Assuntos
Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas de Ligação ao Cálcio/genética , Eritema/genética , Doenças Hereditárias Autoinflamatórias/genética , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Artralgia/tratamento farmacológico , Artralgia/genética , Citocinas/metabolismo , Enterocolite/tratamento farmacológico , Enterocolite/genética , Exantema/tratamento farmacológico , Exantema/genética , Feminino , Doenças Hereditárias Autoinflamatórias/tratamento farmacológico , Humanos , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Urticária/tratamento farmacológico , Urticária/genéticaRESUMO
Epilepsy and mental retardation limited to females (EFMR), caused by PCDH19 mutations, has a variable clinical expression that needs further exploration. Onset of epilepsy may be provoked by fever and can resemble Dravet syndrome. Furthermore, transmitting males have no seizures, but are reported to have rigid personalities suggesting possible autism spectrum disorders (ASD). Therefore, this study aimed to determine the phenotypic spectrum associated with PCDH19 mutations in Dravet-like and EFMR female patients and in males with ASD. We screened 120 females suffering from Dravet-like epilepsy, 136 females with EFMR features and 20 males with ASD. Phenotypes and genotypes of the PCDH19 mutation carriers were compared with those of 125 females with EFMR reported in the literature. We report 15 additional patients with a PCDH19 mutation. Review of clinical data of all reported patients showed that the clinical picture of EFMR is heterogeneous, but epilepsy onset in infancy, fever sensitivity and occurrence of seizures in clusters are key features. Seizures remit in the majority of patients during teenage years. Intellectual disability and behavioural disturbances are common. Fifty percent of all mutations are missense mutations, located in the extracellular domains only. Truncating mutations have been identified in all protein domains. One ASD proband carried one missense mutation predicted to have a deleterious effect, suggesting that ASD in males can be associated with PCDH19 mutations.
Assuntos
Caderinas/genética , Transtornos Globais do Desenvolvimento Infantil/epidemiologia , Transtornos Globais do Desenvolvimento Infantil/genética , Epilepsia/epidemiologia , Epilepsia/genética , Mutação/fisiologia , Adolescente , Caderinas/fisiologia , Criança , Transtornos Globais do Desenvolvimento Infantil/complicações , Pré-Escolar , Estudos de Coortes , Epilepsias Mioclônicas/epidemiologia , Epilepsias Mioclônicas/genética , Epilepsia/complicações , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Deficiência Intelectual/complicações , Deficiência Intelectual/epidemiologia , Deficiência Intelectual/genética , Masculino , Penetrância , Protocaderinas , Caracteres Sexuais , SíndromeRESUMO
Photoparoxysmal response (PPR) is considered to be a risk factor for idiopathic generalised epilepsy (IGE) and it has a strong genetic basis. Two genome-wide linkage studies have been published before and they identified loci for PPR at 6p21, 7q32, 13q13, 13q31 and 16p13. Here we combine these studies, augmented with additional families, in a mega-analysis of 100 families. Non-parametric linkage analysis identified three suggestive peaks for photosensitivity, two of which are novel (5q35.3 and 8q21.13) and one has been found before (16p13.3). We found no evidence for linkage at four previously detected loci (6p21, 7q32, 13q13 and 13q31). Our results suggest that the different family data sets are not linked to a shared locus. Detailed analysis showed that the peak at 16p13 was mainly supported by a single subset of families, while the peaks at 5q35 and 8q21 had weak support from multiple subsets. Family studies clearly support the role of PPR as a risk factor for IGE. This mega-analysis shows that distinct loci seem to be linked to subsets of PPR-positive families that may differ in subtle clinical phenotypes or geographic origin. Further linkage studies of PPR should therefore include in-depth phenotyping to make appropriate subsets and increase genetic homogeneity.
Assuntos
Epilepsia Reflexa/genética , Ligação Genética/genética , Genoma Humano/genética , Mapeamento Cromossômico/métodos , Cromossomos Humanos Par 16/genética , Cromossomos Humanos Par 5/genética , Cromossomos Humanos Par 8/genética , Feminino , Predisposição Genética para Doença , Humanos , MasculinoRESUMO
CONTEXT: Dyslexia is a common disorder with a strong genetic component, but despite significant research effort, the aetiology is still largely unknown. OBJECTIVE: To identify loci contributing to dyslexia risk. METHODS: This was a genomewide linkage analysis in a single large family. Dutch families with at least two first degree relatives suffering from dyslexia participated in the study. Participants were recruited through an advertisement campaign in papers and magazines. The main outcome measure was linkage between genetic markers and dyslexia phenotype. RESULTS: Using parametric linkage analysis, we found strong evidence for a locus influencing dyslexia on Xq27.3 (multipoint lod = 3.68). Recombinations in two family members flanked an 8 cM region, comprising 11 currently confirmed genes. All four males carrying the risk haplotype had very low scores on the reading tests. The presentation in females was more variable, but 8/9 females carrying the risk haplotype were diagnosed dyslexic by our composite score, so we considered the putative risk allele to be dominant with reduced penetrance. Linkage was not found in an additional collection of affected sibling pairs. CONCLUSIONS: A locus influencing dyslexia risk is probably located between markers DXS1227 and DXS8091 on the X chromosome, closely situated to a locus indicated by a published genome scan of English sibling pairs. Although the locus may not be a common cause for dyslexia, the relatively small and gene poor region offers hope to identify the responsible gene.
