A locus for generalized tonic-clonic seizure susceptibility maps to chromosome 10q25-q26.
Inheritance patterns in twins and multiplex families led us to hypothesize that two loci were segregating in subjects with juvenile myoclonic epilepsy (JME), one predisposing to generalized tonic-clonic seizures (GTCS) and a second to myoclonic seizures. We tested this hypothesis by performing genome-wide scan of a large family (Family 01) and used the results to guide analyses of additional families. A locus was identified in Family 01 that was linked to GTCS (10q25-q26). Model-based multipoint analysis of the 10q25-q26 locus showed a logarithm of odds (LOD) score of 2.85; similar results were obtained with model-free analyses (maximum nonparametric linkage [NPL] of 2.71; p = 0.0019). Analyses of the 10q25-q26 locus in 10 additional families assuming heterogeneity revealed evidence for linkage in four families; model-based and model-free analyses showed a heterogeneity LOD (HLOD) of 2.01 (alpha = 0.41) and maximum NPL of 2.56 (p = 0.0027), respectively, when all subjects with GTCS were designated to be affected. Combined analyses of all 11 families showed an HLOD of 4.04 (alpha = 0.51) and maximum NPL score of 4.20 (p = 0.000065). Fine mapping of the locus defined an interval of 4.45Mb. These findings identify a novel locus for GTCS on 10q25-q26 and support the idea that distinct loci underlie distinct seizure types within an epilepsy syndrome such as JME.
Puranam
Ram S
RS
Department of Medicine (Neurology), Duke University, Durham, NC 27710, USA.
Jain
Satish
S
Kleindienst
Amber M
AM
Saxena
Shilpa
S
Kim
Myeong-Kyu
MK
Kelly Changizi
Barbara
B
Padma
M V
MV
Andrews
Ian
I
Elston
Robert C
RC
Tiwari
Hemant K
HK
McNamara
James O
JO
D000328:Adult; D016009:Chi-Square Distribution; D002874:Chromosome Mapping / Q000379:methods; D002879:Chromosomes, Human, Pair 10; D004830:Epilepsy, Tonic-Clonic / Q000235:genetics*; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D008126:Lod Score; D008297:Male; D008875:Middle Aged; D010375:Pedigree