.
AU - Kerr, B.
AU - Fry, A.E.
AU - Thomas, R.H.
AU - Shelagh, J.
AU - Hurst, J.A.
AU - Brittain, H.
AU - Blyth, M.
AU - Lebel, R.R.
AU - Gerkes, E.H.
AU - Davis-Keppen, L.
AU - Stein, Q.
AU - Chung, W.K.
AU - Dorison, S.J.
AU - Benke, P.J.
AU - Fassi, E.
AU - Corsten-Janssen, N.
AU - Kamsteeg, E.-J.
AU - Mau-Them, F.T.
AU - Martinelli, S.
AU - Dallapiccola, B.
AU - Tartaglia, M.
AU - Nava, C.
N1 - Cited By :2 Export Date: 6 April 2018 CODEN: AJHGA Correspondence Address: Minassian, B.A.; Division of Child Neurology, Department of Pediatrics, University of Texas SouthwesternUnited States; email: berge.minassian@sickkids.ca Funding details: Genome Canada Funding details: RO1 NS069605, National Institute of Neurological Disorders and Stroke Funding details: OBI, Ontario Brain Institute Funding details: UofT, University of Toronto Funding text: We thank the individuals participating in this study and their families for their contributions. This study was funded by grants from Genome Canada and Génome Québec, the Jeanne and Jean-Louis Lévesque Foundation (to J.L.M.), the Michael Bahen Chair in Epilepsy Research (to B.A.M.), the Ontario Brain Institute (EpLink), the McLaughlin Foundation and the University of Toronto (to D.M.A. and B.A.M.), and the National Institute of Neurological Disorders and Stroke (RO1 NS069605 to H.C.M.). We thank the members of the massive parallel sequencing and bioinformatics teams at the McGill University and Genome Quebec Innovation Center for their services. S.M.-M. was supported by the University of Toronto McLaughlin Accelerator Grant in Genomic Medicine (MC-2013-08). See Supplemental Data for additional acknowledgements. References: Berg, A.T., Langfitt, J.T., Testa, F.M., Levy, S.R., DiMario, F., Westerveld, M., Kulas, J., Global cognitive function in children with epilepsy: a community-based study (2008) Epilepsia, 49, pp. 608-614; Tuchman, R., Cuccaro, M., Epilepsy and autism: neurodevelopmental perspective (2011) Curr. Neurol. Neurosci. Rep., 11, pp. 428-434; Shepherd, C., Hosking, G., Epilepsy in school children with intellectual impairments in Sheffield: the size and nature of the problem and the implications for service provision (1989) J. Ment. Defic. 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PY - 2017
Y1 - 2017
N2 - 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. © 2017 American Society of Human Genetics
AB - 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. © 2017 American Society of Human Genetics
KW - CLTC
KW - DHDDS
KW - epileptic encephalopathy
KW - GABBR2
KW - GABRB2
KW - NTRK2
KW - NUS1
KW - RAB11
KW - SNAP25
KW - adolescent
KW - adult
KW - Article
KW - Canada
KW - child
KW - CLTC gene
KW - data mining
KW - developmental and epileptic encephalopathy
KW - developmental delay
KW - DHDDS gene
KW - epilepsy
KW - female
KW - frameshift mutation
KW - GABBR2 gene
KW - GABRB2 gene
KW - gene
KW - gene deletion
KW - gene duplication
KW - gene identification
KW - gene mutation
KW - gene sequence
KW - gene targeting
KW - genetic association
KW - genetic linkage
KW - genetic variability
KW - human
KW - intellectual impairment
KW - major clinical study
KW - male
KW - missense mutation
KW - molecular diagnosis
KW - mutational analysis
KW - nonsense mutation
KW - NTRK2 gene
KW - NUS1 gene
KW - preschool child
KW - priority journal
KW - RAB11A gene
KW - school child
KW - SNAP25 gene
KW - whole genome sequencing
KW - young adult
KW - brain disease
KW - genetics
KW - genome-wide association study
KW - human genome
KW - meta analysis
KW - mutation
KW - procedures
KW - recurrent disease
KW - seizure
KW - Brain Diseases
KW - Child
KW - Child, Preschool
KW - Epilepsy
KW - Female
KW - Genome, Human
KW - Genome-Wide Association Study
KW - Humans
KW - Intellectual Disability
KW - Male
KW - Mutation
KW - Recurrence
KW - Seizures
U2 - 10.1016/j.ajhg.2017.09.008
DO - 10.1016/j.ajhg.2017.09.008
M3 - Article
VL - 101
SP - 664
EP - 685
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 5
ER -