title: Chromosome loci vary by juvenile myoclonic epilepsy subsyndromes: linkage and haplotype analysis applied to epilepsy and EEG 3.5-6.0 Hz polyspike waves.
abstract: Juvenile myoclonic epilepsy (JME), the most common genetic epilepsy, remains enigmatic because it is considered one disease instead of several diseases. We ascertained three large multigenerational/multiplex JME pedigrees from Honduras with differing JME subsyndromes, including Childhood Absence Epilepsy evolving to JME (CAE/JME; pedigree 1), JME with adolescent onset pyknoleptic absence (JME/pA; pedigree 2), and classic JME (cJME; pedigree 3). All phenotypes were validated, including symptomatic persons with various epilepsies, asymptomatic persons with EEG 3.5-6.0 Hz polyspike waves, and asymptomatic persons with normal EEGs. Two-point parametric linkage analyses were performed with 5185 single-nucleotide polymorphisms on individual pedigrees and pooled pedigrees using four diagnostic models based on epilepsy/EEG diagnoses. Haplotype analyses of the entire genome were also performed for each individual. In pedigree 1, haplotyping identified a 34 cM region in 2q21.2-q31.1 cosegregating with all affected members, an area close to 2q14.3 identified by linkage (Z max = 1.77; pedigree 1). In pedigree 2, linkage and haplotyping identified a 44 cM cosegregating region in 13q13.3-q31.2 (Z max = 3.50 at 13q31.1; pooled pedigrees). In pedigree 3, haplotyping identified a 6 cM cosegregating region in 17q12. Possible cosegregation was also identified in 13q14.2 and 1q32 in pedigree 3, although this could not be definitively confirmed due to the presence of uninformative markers in key individuals. Differing chromosome regions identified in specific JME subsyndromes may contain separate JME disease-causing genes, favoring the concept of JME as several distinct diseases. Whole-exome sequencing will likely identify a CAE/JME gene in 2q21.2-2q31.1, a JME/pA gene in 13q13.3-q31.2, and a cJME gene in 17q12.
authors.affiliation: Epilepsy Genetics/Genomics LaboratoriesVA GLAHS - West Los AngelesLos AngelesCalifornia; GENESS International ConsortiumLos AngelesCalifornia.
authors.forename: Jenny E
authors.initials: JE
authors.lastname: Wight
authors.affiliation: Epilepsy Genetics/Genomics LaboratoriesVA GLAHS - West Los AngelesLos AngelesCalifornia; GENESS International ConsortiumLos AngelesCalifornia.
authors.forename: Viet-Huong
authors.initials: VH
authors.lastname: Nguyen
authors.affiliation: GENESS International ConsortiumLos AngelesCalifornia; National Autonomous University of HondurasTegucigalpaHonduras.
authors.forename: Marco T
authors.initials: MT
authors.lastname: Medina
authors.affiliation: Epilepsy Genetics/Genomics LaboratoriesVA GLAHS - West Los AngelesLos AngelesCalifornia; GENESS International ConsortiumLos AngelesCalifornia.
authors.forename: Christopher
authors.initials: C
authors.lastname: Patterson
authors.affiliation: Epilepsy Genetics/Genomics LaboratoriesVA GLAHS - West Los AngelesLos AngelesCalifornia; GENESS International ConsortiumLos AngelesCalifornia; National Autonomous University of HondurasTegucigalpaHonduras; Universidad Tecnológica Centroamericana (UNITEC)TegucigalpaHonduras; Department of NeurologyDavid Geffen School of Medicine at UCLALos AngelesCalifornia.
authors.forename: Reyna M
authors.initials: RM
authors.lastname: Durón
authors.affiliation: GENESS International ConsortiumLos AngelesCalifornia; National Autonomous University of HondurasTegucigalpaHonduras.
authors.forename: Yolly
authors.initials: Y
authors.lastname: Molina
authors.affiliation: Epilepsy Genetics/Genomics LaboratoriesVA GLAHS - West Los AngelesLos AngelesCalifornia; GENESS International ConsortiumLos AngelesCalifornia.
authors.forename: Yu-Chen
authors.initials: YC
authors.lastname: Lin
authors.affiliation: GENESS International ConsortiumLos AngelesCalifornia; National Institute of Neurology and NeurosurgeryMexico CityMexico.
authors.forename: Iris E
authors.initials: IE
authors.lastname: Martínez-Juárez
authors.affiliation: GENESS International ConsortiumLos AngelesCalifornia; National Institute of Neurology and NeurosurgeryMexico CityMexico.
authors.forename: Adriana
authors.initials: A
authors.lastname: Ochoa
authors.affiliation: GENESS International ConsortiumLos AngelesCalifornia; National Institute of Neurology and NeurosurgeryMexico CityMexico.
authors.forename: Aurelio
authors.initials: A
authors.lastname: Jara-Prado
authors.affiliation: Epilepsy Genetics/Genomics LaboratoriesVA GLAHS - West Los AngelesLos AngelesCalifornia; GENESS International ConsortiumLos AngelesCalifornia; Department of NeurologyDavid Geffen School of Medicine at UCLALos AngelesCalifornia.
authors.forename: Miyabi
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: Epilepsy Genetics/Genomics LaboratoriesVA GLAHS - West Los AngelesLos AngelesCalifornia; GENESS International ConsortiumLos AngelesCalifornia; Department of NeurologyDavid Geffen School of Medicine at UCLALos AngelesCalifornia.
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Bai
authors.affiliation: Epilepsy Genetics/Genomics LaboratoriesVA GLAHS - West Los AngelesLos AngelesCalifornia; GENESS International ConsortiumLos AngelesCalifornia; Department of NeurologyDavid Geffen School of Medicine at UCLALos AngelesCalifornia.
authors.forename: Sumaya
authors.initials: S
authors.lastname: Aftab
authors.affiliation: Epilepsy Genetics/Genomics LaboratoriesVA GLAHS - West Los AngelesLos AngelesCalifornia; GENESS International ConsortiumLos AngelesCalifornia; Department of EpidemiologyFielding School of Public Health at UCLALos AngelesCalifornia.
authors.forename: Julia N
authors.initials: JN
authors.lastname: Bailey
authors.affiliation: Epilepsy Genetics/Genomics LaboratoriesVA GLAHS - West Los AngelesLos AngelesCalifornia; GENESS International ConsortiumLos AngelesCalifornia; Department of NeurologyDavid Geffen School of Medicine at UCLALos AngelesCalifornia.
authors.forename: Antonio V
authors.initials: AV
authors.lastname: Delgado-Escueta
keywords: Absence; electroencephalogram; endophenotype; epilepsy; juvenile myoclonic; linkage; pyknolepsy