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Common variants associated with general and MMR vaccine-related febrile seizures.

ABSTRACT: Febrile seizures represent a serious adverse event following measles, mumps and rubella (MMR) vaccination. We conducted a series of genome-wide association scans comparing children with MMR-related febrile seizures, children with febrile seizures unrelated to vaccination and controls with no history of febrile seizures. Two loci were distinctly associated with MMR-related febrile seizures, harboring the interferon-stimulated gene IFI44L (rs273259: P = 5.9 × 10(-12) versus controls, P = 1.2 × 10(-9) versus MMR-unrelated febrile seizures) and the measles virus receptor CD46 (rs1318653: P = 9.6 × 10(-11) versus controls, P = 1.6 × 10(-9) versus MMR-unrelated febrile seizures). Furthermore, four loci were associated with febrile seizures in general, implicating the sodium channel genes SCN1A (rs6432860: P = 2.2 × 10(-16)) and SCN2A (rs3769955: P = 3.1 × 10(-10)), a TMEM16 family gene (ANO3; rs114444506: P = 3.7 × 10(-20)) and a region associated with magnesium levels (12q21.33; rs11105468: P = 3.4 × 10(-11)). Finally, we show the functional relevance of ANO3 (TMEM16C) with electrophysiological experiments in wild-type and knockout rats.

SUBMITTER: Feenstra B

PROVIDER: S-EPMC4244308 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Common variants associated with general and MMR vaccine-related febrile seizures.

Feenstra Bjarke B Pasternak Björn B Geller Frank F Carstensen Lisbeth L Wang Tongfei T Huang Fen F Eitson Jennifer L JL Hollegaard Mads V MV Svanström Henrik H Vestergaard Mogens M Hougaard David M DM Schoggins John W JW Jan Lily Yeh LY Melbye Mads M Hviid Anders A

Nature genetics 20141026 12

Febrile seizures represent a serious adverse event following measles, mumps and rubella (MMR) vaccination. We conducted a series of genome-wide association scans comparing children with MMR-related febrile seizures, children with febrile seizures unrelated to vaccination and controls with no history of febrile seizures. Two loci were distinctly associated with MMR-related febrile seizures, harboring the interferon-stimulated gene IFI44L (rs273259: P = 5.9 × 10(-12) versus controls, P = 1.2 × 10( ...[more]

PMID: 25344690

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Project description:To explore the phenotype spectrum of DEPDC5 variants and the possible mechanisms underlying phenotypical variation, we performed targeted next-generation sequencing in 305 patients with focal epilepsies and 91 patients with generalized epilepsies. Protein modeling was performed to predict the effects of missense mutations. All previously reported epilepsy-related DEPDC5 variants were reviewed. The genotype-phenotype correlations with molecular sub-regional implications were analyzed. We identified a homozygous DEPDC5 mutation (p.Pro1031His) in a case with focal cortical dysplasia and eight heterozygous mutations in 11 families with mild focal epilepsies, including 13 patients in eight families with focal epilepsy with febrile seizures plus/febrile seizures (FEFS + /FS). The mutations included one termination codon mutation (p.Ser1601_Ter1604del_ext133), three truncating mutations (p.Val151Serfs?27, p.Arg239?, and p.Arg838?), and four missense mutations (p.Tyr7Cys, p.Tyr836Cys, p.Pro1031His, and p.Gly1545Ser) that were predicted to affect hydrogen bonds and protein stability. Analysis on epilepsy-related DEPDC5 variants revealed that malformations of cortical development (MCDs) had a tendency of higher frequency of null mutations than those without MCD. MCD-associated heterozygous missense mutations were clustered in structural axis for binding arrangement (SABA) domain and close to the binding sites to NPRL2/NPRL3 complex, whereas those associated with FEFS + /FS were a distance away from the binding sites. Evidence from four aspects and one possible evidence from sub-regional implication suggested MCD and FEFS + /FS as phenotypes of DEPDC5 variants. This study suggested that the phenotypes of DEPDC5 variants vary from mild FEFS + /FS to severe MCD. Heterozygous DEPDC5 mutations are generally less pathogenic and commonly associated with mild phenotypes. Bi-allelic mutations and second hit of somatic mutations, together with the genotype-phenotype correlation and sub-regional implication of DEPDC5 variants, explain severe phenotypes.

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Dataset Information

Common variants associated with general and MMR vaccine-related febrile seizures.

Publications

Common variants associated with general and MMR vaccine-related febrile seizures.

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