Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 664-685 |
| Number of pages | 22 |
| Journal | American Journal of Human Genetics |
| Volume | 101 |
| Issue number | 5 |
| DOIs | |
| State | Published - Nov 2 2017 |
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Keywords
- CLTC
- DHDDS
- epileptic encephalopathy
- GABBR2
- GABRB2
- NTRK2
- NUS1
- RAB11
- SNAP25
ASJC Scopus subject areas
- Genetics
- Genetics(clinical)
Cite this
High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies. / Deciphering Developmental Disorders Study.
In: American Journal of Human Genetics, Vol. 101, No. 5, 02.11.2017, 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 - Deciphering Developmental Disorders Study
AU - Hamdan, Fadi F.
AU - Myers, Candace T.
AU - Cossette, Patrick
AU - Lemay, Philippe
AU - Spiegelman, Dan
AU - Laporte, Alexandre Dionne
AU - Nassif, Christina
AU - Diallo, Ousmane
AU - Monlong, Jean
AU - Cadieux-Dion, Maxime
AU - Dobrzeniecka, Sylvia
AU - Meloche, Caroline
AU - Retterer, Kyle
AU - Cho, Megan T.
AU - Rosenfeld, Jill A.
AU - Bi, Weimin
AU - Massicotte, Christine
AU - Miguet, Marguerite
AU - Brunga, Ledia
AU - Regan, Brigid M.
AU - Mo, Kelly
AU - Tam, Cory
AU - Schneider, Amy
AU - Hollingsworth, Georgie
AU - FitzPatrick, David R.
AU - Donaldson, Alan
AU - Canham, Natalie
AU - Blair, Edward
AU - Kerr, Bronwyn
AU - Fry, Andrew E.
AU - Thomas, Rhys H.
AU - Shelagh, Joss
AU - Hurst, Jane A.
AU - Brittain, Helen
AU - Blyth, Moira
AU - Lebel, Robert Roger
AU - Gerkes, Erica H.
AU - Davis-Keppen, Laura
AU - Stein, Quinn
AU - Chung, Wendy K.
AU - Dorison, Sara J.
AU - Benke, Paul J.
AU - Fassi, Emily
AU - Corsten-Janssen, Nicole
AU - Kamsteeg, Erik Jan
AU - Mau-Them, Frederic T.
AU - Bruel, Ange Line
AU - Verloes, Alain
AU - Õunap, Katrin
AU - Minassian, Berge A.
PY - 2017/11/2
Y1 - 2017/11/2
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.
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.
KW - CLTC
KW - DHDDS
KW - epileptic encephalopathy
KW - GABBR2
KW - GABRB2
KW - NTRK2
KW - NUS1
KW - RAB11
KW - SNAP25
UR - http://www.scopus.com/inward/record.url?scp=85033604759&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85033604759&partnerID=8YFLogxK
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 -