title: Evaluation of multiple putative risk alleles within the 15q13.3 region for genetic generalized epilepsy.
abstract: The chromosome 15q13.3 region has been implicated in epilepsy, intellectual disability and neuropsychiatric disorders, especially schizophrenia. Deficiency of the acetylcholine receptor gene CHRNA7 and the partial duplication, CHRFAM7A, may contribute to these phenotypes and we sought to comprehensively analyze these genes in genetic generalized epilepsy. We analyzed using DHPLC, Sanger sequencing and long range PCR, 174 probands with genetic generalized epilepsy with or without intellectual disability or psychosis, including 8 with the recurrent 15q13.3 microdeletion. We searched CHRNA7 and CHRFAM7A for single sequence variants, small copy number variants, and the common 2-bp deletion in CHRFAM7A. We identified two novel and one reported missense variants. The common 2-bp deletion was not enriched in patients compared to controls. Our data suggest that missense mutations in CHRNA7 contribute to complex inheritance in genetic generalized epilepsy in a similar fashion to the 15q13.3 microdeletion. They do not support a pathogenic role for the common 2-bp CHRFAM7A deletion.
authors.affiliation: Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria 3084, Australia.
authors.forename: John A
authors.initials: JA
authors.lastname: Damiano
authors.affiliation: Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria 3084, Australia; Florey Institute, Heidelberg, Victoria 3084, Australia.
authors.forename: Saul A
authors.initials: SA
authors.lastname: Mullen
authors.affiliation: Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria 3084, Australia.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Hildebrand
authors.affiliation: Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria 3084, Australia.
authors.forename: Susannah T
authors.initials: ST
authors.lastname: Bellows
authors.affiliation: Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria 3084, Australia.
authors.forename: Kate M
authors.initials: KM
authors.lastname: Lawrence
authors.affiliation: Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria 3084, Australia.
authors.forename: Todor
authors.initials: T
authors.lastname: Arsov
authors.affiliation: Division of Health Sciences, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia 5000, Australia.
authors.forename: Leanne
authors.initials: L
authors.lastname: Dibbens
authors.affiliation: Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Major
authors.affiliation: Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria 3084, Australia.
authors.forename: Hans-Henrik M
authors.initials: HH
authors.lastname: Dahl
authors.affiliation: Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, USA.
authors.forename: Heather C
authors.initials: HC
authors.lastname: Mefford
authors.affiliation: Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
authors.forename: Benjamin W
authors.initials: BW
authors.lastname: Darbro
authors.affiliation: Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria 3084, Australia; Florey Institute, Heidelberg, Victoria 3084, Australia; Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Parkville, Victoria 3052, Australia.
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Scheffer
authors.affiliation: Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria 3084, Australia. Electronic address: s.berkovic@unimelb.edu.au.
authors.forename: Samuel F
authors.initials: SF
authors.lastname: Berkovic
mesh_terms: D000483:Alleles; D002884:Chromosomes, Human, Pair 15; D056915:DNA Copy Number Variations; D004829:Epilepsy, Generalized / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D010375:Pedigree; D011110:Polymorphism, Genetic; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000235:genetics*
chemical_list: C579167:Chrna7 protein, human; D064569:alpha7 Nicotinic Acetylcholine Receptor
keywords: Complex traits; Epilepsy and seizures; Genetics; Molecular genetics; Neurology