A Rare Novel CLCN2 Variation and Risk of Gilles de la Tourette Syndrome: Whole-Exome Sequencing in a Multiplex Family and a Follow-Up Study in a Chinese Population

Abstract

Rare inherited variations in multiplex families with Gilles de la Tourette syndrome (GTS) are suggested to play an important role in the genetic etiology of GTS. In order to explore the rare inherited variations with the risk of GTS, whole-exome sequencing (WES) was performed in a family with three affected patients with GTS. Among the five novel rare variations identified by WES, CLCN2 G161S was presented in three patients, but not in four unaffected individuals, and thus co-segregated with GTS. A validation study was also performed in a cohort of Chinses Han population to further examine the identified rare variants. CLCN2 G161S was genotyped in 207 sporadic patients with tic disorder including 111 patients with GTS and 489 healthy controls. Compared with that in controls [allele frequency (AF) = 0], CLCN2 G161S had higher variant AF in patients with tic (AF = 0.00483) and in patients with GTS (0.00900), respectively. However, this variant was absent from the current 1000 Genome databases, and the variant AF is very low in the current public databases including ExAC (AF = 0.00001) and gnomAD (AF = 0.00003). Our results suggest that CLCN2 G161S might play a major role in the genetic etiology of GTS, at least in a Chinese Han population.

Molecular Landscape of Tourette’s Disorder

“…Based on the type of omics evidence they provide, we classified the studies as guiding (genomics studies), corroborating (epigenomics and transcriptomics studies) and additional (metabolomics and microbiome) studies. For the genomics data, we compiled a list of TD candidate genes from studies of rare genetic variants/events—(i) eight chromosomal rearrangements studies [ 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 ] (the main list includes 15 genes and the extended list consists of 23 genes), (ii) fifteen single-nucleotide variation (SNV) studies [ 27 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ] (the main list includes 134 genes and the extended list consists of 846 genes), and (iii) eleven copy number variations (CNV) studies [ 37 , 44 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 ] (the main list includes 52 genes, and the extended list consists of 956 genes)—and studies of common genetic variants (of single-nucleotide polymorphisms or SNPs), i.e., genome-wide association studies (GWASs). The GWAS-derived genes include the results from our own unpublished analyses of the summary statistics data from the TD GWAS by Yu et al [ 55 ], i.e., 113 genes from the MAGMA analysis, 224 genes from the FUMA analysis, and 143 genes from the TWAS analysis.…”

Morphological and Molecular Changes in the Cortex and Cerebellum of Immunocompetent Mice Infected with Zika Virus

“…In addition, in mouse models of spinocerebellar ataxia, the loss of Calb and Parv has been reported in Purkinje neurons [ 108 ]. Mutations in CLCN2 have also been associated with cerebellar ataxia occurring during dystrophic leukoencephalopathy, a neurodevelopmental disorder characterized by cerebellar ataxia, spasticity, optic neuropathy, and chorioretinopathy with visual defects [ 109 , 110 ].…”

“…Knockout mice for this gene exhibit blindness, retinal damage, and myelin vacuolization in brain tissue and the spinal cord [ 112 , 113 ]. Dysfunction of this protein has also been associated with neurodevelopmental disorders, Tourette syndrome, and idiopathic epilepsy; however, a direct relationship between the latter and alterations in the channel has not yet been described [ 109 ].…”

Tourette syndrome research highlights from 2020

“…These studies are divided into three main approaches: 1) whole exome sequencing (WES); 2) microarrays, which aim to identify rare coding variants or copy number variants with large effects; and 3) association studies that mainly focus on common variants. WES sequencing in a Chinese family with several affected members identified a missense variant in chloride voltage-gated channel 2 (CLCN2) (G161S), which was enriched in a TS cohort (Yuan et al 2020). Loss-of-function variants in CLCN2, encoding chloride channel 2 (CLC-2), cause a leukoencephalopathy with ataxia, a recessive monogenic disorder (Depienne et al 2013).…”