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dc.contributor.authorMyers, Candace T
dc.contributor.authorMcMahon, Jacinta M
dc.contributor.authorSchneider, Amy L
dc.contributor.authorPetrovski, Slavé
dc.contributor.authorAllen, Andrew S
dc.contributor.authorCarvill, Gemma L
dc.contributor.authorZemel, Matthew
dc.contributor.authorSaykally, Julia E
dc.contributor.authorLaCroix, Amy J
dc.contributor.authorHeinzen, Erin L
dc.contributor.authorHollingsworth, Georgina
dc.contributor.authorNikanorova, Marina
dc.contributor.authorCorbett, Mark
dc.contributor.authorComan, David
dc.contributor.authoret al.
dc.date.accessioned2021-07-13T06:07:02Z
dc.date.available2021-07-13T06:07:02Z
dc.date.issued2016
dc.identifier.issn0002-9297
dc.identifier.doi10.1016/j.ajhg.2016.06.003
dc.identifier.urihttp://hdl.handle.net/10072/405909
dc.description.abstractEpileptic 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.
dc.description.peerreviewedYes
dc.languageEnglish
dc.publisherElsevier
dc.relation.ispartofpagefrom287
dc.relation.ispartofpageto298
dc.relation.ispartofissue2
dc.relation.ispartofjournalAmerican Journal of Human Genetics
dc.relation.ispartofvolume99
dc.subject.fieldofresearchBiological sciences
dc.subject.fieldofresearchBiomedical and clinical sciences
dc.subject.fieldofresearchcode31
dc.subject.fieldofresearchcode32
dc.subject.keywordsScience & Technology
dc.subject.keywordsLife Sciences & Biomedicine
dc.subject.keywordsGenetics & Heredity
dc.subject.keywordsGLUTAMATE TRANSPORTER EAAT2
dc.subject.keywordsINTELLECTUAL DISABILITY
dc.titleDe novo mutations in SLC1A2 and CACNA1A are important causes of epileptic encephalopathies
dc.typeJournal article
dc.type.descriptionC1 - Articles
dcterms.bibliographicCitationMyers, CT; McMahon, JM; Schneider, AL; Petrovski, S; Allen, AS; Carvill, GL; Zemel, M; Saykally, JE; LaCroix, AJ; Heinzen, EL; Hollingsworth, G; Nikanorova, M; Corbett, M; Coman, D; et al., De novo mutations in SLC1A2 and CACNA1A are important causes of epileptic encephalopathies, 2016, 99 (2), pp. 287-298
dcterms.dateAccepted2016-06-01
dc.date.updated2021-07-13T05:59:30Z
gro.hasfulltextNo Full Text
gro.griffith.authorComan, Dave J.


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