Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/116651
Citations
Scopus Web of Science® Altmetric
?
?
Type: Journal article
Title: De novo mutations in SLC1A2 and CACNA1A are important causes of epileptic encephalopathies
Author: Myers, C.
McMahon, J.
Schneider, A.
Petrovski, S.
Allen, A.
Carvill, G.
Zemel, M.
Saykally, J.
LaCroix, A.
Heinzen, E.
Hollingsworth, G.
Nikanorova, M.
Corbett, M.
Gecz, J.
Coman, D.
Freeman, J.
Calvert, S.
Gill, D.
Carney, P.
Lerman-Sagie, T.
et al.
Citation: American Journal of Human Genetics, 2016; 99(2):287-298
Publisher: Cell Press
Issue Date: 2016
ISSN: 0002-9297
1537-6605
Statement of
Responsibility: 
Candace T.Myers, Jacinta M.McMahon, Amy L.Schneider, Slavé Petrovski ... Mark Corbett, Jozef Gecz ... et al.
Abstract: Epileptic encephalopathies (EEs) are the most clinically important group of severe early-onset epilepsies. Next-generation sequencing has highlighted the crucial contribution of de novo mutations to the genetic architecture of EEs as well as to their underlying genetic heterogeneity. Our previous whole-exome sequencing study of 264 parent-child trios revealed more than 290 candidate genes in which only a single individual had a de novo variant. We sought to identify additional pathogenic variants in a subset (n = 27) of these genes via targeted sequencing in an unsolved cohort of 531 individuals with a diverse range of EEs. We report 17 individuals with pathogenic variants in seven of the 27 genes, defining a genetic etiology in 3.2% of this unsolved cohort. Our results provide definitive evidence that de novo mutations in SLC1A2 and CACNA1A cause specific EEs and expand the compendium of clinically relevant genotypes for GABRB3. We also identified EEs caused by genetic variants in ALG13, DNM1, and GNAO1 and report a mutation in IQSEC2. Notably, recurrent mutations accounted for 7/17 of the pathogenic variants identified. As a result of high-depth coverage, parental mosaicism was identified in two out of 14 cases tested with mutant allelic fractions of 5%-6% in the unaffected parents, carrying significant reproductive counseling implications. These results confirm that dysregulation in diverse cellular neuronal pathways causes EEs, and they will inform the diagnosis and management of individuals with these devastating disorders.
Keywords: GTP-Binding Protein alpha Subunits, Gi-Go
Rights: © 2016 American Society of Human Genetics.
DOI: 10.1016/j.ajhg.2016.06.003
Appears in Collections:Aurora harvest 8
Medicine publications

Files in This Item:
There are no files associated with this item.


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.