The Dyslexia-associated gene KIAA0319L is involved in neuronal migration in the developing chick visual system.

The gene KIAA0319-Like (KIAA0319L) is thought to confer susceptibility for developmental dyslexia. Dyslexia may be caused by alterations in neuronal migration, and in utero knockdown of KIAA0319L in rats indicated migration errors. However, studies carried out with KIAA0319L knockout mice did not reveal an altered neuronal migration phenotype. Gene knockout may activate compensatory mechanisms to buffer against genetic mutations during development. Here we assessed the role of KIAA0319L on migrating neurons in the chick developing tectum. Whole mount in situ hybridization was performed for KIAA0319L on embryonic day (E)3 - E5 chick embryos and in situ hybridization on sections was performed at later stages. The specificity and efficiency of engineered microRNA (miRNA) constructs targeting KIAA0319L for knocking down KIAA0319L were verified. miRNAs were electroporated into E5 chick optic tecta. Our studies demonstrate that KIAA0319L is expressed in the developing chick visual system, as well as in the otic vesicles. Knockdown of KIAA0319L in the optic tectum results in abnormal neuronal migration, strengthening the argument that KIAA0319L is involved in this developmental process.

Integrated analysis of single-cell chromatin state and transcriptome identified common vulnerability despite glioblastoma heterogeneity.

In 2021, the World Health Organization reclassified glioblastoma, the most common form of adult brain cancer, into isocitrate dehydrogenase (IDH)-wild-type glioblastomas and grade IV IDH mutant (G4 IDHm) astrocytomas. For both tumor types, intratumoral heterogeneity is a key contributor to therapeutic failure. To better define this heterogeneity, genome-wide chromatin accessibility and transcription profiles of clinical samples of glioblastomas and G4 IDHm astrocytomas were analyzed at single-cell resolution. These profiles afforded resolution of intratumoral genetic heterogeneity, including delineation of cell-to-cell variations in distinct cell states, focal gene amplifications, as well as extrachromosomal circular DNAs. Despite differences in IDH mutation status and significant intratumoral heterogeneity, the profiled tumor cells shared a common chromatin structure defined by open regions enriched for nuclear factor 1 transcription factors (NFIA and NFIB). Silencing of NFIA or NFIB suppressed in vitro and in vivo growths of patient-derived glioblastomas and G4 IDHm astrocytoma models. These findings suggest that despite distinct genotypes and cell states, glioblastoma/G4 astrocytoma cells share dependency on core transcriptional programs, yielding an attractive platform for addressing therapeutic challenges associated with intratumoral heterogeneity.

Language and reading impairments are associated with increased prevalence of non-right-handedness.

Handedness has been studied for association with language-related disorders because of its link with language hemispheric dominance. No clear pattern has emerged, possibly because of small samples, publication bias, and heterogeneous criteria across studies. Non-right-handedness (NRH) frequency was assessed in N = 2503 cases with reading and/or language impairment and N = 4316 sex-matched controls identified from 10 distinct cohorts (age range 6-19 years old; European ethnicity) using a priori set criteria. A meta-analysis (Ncases  = 1994) showed elevated NRH % in individuals with language/reading impairment compared with controls (OR = 1.21, CI = 1.06-1.39, p = .01). The association between reading/language impairments and NRH could result from shared pathways underlying brain lateralization, handedness, and cognitive functions.

Identification of brain cell types underlying genetic association with word reading and correlated traits.

Neuroimaging studies implicate multiple cortical regions in reading ability/disability. However, the neural cell types integral to the reading process are unknown. To contribute to this gap in knowledge, we integrated genetic results from genome-wide association studies for word reading (n = 5054) with gene expression datasets from adult/fetal human brain. Linkage disequilibrium score regression (LDSC) suggested that variants associated with word reading were enriched in genes expressed in adult excitatory neurons, specifically layer 5 and 6 FEZF2 expressing neurons and intratelencephalic (IT) neurons, which express the marker genes LINC00507, THEMIS, or RORB. Inhibitory neurons (VIP, SST, and PVALB) were also found. This finding was interesting as neurometabolite studies previously implicated excitatory-inhibitory imbalances in the etiology of reading disabilities (RD). We also tested traits that shared genetic etiology with word reading (previously determined by polygenic risk scores): attention-deficit/hyperactivity disorder (ADHD), educational attainment, and cognitive ability. For ADHD, we identified enrichment in L4 IT adult excitatory neurons. For educational attainment and cognitive ability, we confirmed previous studies identifying multiple subclasses of adult cortical excitatory and inhibitory neurons, as well as astrocytes and oligodendrocytes. For educational attainment and cognitive ability, we also identified enrichment in multiple fetal cortical excitatory and inhibitory neurons, intermediate progenitor cells, and radial glial cells. In summary, this study supports a role of excitatory and inhibitory neurons in reading and excitatory neurons in ADHD and contributes new information on fetal cell types enriched in educational attainment and cognitive ability, thereby improving our understanding of the neurobiological basis of reading/correlated traits.

Hypothesis-driven genome-wide association studies provide novel insights into genetics of reading disabilities.

Reading Disability (RD) is often characterized by difficulties in the phonology of the language. While the molecular mechanisms underlying it are largely undetermined, loci are being revealed by genome-wide association studies (GWAS). In a previous GWAS for word reading (Price, 2020), we observed that top single-nucleotide polymorphisms (SNPs) were located near to or in genes involved in neuronal migration/axon guidance (NM/AG) or loci implicated in autism spectrum disorder (ASD). A prominent theory of RD etiology posits that it involves disturbed neuronal migration, while potential links between RD-ASD have not been extensively investigated. To improve power to identify associated loci, we up-weighted variants involved in NM/AG or ASD, separately, and performed a new Hypothesis-Driven (HD)-GWAS. The approach was applied to a Toronto RD sample and a meta-analysis of the GenLang Consortium. For the Toronto sample (n = 624), no SNPs reached significance; however, by gene-set analysis, the joint contribution of ASD-related genes passed the threshold (p~1.45 × 10-2, threshold = 2.5 × 10-2). For the GenLang Cohort (n = 26,558), SNPs in DOCK7 and CDH4 showed significant association for the NM/AG hypothesis (sFDR q = 1.02 × 10-2). To make the GenLang dataset more similar to Toronto, we repeated the analysis restricting to samples selected for reading/language deficits (n = 4152). In this GenLang selected subset, we found significant association for a locus intergenic between BTG3-C21orf91 for both hypotheses (sFDR q < 9.00 × 10-4). This study contributes candidate loci to the genetics of word reading. Data also suggest that, although different variants may be involved, alleles implicated in ASD risk may be found in the same genes as those implicated in word reading. This finding is limited to the Toronto sample suggesting that ascertainment influences genetic associations.

Language Difficulties in School-Age Children With Developmental Dyslexia.

Developmental dyslexia (DD) is a common reading disability, affecting 5% to 11% of children in North America. Children classified as having DD often have a history of early language delay (ELD) or language impairments. Nevertheless, studies have reported conflicting results as to the association between DD-ELD and the extent of current language difficulties in children with DD. To examine these relationships, we queried the parents of school-age children with reading difficulties on their child's early and current language ability. Siblings were also examined. Children were directly assessed using quantitative tests of language and reading skills. To compare this study with the literature, we divided the sample (N = 674) into three groups: DD, intermediate readers (IR), and skilled readers (SR). We found a significant association between DD and ELD, with parents of children in the DD/IR groups reporting their children put words together later than the SR group. We also found a significant association between DD and language difficulties, with children with low reading skills having low expressive/receptive language abilities. Finally, we identified early language predicted current language, which predicted reading skills. These data contribute to research indicating that children with DD experience language difficulties, suggesting early recognition may help identify reading problems.

Synaptic processes and immune-related pathways implicated in Tourette syndrome.

Tourette syndrome (TS) is a neuropsychiatric disorder of complex genetic architecture involving multiple interacting genes. Here, we sought to elucidate the pathways that underlie the neurobiology of the disorder through genome-wide analysis. We analyzed genome-wide genotypic data of 3581 individuals with TS and 7682 ancestry-matched controls and investigated associations of TS with sets of genes that are expressed in particular cell types and operate in specific neuronal and glial functions. We employed a self-contained, set-based association method (SBA) as well as a competitive gene set method (MAGMA) using individual-level genotype data to perform a comprehensive investigation of the biological background of TS. Our SBA analysis identified three significant gene sets after Bonferroni correction, implicating ligand-gated ion channel signaling, lymphocytic, and cell adhesion and transsynaptic signaling processes. MAGMA analysis further supported the involvement of the cell adhesion and trans-synaptic signaling gene set. The lymphocytic gene set was driven by variants in FLT3, raising an intriguing hypothesis for the involvement of a neuroinflammatory element in TS pathogenesis. The indications of involvement of ligand-gated ion channel signaling reinforce the role of GABA in TS, while the association of cell adhesion and trans-synaptic signaling gene set provides additional support for the role of adhesion molecules in neuropsychiatric disorders. This study reinforces previous findings but also provides new insights into the neurobiology of TS.

DNA Variant in the RPGRIP1L Gene Influences Alternative Splicing.

The retinitis pigmentosa GTPase regulator interacting protein 1-like (RPGRIP1L) gene encodes a ciliary protein that is critical for processes related to brain development, including development of left-right asymmetry, sonic hedgehog signaling, and neural tube formation. RPGRIP1L is a risk factor for retinal degeneration, and rare, deleterious variants in the RPGRIP1L gene cause Joubert syndrome and Meckel syndrome, both autosomal recessive disorders. These syndromes are characterized by dysfunctional primary cilia that result in abnormal development - and even lethality in the case of Meckel syndrome. Genetic studies have also implicated RPGRIP1L in psychiatric disorders by suggestive findings from genome-wide association studies and findings from rare-variant exome analyses for bipolar disorder and de novo mutations in autism. In this study we identify a common variant in RPGRIP1L, rs7203525, that influences alternative splicing, increasing the inclusion of exon 20 of RPGRIP1L. We detected this alternative splicing association in human postmortem brain tissue samples and, using a minigene assay combined with in vitro mutagenesis, confirmed that the alternative splicing is attributable to the alleles of this variant. The predominate RPGRIP1L isoform expressed in adult brains does not contain exon 20; thus, a shift to include this exon may impact brain function.

Genome-wide association study of word reading: Overlap with risk genes for neurodevelopmental disorders.

Reading disabilities (RD) are the most common neurocognitive disorder, affecting 5% to 17% of children in North America. These children often have comorbid neurodevelopmental/psychiatric disorders, such as attention deficit/hyperactivity disorder (ADHD). The genetics of RD and their overlap with other disorders is incompletely understood. To contribute to this, we performed a genome-wide association study (GWAS) for word reading. Then, using summary statistics from neurodevelopmental/psychiatric disorders, we computed polygenic risk scores (PRS) and used them to predict reading ability in our samples. This enabled us to test the shared aetiology between RD and other disorders. The GWAS consisted of 5.3 million single nucleotide polymorphisms (SNPs) and two samples; a family-based sample recruited for reading difficulties in Toronto (n = 624) and a population-based sample recruited in Philadelphia [Philadelphia Neurodevelopmental Cohort (PNC)] (n = 4430). The Toronto sample SNP-based analysis identified suggestive SNPs (P ~ 5 × 10-7 ) in the ARHGAP23 gene, which is implicated in neuronal migration/axon pathfinding. The PNC gene-based analysis identified significant associations (P < 2.72 × 10-6 ) for LINC00935 and CCNT1, located in the region of the KANSL2/CCNT1/LINC00935/SNORA2B/SNORA34/MIR4701/ADCY6 genes on chromosome 12q, with near significant SNP-based analysis. PRS identified significant overlap between word reading and intelligence (R2 = 0.18, P = 7.25 × 10-181 ), word reading and educational attainment (R2 = 0.07, P = 4.91 × 10-48 ) and word reading and ADHD (R2 = 0.02, P = 8.70 × 10-6 ; threshold for significance = 7.14 × 10-3 ). Overlap was also found between RD and autism spectrum disorder (ASD) as top-ranked genes were previously implicated in autism by rare and copy number variant analyses. These findings support shared risk between word reading, cognitive measures, educational outcomes and neurodevelopmental disorders, including ASD.

A compendium of promoter-centered long-range chromatin interactions in the human genome.

A large number of putative cis-regulatory sequences have been annotated in the human genome, but the genes they control remain poorly defined. To bridge this gap, we generate maps of long-range chromatin interactions centered on 18,943 well-annotated promoters for protein-coding genes in 27 human cell/tissue types. We use this information to infer the target genes of 70,329 candidate regulatory elements and suggest potential regulatory function for 27,325 noncoding sequence variants associated with 2,117 physiological traits and diseases. Integrative analysis of these promoter-centered interactome maps reveals widespread enhancer-like promoters involved in gene regulation and common molecular pathways underlying distinct groups of human traits and diseases.

Interrogating the Genetic Determinants of Tourette's Syndrome and Other Tic Disorders Through Genome-Wide Association Studies.

OBJECTIVE: Tourette's syndrome is polygenic and highly heritable. Genome-wide association study (GWAS) approaches are useful for interrogating the genetic architecture and determinants of Tourette's syndrome and other tic disorders. The authors conducted a GWAS meta-analysis and probed aggregated Tourette's syndrome polygenic risk to test whether Tourette's and related tic disorders have an underlying shared genetic etiology and whether Tourette's polygenic risk scores correlate with worst-ever tic severity and may represent a potential predictor of disease severity. METHODS: GWAS meta-analysis, gene-based association, and genetic enrichment analyses were conducted in 4,819 Tourette's syndrome case subjects and 9,488 control subjects. Replication of top loci was conducted in an independent population-based sample (706 case subjects, 6,068 control subjects). Relationships between Tourette's polygenic risk scores (PRSs), other tic disorders, ascertainment, and tic severity were examined. RESULTS: GWAS and gene-based analyses identified one genome-wide significant locus within FLT3 on chromosome 13, rs2504235, although this association was not replicated in the population-based sample. Genetic variants spanning evolutionarily conserved regions significantly explained 92.4% of Tourette's syndrome heritability. Tourette's-associated genes were significantly preferentially expressed in dorsolateral prefrontal cortex. Tourette's PRS significantly predicted both Tourette's syndrome and tic spectrum disorders status in the population-based sample. Tourette's PRS also significantly correlated with worst-ever tic severity and was higher in case subjects with a family history of tics than in simplex case subjects. CONCLUSIONS: Modulation of gene expression through noncoding variants, particularly within cortico-striatal circuits, is implicated as a fundamental mechanism in Tourette's syndrome pathogenesis. At a genetic level, tic disorders represent a continuous spectrum of disease, supporting the unification of Tourette's syndrome and other tic disorders in future diagnostic schemata. Tourette's PRSs derived from sufficiently large samples may be useful in the future for predicting conversion of transient tics to chronic tic disorders, as well as tic persistence and lifetime tic severity.

Rare Copy Number Variants in NRXN1 and CNTN6 Increase Risk for Tourette Syndrome.

Tourette syndrome (TS) is a model neuropsychiatric disorder thought to arise from abnormal development and/or maintenance of cortico-striato-thalamo-cortical circuits. TS is highly heritable, but its underlying genetic causes are still elusive, and no genome-wide significant loci have been discovered to date. We analyzed a European ancestry sample of 2,434 TS cases and 4,093 ancestry-matched controls for rare (< 1% frequency) copy-number variants (CNVs) using SNP microarray data. We observed an enrichment of global CNV burden that was prominent for large (> 1 Mb), singleton events (OR = 2.28, 95% CI [1.39-3.79], p = 1.2 × 10-3) and known, pathogenic CNVs (OR = 3.03 [1.85-5.07], p = 1.5 × 10-5). We also identified two individual, genome-wide significant loci, each conferring a substantial increase in TS risk (NRXN1 deletions, OR = 20.3, 95% CI [2.6-156.2]; CNTN6 duplications, OR = 10.1, 95% CI [2.3-45.4]). Approximately 1% of TS cases carry one of these CNVs, indicating that rare structural variation contributes significantly to the genetic architecture of TS.

A Compendium of Chromatin Contact Maps Reveals Spatially Active Regions in the Human Genome.

The three-dimensional configuration of DNA is integral to all nuclear processes in eukaryotes, yet our knowledge of the chromosome architecture is still limited. Genome-wide chromosome conformation capture studies have uncovered features of chromatin organization in cultured cells, but genome architecture in human tissues has yet to be explored. Here, we report the most comprehensive survey to date of chromatin organization in human tissues. Through integrative analysis of chromatin contact maps in 21 primary human tissues and cell types, we find topologically associating domains highly conserved in different tissues. We also discover genomic regions that exhibit unusually high levels of local chromatin interactions. These frequently interacting regions (FIREs) are enriched for super-enhancers and are near tissue-specifically expressed genes. They display strong tissue-specificity in local chromatin interactions. Additionally, FIRE formation is partially dependent on CTCF and the Cohesin complex. We further show that FIREs can help annotate the function of non-coding sequence variants.

Targeted Re-Sequencing Approach of Candidate Genes Implicates Rare Potentially Functional Variants in Tourette Syndrome Etiology.

Although the genetic basis of Tourette Syndrome (TS) remains unclear, several candidate genes have been implicated. Using a set of 382 TS individuals of European ancestry we investigated four candidate genes for TS (HDC, SLITRK1, BTBD9, and SLC6A4) in an effort to identify possibly causal variants using a targeted re-sequencing approach by next generation sequencing technology. Identification of possible disease causing variants under different modes of inheritance was performed using the algorithms implemented in VAAST. We prioritized variants using Variant ranker and validated five rare variants via Sanger sequencing in HDC and SLITRK1, all of which are predicted to be deleterious. Intriguingly, one of the identified variants is in linkage disequilibrium with a variant that is included among the top hits of a genome-wide association study for response to citalopram treatment, an antidepressant drug with off-label use also in obsessive compulsive disorder. Our findings provide additional evidence for the implication of these two genes in TS susceptibility and the possible role of these proteins in the pathobiology of TS should be revisited.

EGFR Mutation Promotes Glioblastoma through Epigenome and Transcription Factor Network Remodeling.

Epidermal growth factor receptor (EGFR) gene amplification and mutations are the most common oncogenic events in glioblastoma (GBM), but the mechanisms by which they promote aggressive tumor growth are not well understood. Here, through integrated epigenome and transcriptome analyses of cell lines, genotyped clinical samples, and TCGA data, we show that EGFR mutations remodel the activated enhancer landscape of GBM, promoting tumorigenesis through a SOX9 and FOXG1-dependent transcriptional regulatory network in vitro and in vivo. The most common EGFR mutation, EGFRvIII, sensitizes GBM cells to the BET-bromodomain inhibitor JQ1 in a SOX9, FOXG1-dependent manner. These results identify the role of transcriptional/epigenetic remodeling in EGFR-dependent pathogenesis and suggest a mechanistic basis for epigenetic therapy.

BDNF Val66Met polymorphism and stressful life events in melancholic childhood-onset depression.

INTRODUCTION: Brain-derived neurotrophic factor (BDNF) polymorphisms have been examined for their contribution toward depression with equivocal results. More homogeneous phenotypes might be used to improve our understanding of genetic liability to depression. The aim of our study was to (a) test for an association between the BDNF Val66Met polymorphism and childhood-onset melancholic depression and (b) to examine the interactive effects of stressful life events (SLE) and the Val66Met polymorphism on the risk of childhood-onset melancholic depression. MATERIALS AND METHODS: A total of 583 depressed probands were involved in this study (162 of the melancholic subtype). Diagnoses were derived through the Interview Schedule for Children and Adolescents - Diagnostic Version and life event data were collected using an Intake General Information Sheet. RESULTS: Overall, 27.8% of the participants fulfilled the criteria for melancholy. In the melancholic group, the proportion of females was higher (53.1%), although there were more males in the overall depressed sample. We detected no significant differences in genotype or allele frequency between the melancholic and the nonmelancholic depressed group. The BDNF Val66Met polymorphism and SLE interaction was not significantly associated with the melancholy outcome. CONCLUSION: In our study, females were more prone to developing the early-onset melancholic phenotype. To our knowledge, this is the first study to investigate the differentiating effect of the genotype and the G×E interaction on the melancholic phenotype in a large sample of depressed young patients. We did not find an association between the melancholic subtype of major depression and the BDNF genotype and SLE interaction in this sample, which is representative of the Hungarian clinic-referred population of depressed youths.

Association study of the SLITRK5 gene and Tourette syndrome.

Tourette syndrome (TS) and obsessive-compulsive disorder commonly occur together. Family studies indicate shared genetic risk factors. SLITRK5, one of a family of six SLITRK genes, has been suggested as a possible candidate gene contributing towards obsessive-compulsive disorder on the basis of the mouse knockout model that shows excessive grooming behaviours that are alleviated with fluoxetine. In this study, we tested the SLITRK5 gene as a candidate for TS in a family-based sample with 377 affected children. Using single nucleotide polymorphisms tagging the gene, we did not find any evidence supporting the association of TS and SLITRK5.

Cross-disorder genome-wide analyses suggest a complex genetic relationship between Tourette's syndrome and OCD.

OBJECTIVE: Obsessive-compulsive disorder (OCD) and Tourette's syndrome are highly heritable neurodevelopmental disorders that are thought to share genetic risk factors. However, the identification of definitive susceptibility genes for these etiologically complex disorders remains elusive. The authors report a combined genome-wide association study (GWAS) of Tourette's syndrome and OCD. METHOD: The authors conducted a GWAS in 2,723 cases (1,310 with OCD, 834 with Tourette's syndrome, 579 with OCD plus Tourette's syndrome/chronic tics), 5,667 ancestry-matched controls, and 290 OCD parent-child trios. GWAS summary statistics were examined for enrichment of functional variants associated with gene expression levels in brain regions. Polygenic score analyses were conducted to investigate the genetic architecture within and across the two disorders. RESULTS: Although no individual single-nucleotide polymorphisms (SNPs) achieved genome-wide significance, the GWAS signals were enriched for SNPs strongly associated with variations in brain gene expression levels (expression quantitative loci, or eQTLs), suggesting the presence of true functional variants that contribute to risk of these disorders. Polygenic score analyses identified a significant polygenic component for OCD (p=2×10(-4)), predicting 3.2% of the phenotypic variance in an independent data set. In contrast, Tourette's syndrome had a smaller, nonsignificant polygenic component, predicting only 0.6% of the phenotypic variance (p=0.06). No significant polygenic signal was detected across the two disorders, although the sample is likely underpowered to detect a modest shared signal. Furthermore, the OCD polygenic signal was significantly attenuated when cases with both OCD and co-occurring Tourette's syndrome/chronic tics were included in the analysis (p=0.01). CONCLUSIONS: Previous work has shown that Tourette's syndrome and OCD have some degree of shared genetic variation. However, the data from this study suggest that there are also distinct components to the genetic architectures of these two disorders. Furthermore, OCD with co-occurring Tourette's syndrome/chronic tics may have different underlying genetic susceptibility compared with OCD alone.

Genetic association signal near NTN4 in Tourette syndrome.

Tourette syndrome (TS) is a neurodevelopmental disorder with a complex genetic etiology. Through an international collaboration, we genotyped 42 single nucleotide polymorphisms (p < 10(-3) ) from the recent TS genomewide association study (GWAS) in 609 independent cases and 610 ancestry-matched controls. Only rs2060546 on chromosome 12q22 (p = 3.3 × 10(-4) ) remained significant after Bonferroni correction. Meta-analysis with the original GWAS yielded the strongest association to date (p = 5.8 × 10(-7) ). Although its functional significance is unclear, rs2060546 lies closest to NTN4, an axon guidance molecule expressed in developing striatum. Risk score analysis significantly predicted case-control status (p = 0.042), suggesting that many of these variants are true TS risk alleles.

Copy number variation in obsessive-compulsive disorder and tourette syndrome: a cross-disorder study.

OBJECTIVE: Obsessive-compulsive disorder (OCD) and Tourette syndrome (TS) are heritable neurodevelopmental disorders with a partially shared genetic etiology. This study represents the first genome-wide investigation of large (>500 kb), rare (<1%) copy number variants (CNVs) in OCD and the largest genome-wide CNV analysis in TS to date. METHOD: The primary analyses used a cross-disorder design for 2,699 case patients (1,613 ascertained for OCD, 1,086 ascertained for TS) and 1,789 controls. Parental data facilitated a de novo analysis in 348 OCD trios. RESULTS: Although no global CNV burden was detected in the cross-disorder analysis or in secondary, disease-specific analyses, there was a 3.3-fold increased burden of large deletions previously associated with other neurodevelopmental disorders (p = .09). Half of these neurodevelopmental deletions were located in a single locus, 16p13.11 (5 case patient deletions: 0 control deletions, p = .08 in the current study, p = .025 compared to published controls). Three 16p13.11 deletions were confirmed de novo, providing further support for the etiological significance of this region. The overall OCD de novo rate was 1.4%, which is intermediate between published rates in controls (0.7%) and in individuals with autism or schizophrenia (2-4%). CONCLUSION: Several converging lines of evidence implicate 16p13.11 deletions in OCD, with weaker evidence for a role in TS. The trend toward increased overall neurodevelopmental CNV burden in TS and OCD suggests that deletions previously associated with other neurodevelopmental disorders may also contribute to these phenotypes.