A new locus on chromosome 22q13.31 linked to recessive genetic epilepsy with febrile seizures plus (GEFS+) in a Tunisian consanguineous family

Nejla Belhedi,Frédérique Bena,Amel Mrabet,Hela Mrabet,Chiraz Souissi,Annick Salzmann,Amel Elgaaied,Michel Guipponi,Alain Malafosse

doi:10.1186/1471-2156-14-93

Abstract

BackgroundGenetic epilepsy with febrile seizures plus (GEFS+) is a familial epilepsy syndrome with extremely variable expressivity. The aim of our study was to identify the responsible locus for GEFS+ syndrome in a consanguineous Tunisian family showing three affected members, by carrying out a genome-wide single nucleotide polymorphisms (SNPs) genotyping followed by a whole-exome sequencing. We hypothesized an autosomal recessive (AR) mode of inheritance.ResultsParametric linkage analysis and haplotype reconstruction identified a new unique identical by descent (IBD) interval of 527 kb, flanking by two microsatellite markers, 18GTchr22 and 15ACchr22b, on human chromosome 22q13.31 with a maximum multipoint LOD score of 2.51. Our analysis was refined by the use of a set of microsatellite markers. We showed that one of them was homozygous for the same allele in all affected individuals and heterozygous in healthy members of this family. This microsatellite marker, we called 17ACchr22, is located in an intronic region of TBC1D22A gene, which encodes a GTPase activator activity. Whole-exome sequencing did not reveal any mutation on chromosome 22q13.31 at the genome wide level.ConclusionsOur findings suggest that TBC1D22A is a new locus for GEFS+.

Highlights

Genetic epilepsy with febrile seizures plus (GEFS+) is a familial epilepsy syndrome with extremely variable expressivity
Genetic epilepsy with febrile seizures plus (GEFS+) is such a Mendelian inherited epileptic syndrome. This familial autosomal dominant (AD) epilepsy shows a wide range of phenotypes such as febrile seizures (FS), FS plus (FS+) – defined as FS persisting beyond the age of 6 – as well generalized and partial seizures [2,3]
The occurrence of generalized tonico clonic seizures (GTCS), absence seizure and FS+ led us to consider a GEFS+ syndrome in the present family

Summary

Introduction

Genetic epilepsy with febrile seizures plus (GEFS+) is a familial epilepsy syndrome with extremely variable expressivity. Segregation studies suggest that most epileptic syndromes are complex disorders, but several monogenic forms have been described. Genetic (formerly named generalized [2]) epilepsy with febrile seizures plus (GEFS+) is such a Mendelian inherited epileptic syndrome. This familial autosomal dominant (AD) epilepsy shows a wide range of phenotypes such as febrile seizures (FS), FS plus (FS+) – defined as FS persisting beyond the age of 6 – as well generalized and partial seizures [2,3]. Most severe epileptic phenotypes have been described

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