Genome wide high density SNP-based linkage analysis of childhood absence epilepsy identifies a susceptibility locus on chromosome 3p23-p14

Barry A Chioza,Elaine Wirrell,Martina Durner,Renzo Guerrini,Paul Mckeigue,Athanasios Covanis,Thomas Sander,Jean Aicardi,Joseph M Dooley,Kate V Everett,Lina Nashef,Martha Feucht,Mogens Laue Friis,Marianne Juel Kjeldsen,Rima Nabbout,Olivier Dulac,Harald Aschauer,Auli Sirén,Robert A Robinson ,R M Gardiner ,Oebele F Brouwer ,Petra M C Callenbach ,Orvar Eeg‐Olofsson

doi:10.1016/j.eplepsyres.2009.09.010

Abstract

SummaryChildhood absence epilepsy (CAE) is an idiopathic generalised epilepsy (IGE) characterised by typical absence seizures manifested by transitory loss of awareness with 2.5–4 Hz spike-wave complexes on ictal EEG. A genetic component to the aetiology is well recognised but the mechanism of inheritance and the genes involved are yet to be fully established.A genome wide single nucleotide polymorphism (SNP)-based high density linkage scan was carried out using 41 nuclear pedigrees with at least two affected members. Multipoint parametric and non-parametric linkage analyses were performed using MERLIN 1.1.1 and a susceptibility locus was identified on chromosome 3p23-p14 (Zmean = 3.9, p < 0.0001; HLOD = 3.3, α = 0.7). The linked region harbours the functional candidate genes TRAK1 and CACNA2D2. Fine-mapping using a tagSNP approach demonstrated disease association with variants in TRAK1.

Highlights

The absence epilepsies are a group of idiopathic generalised epilepsies (IGEs) which differ in their seizure frequency, age of onset and pattern of evolution
The International League Against Epilepsy (ILAE) classification recognises a number of distinct absence epilepsy syndromes including childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), epilepsy with myoclonic absences, juvenile myoclonic epilepsy (JME) and eyelid myoclonia with absences as a seizure type (Engel, 2001)
Frequency of absence seizures per day is greater in Childhood absence epilepsy (CAE) than JAE, and the occurrence of generalised tonic—clonic seizures (GTCS) is greater in patients with JAE than CAE

Summary

Introduction

The absence epilepsies are a group of idiopathic generalised epilepsies (IGEs) which differ in their seizure frequency, age of onset and pattern of evolution. The International League Against Epilepsy (ILAE) classification recognises a number of distinct absence epilepsy syndromes including childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), epilepsy with myoclonic absences, juvenile myoclonic epilepsy (JME) and eyelid myoclonia with absences as a seizure type (Engel, 2001). It is still unclear whether these syndromes represent a ‘biological continuum’ or distinct entities. Frequency of absence seizures per day is greater in CAE than JAE, and the occurrence of GTCS is greater in patients with JAE than CAE. There is evidence that CAE and JAE share a close genetic relationship allowing them to be considered as one phenotype in genetic studies (Berkovic et al, 1987; Marini et al, 2004)

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