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Background: Tourette syndrome (TS) is a neurodevelopmental disorder characterized by motor and vocal tics. Several susceptibility loci associated with TS have been identified previously in populations of European descent using genome-wide association studies (GWAS). However, the exact pathogenic mechanism underlying TS is unknown; additionally, the results of previous GWAS for TS were based on Western populations, which may not translate to other populations. Therefore, we conducted a GWAS in Taiwanese patients with TS and chronic tic disorders (CTDs), with an aim to elucidate the genetic basis and potential risk factors for TS in this population., Methods: GWAS was performed on a Taiwanese TS/CTDs cohort with a sample size of 1007 patients with TS and 25,522 ancestry-matched controls. Additionally, polygenic risk score was calculated and assessed., Results: Genome-wide significant locus, rs12313062 (p = 1.43 × 10 -8 ) and other 9 single nucleotide polymorphisms, were identified in chromosomes 12q23.2, associated with DRAM1 and was a novel susceptibility locus identified in TS/CTDs group. DRAM1, a lysosomal transmembrane protein regulated by p53, modulates autophagy and apoptosis, with potential implications for neuropsychiatric conditions associated with autophagy disruption., Conclusions: This study conducted the first GWAS for TS in a Taiwanese population, identifying a significant locus on chromosome 12q23.2 associated with DRAM1. These findings provide novel insights into the neurobiology of TS and potential directions for future research in this area., (© 2024 The Authors. Published by Elsevier B.V. on behalf of Chang Gung University. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

Background: Dravet syndrome (DS) is a rare form of intractable epilepsy. Children with DS often start having seizures in infancy, and gradually develop other seizure types. Several studies have demonstrated that certain gene mutations and submicroscopic copy number variations (CNV) in DS patients are strongly associated with intractable epilepsy. In this study, directed DNA sequencing and microarray technology were used to investigate genomic variations in DS patients., Methods: A total of nine DS patients were enrolled in this genetic study. A detailed medical history was obtained from each participant, and appropriate neurological examinations performed. Seizure types and epilepsy syndromes were classified according to ILAE criteria. The complete coding regions of SCN1A, SCN1B, SCN2A, GABRG2, and GABRD, including the intron/exon boundaries, were sequenced using DNA samples drawn from participants. In addition, whole genome CNV analysis was conducted via SNP microarray analysis., Results: DNA sequencing revealed a mutation in the SCN1A gene in five (55.6%) of the DS patients, within which three missense mutations, c.719T>C (p.Leu240Pro), c.2807A>T (p.Asp936Val), c.4349A>C (p.Gln1450Pro), and two frameshift mutations, c.2277insAACA (p.His759fsX772) and c.3972insT (p.Leu1324fsX1331) were observed. Upon CNV analysis, a novel duplication region, 4q13.1-q13.2, was detected in one DS patient; this variant region contained a gene, EPHA5, related to cerebral neuron development., Conclusion: This study extended the spectrum of SCN1A mutations in Taiwanese DS patients and confirms the high sensitivity of SCN1A for the DS phenotype. In addition, a novel duplication region identified within EPHA5 should be considered in future screening procedures for DS., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Tourette syndrome has a multifactorial etiology in which genetic, environmental, and immunologic factors interact to establish vulnerability. Various interleukin 1 genes are associated with several immunoinflammatory diseases. It is not known whether polymorphisms in those genes are involved in the pathogenesis of Tourette syndrome. In this association study, single nucleotide polymorphisms were used to investigate the distribution of genotypes of the interleukin 1 receptor antagonist gene (IL1RN; alias IL1RA) and of the interleukin 1beta gene (IL1B) in patients with Tourette syndrome. A total of 159 children with Tourette syndrome and 175 healthy control subjects were included in the study. There was no significant difference between patients and control subjects in the distribution of genotype and allele frequencies for IL1B exon 5 and promoter region; however, the number of individuals homozygotic for IL1RN( *)1 was significantly greater (P < 0.0001), and the IL1RN( *)1 allele frequency was significantly higher (P < 0.0001), among patients than among control subjects. The odds ratio for developing Tourette syndrome in individuals with the IL1RN( *)1 allele, compared with IL1RN( *)2, was 7.65. Thus, the IL1RN gene may be a useful marker for prediction of the susceptibility to Tourette syndrome., (Copyright 2010 Elsevier Inc. All rights reserved.)

Missense mutations in the gamma2 subunit of gamma-aminobutyric acid (GABA) receptor gene have recently been described in families with idiopathic generalized epilepsies. This study aimed to evaluate whether polymorphisms of the gamma2 subunit of the GABA receptor gene are associated with idiopathic generalized epilepsies. A total of 77 children with idiopathic generalized epilepsies and 83 normal control subjects were included in the study. Polymerase chain reaction was used to identify the C/T and A/G polymorphisms of the gamma2 subunit of the GABA receptor gene on chromosome 5q33. Genotypes and allelic frequencies in both groups were compared. The gamma2 subunit of the GABA receptor (nucleotide position 3145 in intron G-> A) gene in both groups was not significantly different. In contrast, the gamma2 subunit of GABA receptor (SNP211037)-C allele frequency in patients with idiopathic generalized epilepsies was significantly higher than that in healthy control subjects (P = 0.002). The odds ratio for developing idiopathic generalized epilepsies in individuals with the gamma2 subunit of the GABA receptor (SNP211037)-C/C genotype was 3.61 compared with individuals with the gamma2 subunit of the GABA receptor (SNP211037)-T/T genotype. These data suggest that the gamma2 subunit of the GABA receptor gene might be one of the susceptibility factors for idiopathic generalized epilepsies.

Various studies have shown that brain-derived neurotrophic factor (BDNF) increased neuronal excitability. We tested that BDNF might be involved in the etiology of febrile seizures (FSs). A total of 186 Taiwanese children were divided into two groups: (1) FSs (n = 104); (2) normal control subjects (n = 83). A single base pair polymorphism SNP6265 (Val66Met) at position 196 was analyzed. Our findings suggest that the BDNF polymorphisms were not candidate genetic markers.

Febrile convulsions (FCs) represent the majority of childhood seizures, and patients have a genetic predisposition to their development. The genetic susceptibility to FCs seems to involve multiple genes in most instances. Recent studies provided evidence that mutations in SCN1A represent the most frequent cause of generalized epilepsy with febrile seizures plus an autosomal-dominant epilepsy syndrome. SCN1A mutations alter channel inactivation, resulting in persistent inward sodium current. It is not known if polymorphisms in those genes involved in familial epilepsies also contribute to the pathogenesis of FCs. By performing an association study, we used single nucleotide polymorphisms to investigate the distribution of genotypes of SCN1A in patients with FCs. A total of 104 Taiwanese children with FCs and 83 normal control subjects were included in the study. Polymerase chain reaction was used to identify the A/G polymorphism of the SCN1A gene. The results showed that genotypes and allelic frequencies for the SCN1A gene polymorphisms in both groups were not significantly different. These data suggest that the SCN1A gene might not be one of the susceptibility factors for FCs. Pure FCs and febrile convulsions associated with idiopathic generalized epilepsy may not share a common genetic etiology.