Whole-exome sequencing identifies high-confidence genes for tic disorders in a Chinese Han population.

BACKGROUND: Tic disorder (TD) is a polygenic neurodevelopmental disorder with high susceptibility. However, identifying high-confidence risk genes has been challenging due to poor replication across multiple studies. METHODS: Whole-exome sequencing was performed on 390 TD patients and 372 unaffected individuals in a Chinese Han population. Analysis of variance, burden analysis and in silico prediction were used to identify candidate genes for TD. To facilitate data analysis and to focus on high-confidence genes, we defined a panel of 160 genes as known causal or candidate TD genes from previous studies. Gene enrichment and protein-protein interaction analysis were utilized to detect potential novel TD risk genes. RESULTS: Totally, 14 variants across 12 known TD candidate genes were considered potential susceptibility variants. Ten variants across 10 known TD candidate genes were identified as potential disease-causing variants. Burden analysis identified variants of 28 known genes were significantly excess in TD patients. In addition, 354 previously unproven TD genes are over-represented in patients. Genes enriched in the PI3K-Akt signaling, sphingolipid metabolism and serotonergic synaptic pathways, as well as those interacting with FN1, were considered potential new candidate genes for TD. CONCLUSIONS: This is the largest WES study focusing on TD patients in a Chinese Han population. Several variants recurring in our cohort were identified as high-confidence risk loci for TD. Moreover, we provided potential new risk genes that may be prioritized for further investigation.

Understanding inter-individual variability in pharmacokinetics/pharmacodynamics of aripiprazole in children with tic disorders: Individualized administration based on physiological development and CYP2D6 genotypes.

Objective: This study aims to develop a combined population pharmacokinetic (PPK) model for aripiprazole (ARI) and its main active metabolite dehydroaripiprazole (DARI) in pediatric patients with tic disorders (TD), to investigate the inter-individual variability caused by physiological and genetic factors in pharmacokinetics of ARI and optimize the dosing regimens for pediatric patients. Methods: A prospective PPK research was performed in Chinese children with TD. Totally 84 patients aged 4.83-17.33 years were obtained for the pharmacokinetic analysis. 27 CYP2D6 and ABCB1 gene alleles were detected. Moreover, the clinical efficacy was evaluated according to reduction rate of Yale Global Tic Severity Scale (YGTSS) score at the 12th week comparing with the baseline. Monte Carlo simulations were used to evaluate and optimize dosing regimens. Results: The PPK model was established to predict the concentrations of ARI and DARI. Body weight and CYP2D6 genotype were the significant covariates affecting the clearance of ARI. The DARI/ARI metabolic ratios (MRs) of AUC24h, Cmin and Cmax at the steady state of results were ultra-rapid metabolizers (UMs) > normal metabolizers (NMs) > intermediated metabolizers (IMs). MRs could be used to distinguish UMs or IMs from other patients. The best predictor of clinical efficacy for TD was the trough concentration of ARI and the cut-off point was 101.636 ng/ml. Conclusion: The pharmacokinetics of ARI and DARI in pediatric TD were significantly influenced by body weight and CYP2D6 genotype. Individualized dosing regimens were recommended for pediatric patients with TD to ensure clinical efficacy.

A Pilot Study on Plasma and Urine Neurotransmitter Levels in Children with Tic Disorders.

BACKGROUND: Tic disorders (TDs), including Tourette syndrome, are childhood-onset neuropsychiatric disorders characterized by motor and/or vocal tics that commonly affect children's physical and mental health. The pathogenesis of TDs may be related to abnormal neurotransmitters in the cortico-striatal-thalamo-cortical circuitry, especially dopaminergic, glutamatergic, and serotonergic neurotransmitters. The purpose of this study was to preliminarily investigate the differences in the three types of neurotransmitters in plasma and urine between children with TD and healthy children. METHODS: We collected 94 samples of plasma and 69 samples of urine from 3-12-year-old Chinese Han children with TD before treatment. The plasma and urine of the same number of healthy Chinese Han children, matched for age and sex, participating in a physical examination, were collected. Ultra-performance liquid chromatography-tandem mass spectrometry was used to detect the three types of neurotransmitters in the above samples. RESULTS: The plasma levels of norepinephrine, glutamic acid, and γ-aminobutyric acid, and the urine levels of normetanephrine and 5-hydroxyindoleacetic acid were higher in the TD children than in healthy children. The area under the curve (AUC) values of the above neurotransmitters in plasma and urine analyzed by receiver operating characteristic curve analysis were all higher than 0.6, with significant differences. Among them, the combined AUC of dopamine, norepinephrine, normetanephrine, glutamic acid, and γ-aminobutyric acid in the 8-12-year-old subgroup was 0.930, and the sensitivity and specificity for TD were 0.821 and 0.974, respectively (p = 0.000). CONCLUSIONS: There are differences in plasma and urine neurotransmitters between TD children and healthy children, which lays a foundation for further research on the pathogenesis of TD.

De novo variants in AGO1 recapitulate a heterogeneous neurodevelopmental disorder phenotype.

AGO1, as one of the rare genes in neurodevelopmental disorders, is involved in the microRNA-induced silencing complex. Here, we describe the clinical and genetic features of 18 individuals with de novo AGO1 variants: four new and 14 previously reported. Three variants are identified: two in-frame deletion variants and one missense variant. The spectrum of AGO1-related disorders included global development delay (GDD), intellectual disability (ID) with or without epilepsy, autism spectrum disorder, hypotonia and dysmorphisms. Focal seizures are the most common type of seizure, occasionally with atypical absence. Mild deafness may be a new phenotype of AGO1-releated disease. Gly199Ser may be a hot-spot variant of AGO1 with the same phenotype: GDD/ID, intractable epilepsy, remarkably with Rolandic discharges, and even reaching electrical status epilepticus during sleep.

Generation of an induced pluripotent stem cell line ATCi001-A from a three-year-old Chinese girl with Brown-Vialetto-Van Laere syndrome-2.

Brown-Vialetto-Van Laere syndrome-2 is a rare neurological disorder characterized by sensory neuronopathy and pontobulbar palsy, caused by variations in SLC52A2 and SLC52A3 genes, encoding the riboflavin transporters. By reprogramming with SOX2, KLF4, c-MYC and OCT3/4, we generated an iPSC cell line from peripheral blood mononuclear cells (PBMCs) collected from a three-year-old Chinese female individual to be used as a disease model. By fully examination, the resulting iPSCs expressed pluripotency-associated stem cell markers, maintained the normal karyotype and proliferative potential for three-germ layer differentiation.

Child-Onset Cerebellar Ataxia Caused by Two Compound Heterozygous Variants in ADPRS Gene: A Case Report.

Background: Gene variants of ADP-ribosylserine hydrosylase, also known as ADP-ribosylhydrolase-like 2 (ADPRS or ADPRLH2; OMIM: 610624), can cause stress-induced childhood-onset neurodegeneration with variable ataxia and seizures (CONDSIAS, OMIM: 618170), an ultra-rare neurodegenerative autosomal recessive disorder. ADPRS encodes ADP-ribosylhydrolase 3, which removes poly(ADP-ribose) polymers, whose posttranslational addition occurs under stressful conditions. Case Presentation: After a respiratory tract infection, a 30-month-old male patient presented with unsteady gait that rendered walking impossible without external help. Neurological examination revealed acute cerebellar ataxia, electroencephalogram results were abnormal, and brain magnetic resonance imaging revealed slightly widened cerebellar sulci. Laboratory tests showed decreased levels of thyroid-stimulating hormone, and increased levels of plasma lactic acid and serum cardiac enzymes. The cerebrospinal fluid glucose test was positive. Four months after onset, the patient died of sudden convulsions. Using whole exome sequencing, we identified two novel compound heterozygous ADPRS variants: NM_017825.3:c.580C>T (p.Gln194Ter) and NM_017825.3:c.803-1G>A. RNA sequencing indicated that the former mutation might cause nonsense-mediated mRNA decay. The c.803-1G>A variant was found to be a splice-site mutation that leads to the transcriptional retention of intron 5. According to the guidelines of the American College of Medical Genetics and Genomics, the two variants were classified as pathogenic. Conclusion: We present the first report of the existence of two compound heterozygous variants of ADPRS, which leads to CONDSIAS.