RESUMO
Epilepsies are common neurological disorders and genetic factors contribute to their pathogenesis. Copy number variations (CNVs) are increasingly recognized as an important etiology of many human diseases including epilepsy. Whole-exome sequencing (WES) is becoming a standard tool for detecting pathogenic mutations and has recently been applied to detecting CNVs. Here, we analyzed 294 families with epilepsy using WES, and focused on 168 families with no causative single nucleotide variants in known epilepsy-associated genes to further validate CNVs using 2 different CNV detection tools using WES data. We confirmed 18 pathogenic CNVs, and 2 deletions and 2 duplications at chr15q11.2 of clinically unknown significance. Of note, we were able to identify small CNVs less than 10 kb in size, which might be difficult to detect by conventional microarray. We revealed 2 cases with pathogenic CNVs that one of the 2 CNV detection tools failed to find, suggesting that using different CNV tools is recommended to increase diagnostic yield. Considering a relatively high discovery rate of CNVs (18 out of 168 families, 10.7%) and successful detection of CNV with <10 kb in size, CNV detection by WES may be able to surrogate, or at least complement, conventional microarray analysis.
Assuntos
Variações do Número de Cópias de DNA , Epilepsia/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Testes Genéticos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Criança , Pré-Escolar , Hibridização Genômica Comparativa , Biologia Computacional/métodos , Epilepsia/diagnóstico , Exoma , Feminino , Estudos de Associação Genética/métodos , Testes Genéticos/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Sequenciamento do Exoma , Adulto JovemRESUMO
Febrile infection-related epilepsy syndrome (FIRES), or acute encephalitis with refractory, repetitive partial seizures (AERRPS), is an epileptic encephalopathy beginning with fever-mediated seizures. The etiology remains unclear. To elucidate the genetic background of FIRES/AERRPS (hereafter FIRES), we recruited 19 Japanese patients, genotyped polymorphisms of the IL1B, IL6, IL10, TNFA, IL1RN, SCN1A and SCN2A genes, and compared their frequency between the patients and controls. For IL1RN, the frequency of a variable number of tandem repeat (VNTR) allele, RN2, was significantly higher in the patients than in controls (p=0.0067), and A allele at rs4251981 in 5' upstream of IL1RN with borderline significance (p=0.015). Haplotype containing RN2 was associated with an increased risk of FIRES (OR 3.88, 95%CI 1.40-10.8, p=0.0057). For SCN1A, no polymorphisms showed a significant association, whereas a missense mutation, R1575C, was found in two patients. For SCN2A, the minor allele frequency of G allele at rs1864885 was higher in patients with borderline significance (p=0.011). We demonstrated the association of IL1RN haplotype containing RN2 with FIRES, and showed a possible association of IL1RN rs4251981 G>A and SCN2A rs1864885 A>G, in Japanese patients. These preliminary findings suggest the involvement of multiple genetic factors in FIRES, which needs to be confirmed by future studies in a larger number of FIRES cases.
Assuntos
Encefalopatias/genética , Citocinas/genética , Predisposição Genética para Doença/genética , Polimorfismo Genético/genética , Canais de Sódio/genética , Encefalopatias/complicações , Criança , Pré-Escolar , Epilepsias Parciais/complicações , Feminino , Genótipo , Humanos , Lactente , Japão , Masculino , Estudos Retrospectivos , Convulsões Febris/complicaçõesRESUMO
Velopharyngeal closure plays an important role in preventing air pressure leakage during swallowing and phonation from oropharynx to nasopharynx. Levator veli palatini muscle activity is influenced by oral and nasal air pressure, volume of the swallow bolus and postural changes. However, it is unclear how velopharyngeal closing pressure is affected by reclining posture. The purpose of this study was to investigate the effects of reclining posture on velopharyngeal closing pressure during swallowing and phonation. Nine healthy male volunteers (age range, 27-34 years) participated in this study. Velopharyngeal closing pressure during a dry swallow, a 5-mL liquid swallow, a 5-mL honey-thick liquid swallow and phonations of /Pâ§/ and /Kâ§/ were evaluated in an upright posture and at reclining postures of 60° and 30°. A manometer catheter was inserted transnasally onto the soft palate, and each trial was repeated three times. A solid-state manometer catheter with an intra-luminal transducer was used to evaluate the amplitude and duration of each trial, and data were statistically analysed. Average amplitudes during dry and liquid swallows were significantly lower in reclining postures compared with the upright posture, but the amplitude was not significantly different during the thick liquid swallow. Average durations were not affected by postural changes. The amplitudes during phonations were lower in reclining postures, but the differences were not significant. Velopharyngeal closure is significantly affected by reclining posture. This suggests that velopharyngeal closing pressure may be adjusted according to afferent inputs, such as reclining posture and bolus viscosity.