Williams Syndrome Region Research Articles

Extensive characterization of a Williams syndrome murine model shows Gtf2ird1-mediated rescue of select sensorimotor tasks, but no effect on enhanced social behavior.

Williams syndrome is a rare neurodevelopmental disorder exhibiting cognitive and behavioral abnormalities, including increased social motivation, risk of anxiety and specific phobias along with perturbed motor function. Williams syndrome is caused by a microdeletion of 26-28 genes on chromosome 7, including GTF2IRD1, which encodes a transcription factor suggested to play a role in the behavioral profile of Williams syndrome. Duplications of the full region also lead to frequent autism diagnosis, social phobias and language delay. Thus, genes in the region appear to regulate social motivation in a dose-sensitive manner. A "complete deletion" mouse, heterozygously eliminating the syntenic Williams syndrome region, has been deeply characterized for cardiac phenotypes, but direct measures of social motivation have not been assessed. Furthermore, the role of Gtf2ird1 in these behaviors has not been addressed in a relevant genetic context. Here, we have generated a mouse overexpressing Gtf2ird1, which can be used both to model duplication of this gene alone and to rescue Gtf2ird1 expression in the complete deletion mice. Using a comprehensive behavioral pipeline and direct measures of social motivation, we provide evidence that the Williams syndrome critical region regulates social motivation along with motor and anxiety phenotypes, but that Gtf2ird1 complementation is not sufficient to rescue most of these traits, and duplication does not decrease social motivation. However, Gtf2ird1 complementation does rescue light-aversive behavior and performance on select sensorimotor tasks, perhaps indicating a role for this gene in sensory processing or integration.

Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.

We performed a comprehensive assessment of rareinherited variation in autism spectrum disorder (ASD) by analyzing whole-genome sequences of 2,308 individuals from families with multiple affected children. We implicate 69 genes in ASD risk, including 24 passing genome-wide Bonferroni correction and 16 new ASD risk genes, most supported by rare inherited variants, a substantial extensionof previousfindings. Biological pathways enriched for genes harboring inherited variants represent cytoskeletal organization and ion transport, which are distinct from pathways implicated in previous studies. Nevertheless, the de novo and inherited genes contribute to a common protein-protein interaction network. We also identified structural variants (SVs) affecting non-coding regions, implicating recurrent deletions in the promoters of DLG2 and NR3C2. Loss of nr3c2 function in zebrafish disrupts sleep and social function, overlapping with human ASD-related phenotypes. These data support the utility of studying multiplex families in ASD and are available through the Hartwell Autism Research and Technology portal.

Children with 7q11.23 duplication syndrome: psychological characteristics.

To begin to delineate the psychological characteristics associated with classic 7q11.23 duplication syndrome (duplication of the classic Williams syndrome region; hereafter classic Dup7), we tested 63 children with classic Dup7 aged 4-17 years. Sixteen toddlers aged 18-45 months with classic Dup7 and 12 adults identified by cascade testing also were assessed. For the child group, median General Conceptual Ability (similar to IQ) on the Differential Ability Scales-II was 85.0 (low average), with a range from severe disability to high average ability. Median reading and mathematics achievement standard scores were at the low average to average level, with a range from severe impairment to high average or superior ability. Adaptive behavior was considerably more limited; median Scales of Independent Behavior-Revised Broad Independence standard score was 62.0 (mild impairment), with a range from severe adaptive impairment to average adaptive ability. Anxiety disorders were common, with 50.0% of children diagnosed with Social Phobia, 29.0% with Selective Mutism, 12.9% with Separation Anxiety Disorder, and 53.2% with Specific Phobia. In addition, 35.5% were diagnosed with Attention Deficit/Hyperactivity Disorder and 24.2% with Oppositional Defiant Disorder or Disruptive Behavior Disorder-Not Otherwise Specified. 33.3% of the children screened positive for a possible Autism Spectrum Disorder and 82.3% were diagnosed with Speech Sound Disorder. We compare these findings to previously reported results for children with Williams syndrome and argue that genotype/phenotype studies involving the Williams syndrome region offer important opportunities to understand the contribution of genes in this region to common disorders affecting the general population.

Genome-wide Transcriptome Profiling Reveals the Functional Impact of Rare De Novo and Recurrent CNVs in Autism Spectrum Disorders

Copy-number variants (CNVs) are a major contributor to the pathophysiology of autism spectrum disorders (ASDs), but the functional impact of CNVs remains largely unexplored. Because brain tissue is not available from most samples, we interrogated gene expression in lymphoblasts from 244 families with discordant siblings in the Simons Simplex Collection in order to identify potentially pathogenic variation. Our results reveal that the overall frequency of significantly misexpressed genes (which we refer to here as outliers) identified in probands and unaffected siblings does not differ. However, in probands, but not their unaffected siblings, the group of outlier genes is significantly enriched in neural-related pathways, including neuropeptide signaling, synaptogenesis, and cell adhesion. We demonstrate that outlier genes cluster within the most pathogenic CNVs (rare de novo CNVs) and can be used for the prioritization of rare CNVs of potentially unknown significance. Several nonrecurrent CNVs with significant gene-expression alterations are identified (these include deletions in chromosomal regions 3q27, 3p13, and 3p26 and duplications at 2p15), suggesting that these are potential candidate ASD loci. In addition, we identify distinct expression changes in 16p11.2 microdeletions, 16p11.2 microduplications, and 7q11.23 duplications, and we show that specific genes within the 16p CNV interval correlate with differences in head circumference, an ASD-relevant phenotype. This study provides evidence that pathogenic structural variants have a functional impact via transcriptome alterations in ASDs at a genome-wide level and demonstrates the utility of integrating gene expression with mutation data for the prioritization of genes disrupted by potentially pathogenic mutations.

Multiple Recurrent De Novo CNVs, Including Duplications of the 7q11.23 Williams Syndrome Region, Are Strongly Associated with Autism

We have undertaken a genome-wide analysis of rare copy-number variation (CNV) in 1124 autism spectrum disorder (ASD) families, each comprised of a single proband, unaffected parents, and, in most kindreds, an unaffected sibling. We find significant association of ASD with de novo duplications of 7q11.23, where the reciprocal deletion causes Williams-Beuren syndrome, characterized by a highly social personality. We identify rare recurrent de novo CNVs at five additional regions, including 16p13.2 (encompassing genes USP7 and C16orf72) and Cadherin 13, and implement a rigorous approach to evaluating the statistical significance of these observations. Overall, large de novo CNVs, particularly those encompassing multiple genes, confer substantial risks (OR = 5.6; CI = 2.6-12.0, p = 2.4 × 10(-7)). We estimate there are 130-234 ASD-related CNV regions in the human genome and present compelling evidence, based on cumulative data, for association of rare de novo events at 7q11.23, 15q11.2-13.1, 16p11.2, and Neurexin 1.

Inversion of the Williams syndrome region is a common polymorphism found more frequently in parents of children with Williams syndrome

Williams syndrome (WS) is a multisystem disorder caused by deletion of about 1.55 Mb of DNA (including 26 genes) on chromosome 7q11.23, a region predisposed to recombination due to its genomic structure. Deletion of the Williams syndrome chromosome region (WSCR) occurs sporadically. To better define chance for familial recurrence and to investigate the prevalence of genomic rearrangements of the region, 257 children with WS and their parents were studied. We determined deletion size in probands by metaphase FISH, parent-of-origin of the deleted chromosome by molecular genetic methods, and inversion status of the WSCR in both parents by interphase FISH. The frequency of WSCR inversion in the transmitting parent group was 24.9%. In contrast, the rate of inversion in the non-transmitting parent group (a reasonable estimate of the rate in the general population) was 5.8%. There were no significant gender differences with respect to parent-of-origin for the deleted chromosome or the incidence of the inversion polymorphism. There was no difference in the rate of spontaneous abortion for mothers heterozygous for the WSCR inversion relative to mothers without the inversion. We calculate that for a parent heterozygous for a WSCR inversion, the chance to have a child with WS is about 1 in 1,750, in contrast to the 1 in 9,500 chance for a parent without an inversion.

Animal models of Williams syndrome

In recent years, researchers have generated a variety of mouse models in an attempt to dissect the contribution of individual genes to the complex phenotype associated with Williams syndrome (WS). The mouse genome is easily manipulated to produce animals that are copies of humans with genetic conditions, be it with null mutations, hypomorphic mutations, point mutations, or even large deletions encompassing many genes. The existing mouse models certainly seem to implicate hemizygosity for ELN, BAZ1B, CLIP2, and GTF2IRD1 in WS, and new mice with large deletions of the WS region are helping us to understand both the additive and potential combinatorial effects of hemizygosity for specific genes. However, not all genes that are haploinsufficient in humans prove to be so in mice and the effect of genetic background can also have a significant effect on the penetrance of many phenotypes. Thus although mouse models are powerful tools, the information garnered from their study must be carefully interpreted. Nevertheless, mouse models look set to provide a wealth of information about the neuroanatomy, neurophysiology and molecular pathways that underlie WS and in the future will act as essential tools for the development and testing of therapeutics.

Anxiety disorders in children with Williams syndrome, their mothers, and their siblings: Implications for the etiology of anxiety disorders

This study examines the prevalence of anxiety disorders in children with Williams syndrome (WS), their sibling closest in age, and their mothers as well as the predictors of anxiety in these groups. The prevalence of anxiety disorders was assessed and compared to that in the general population. Children with WS had a significantly higher prevalence of specific phobia, generalized anxiety disorder (GAD), and separation anxiety in comparison to children in the general population. While mothers had a higher prevalence of GAD than population controls, the excess was accounted for by mothers who had onset after the birth of their WS child. The siblings had rates similar to the general population. This pattern of findings suggests the presence of a gene in the WS region whose deletion predisposes to anxiety disorders. It is also worthwhile to investigate relations between genes deleted in WS and genes previously implicated in anxiety disorders.

Copy Number Variation in the Williams Syndrome Region: Detection of 7q11.23 Duplication by Microarray Allows Phenotypic Comparison

Event Abstract Back to Event Copy Number Variation in the Williams Syndrome Region: Detection of 7q11.23 Duplication by Microarray Allows Phenotypic Comparison C. A. Morris1*, S. L. Velleman2, C. B. Mervis3, A. E. John3, A. Currier3, E. Peregrine3, C. Rios1, K. Kimberley1, H. Hobart1, G. Gowans3 and M. Gulbronson3 1 University of Nevada, School of Medicine, United States 2 University of Massachusetts, United States 3 University of Louisville, United States Williams syndrome (WS) is caused by a deletion of ~25 genes on chromosome 7q11.23 mediated by nonallelic homologous recombination. The advent of chromosome microarray technology has resulted in detection of the reciprocal duplication of the region. The purpose of this report is to define the WS region duplication phenotype, and to compare it to WS in order to identify traits that are sensitive to copy number/gene dosage. Method: Physical examinations and cognitive and language assessments were performed on 8 children and one adult (mother of 2 of the children) with duplications of the classic WS region (dup7q11.23), and on 2 children with longer duplications including HSP27 (deletion of which is associated with more severe intellectual disability in individuals with WS with long deletions). Phenotypic features were compared to individuals with classic WS. Results: Dysmorphic features included prominent forehead (65%), high broad nose (70%), long columnella (41% of total, but 90% of those over age 8), short philtrum (54%), and facial asymmetry (95%). Birth defects were rare, including one person each with ASD/VSD, microcephaly, hydrocephaly, and severe micrognathia. About 50% had ADHD, and 82% had anxiety (social and separation anxiety). Interestingly, all individuals with a duplication had language delay and current or former difficulty with motor speech. Discussion: The facial phenotype of duplication of the WS region is subtle, but recognizable. GTF2IRD1 has been implicated in the facial asymmetry in WS, and may be copy number sensitive, since it is a trait shared by the dup7 group. Both groups share anxiety as a behavioral problem, but those with WS typically have specific phobia (loud noises), while those with dup7 have separation and social anxiety. These findings suggest that one or more genes in the Williams syndrome region are dosage sensitive, including genes that contribute to facial and language development. Conference: 12th International Professional Conference on Williams Syndrome, Garden Grove,CA, United States, 13 Jul - 14 Jul, 2008. Presentation Type: Oral Presentation Topic: SESSION 4: Phenotype of the 7Q11.23 Duplication Citation: Morris CA, Velleman SL, Mervis CB, John AE, Currier A, Peregrine E, Rios C, Kimberley K, Hobart H, Gowans G and Gulbronson M (2009). Copy Number Variation in the Williams Syndrome Region: Detection of 7q11.23 Duplication by Microarray Allows Phenotypic Comparison. Conference Abstract: 12th International Professional Conference on Williams Syndrome. doi: 10.3389/conf.neuro.09.2009.07.012 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 29 Apr 2009; Published Online: 29 Apr 2009. * Correspondence: C. A Morris, University of Nevada, School of Medicine, Las Vegas, United States, cmorris@medicine.nevada.edu Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers C. A Morris S. L Velleman C. B Mervis A. E John A. Currier E. Peregrine C. Rios K. Kimberley H. Hobart G. Gowans M. Gulbronson Google C. A Morris S. L Velleman C. B Mervis A. E John A. Currier E. Peregrine C. Rios K. Kimberley H. Hobart G. Gowans M. Gulbronson Google Scholar C. A Morris S. L Velleman C. B Mervis A. E John A. Currier E. Peregrine C. Rios K. Kimberley H. Hobart G. Gowans M. Gulbronson PubMed C. A Morris S. L Velleman C. B Mervis A. E John A. Currier E. Peregrine C. Rios K. Kimberley H. Hobart G. Gowans M. Gulbronson Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Language and Cognitive Development of Children Who Have Williams Syndrome or Duplication of the Williams Syndrome Region

Language and Cognitive Development of Children Who Have Williams Syndrome or Duplication of the Williams Syndrome Region

Molecular Genetics of Williams Syndrome: Windows into Human Biology

Event Abstract Back to Event Molecular Genetics of Williams Syndrome: Windows into Human Biology Julie Korenberg1* 1 Cedars-Sinai Medical Center at UCLA, Departments of Pediatrics and Medical Genetics Institute, United States Genetics is my favorite way of thinking: Williams syndrome seen through the eyes of a geneticist. Williams syndrome (WS) is the most compelling model in which to link the basis of human emotion and behavior to their biological origins. The explanatory power of human genetics in WS rests on the recent revolution in understanding the human genome but more specifically on the ability to link genetic with behavioral variation at high resolution. WS is due to the deletion of about 25 genes located in a stretch of genomic DNA located on chromosome 7q11.23. Further understanding of which genes may contribute to specific features of WS makes use of rare individuals with smaller deletions, of variation in gene expression remaining on the nondeleted chromosome 7, and of further study of the expression of WS region genes in nonhuman primate brain. The goal of this presentation is to describe some of these genetic mechanisms that appear to contribute to the features of Williams syndrome and to suggest how to use this information may inform brain development and adult function. Conference: 12th International Professional Conference on Williams Syndrome, Garden Grove,CA, United States, 13 Jul - 14 Jul, 2008. Presentation Type: Oral Presentation Topic: SESSION 1: Genetics and Genotype- Phenotype Correlations Citation: Korenberg J (2009). Molecular Genetics of Williams Syndrome: Windows into Human Biology. Conference Abstract: 12th International Professional Conference on Williams Syndrome. doi: 10.3389/conf.neuro.09.2009.07.001 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 28 Apr 2009; Published Online: 28 Apr 2009. * Correspondence: Julie Korenberg, Cedars-Sinai Medical Center at UCLA, Departments of Pediatrics and Medical Genetics Institute, Los Angeles, United States, USA.julie.korenberg@hsc.utah.edu Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Julie Korenberg Google Julie Korenberg Google Scholar Julie Korenberg PubMed Julie Korenberg Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Renal and urinary findings in 20 patients with Williams-Beuren syndrome diagnosed by fluorescence in situ hybridization (FISH)

Williams-Beuren syndrome is a rare multiple anomalies/mental retardation syndrome caused by deletion of contiguous genes at chromosome region 7q11.23. The aim of this work was to determine the frequency and the types of renal and urinary tract anomalies in 20 patients with Williams-Beuren syndrome. The fluorescence in situ hybridization test using a LSI Williams syndrome region DNA probe was performed for all 20 patients to confirm the diagnosis of Williams-Beuren syndrome. A prospective study was performed in order to investigate renal and urinary aspects using laboratory assays to check renal function, ultrasonography of the kidneys and urinary tract, voiding cystourethrogram and urodynamics. Deletion of the elastin gene (positive fluorescence in situ hybridization test) was found in 17 out of 20 patients. Renal alterations were diagnosed in 5 of 17 (29%) the patients with the deletion and in 1 of 3 patients without the deletion. Fourteen patients with the deletion presented dysfunctional voiding. Arterial hypertension was diagnosed in 3 patients with deletions and 1 of these presented bilateral stenosis of the renal arteries. Due to the high incidence of renal and urinary abnormalities in Williams-Beuren syndrome, performing a systematic laboratory and sonographic evaluation of the patients is recommended.

GTF2I hemizygosity implicated in mental retardation in Williams syndrome: genotype-phenotype analysis of five families with deletions in the Williams syndrome region.

Most individuals with Williams syndrome (WS) have a 1.6 Mb deletion in chromosome 7q11.23 that encompasses the elastin (ELN) gene, while most families with autosomal dominant supravalvar aortic stenosis (SVAS) have point mutations in ELN. The overlap of the clinical phenotypes of the two conditions (cardiovascular disease and connective tissue abnormalities such as hernias) is due to the effect of haploinsufficiency of ELN. SVAS families often have affected individuals with some WS facial features, most commonly in infancy, suggesting that ELN plays a role in WS facial gestalt as well. To find other genes contributing to the WS phenotype, we studied five families with SVAS who have small deletions in the WS region. None of the families had mental retardation, but affected family members had the Williams Syndrome Cognitive Profile (WSCP). All families shared a deletion of LIMK1, which encodes a protein strongly expressed in the brain, supporting the hypothesis that LIMK1 hemizygosity contributes to impairment in visuospatial constructive cognition. While the deletions from the families nearly spanned the WS region, none had a deletion of FKBP6 or GTF2I, suggesting that the mental retardation seen in WS is associated with deletion of either the centromeric and/or telomeric portions of the region. Comparison of these five families with reports of other individuals with partial deletions of the WS region most strongly implicates GTF2I in the mental retardation of WS.

Comparative genomic sequence analysis of the Williams syndrome region (LIMK1-RFC2) of human chromosome 7q11.23.

Williams syndrome (WS) is a complex neurodevelopmental disorder arising from a microdeletion at Chr band 7q11.23, which results in a hemizygous condition for a number of genes. Within this region we have completely characterized 200 kb containing the genes LIMK1, WBSCR1, and RFC2. Evidence was also found for WBSCR5 in this region, but not the previously proposed genes WSCR2 and WSCR6. The syntenic region in mouse was also sequenced (115 kb) and characterized, and a comparative sequence analysis with a percent identity plot (PIP) easily allowed us to identify coding exons. This genomic region is GC rich (50.1% human, 49.9% mouse) and contains an unusually high abundance of repetitive elements consisting primarily of Alu (45.4%, one of the highest levels identified to date) in human, and the B family of SINES (30.6% of the total sequence) in mouse. WBSCR1 corresponds to eukaryotic initiation factor 4H, identified in rabbit, and is herein found to be constitutively expressed in both human and mouse, with two RNA and protein products formed (exon 5 is alternatively spliced). The transcription pattern of WBSCR5 was also examined and discussed along with its putative amino acid sequence.

Comparative Mapping of the Region of Human Chromosome 7 Deleted in Williams Syndrome

Williams syndrome (WS) is a complex developmental disorder resulting from the deletion of a large (approximately 1.5-2 Mb) segment of human chromosome 7q11.23. Physical mapping studies have revealed that this deleted region, which contains a number of known genes, is flanked by several large, nearly identical blocks of DNA. The presence of such highly related DNA segments in close physical proximity to one another has hampered efforts to elucidate the precise long-range organization of this segment of chromosome 7. To gain insight about the structure and evolutionary origins of this important and complex genomic region, we have constructed a fully contiguous bacterial artificial chromosome (BAC) and P1-derived artificial chromosome (PAC) contig map encompassing the corresponding region on mouse chromosome 5. In contrast to the difficulties encountered in constructing a clone-based physical map of the human WS region, the BAC/PAC-based map of the mouse WS region was straightforward to construct, with no evidence of large duplicated segments, such as those encountered in the human WS region. To confirm this difference, representative human and mouse BACs were used as probes for performing fluorescence in situ hybridization (FISH) to metaphase and interphase chromosomes. Human BACs derived from the nonunique portion of the WS region hybridized to multiple, closely spaced regions on human chromosome 7q11.23. In contrast, corresponding mouse BACs hybridized to a single site on mouse chromosome 5. Furthermore, FISH analysis revealed the presence of duplicated segments within the WS region of various nonhuman primates (chimpanzee, gorilla, orangutan, and gibbon). Hybridization was also noted at the genomic locations corresponding to human chromosome 7p22 and 7q22 in human, chimpanzee, and gorilla, but not in the other animal species examined. Together, these results indicate that the WS region is associated with large, duplicated blocks of DNA on human chromosome 7q11.23 as well as the corresponding genomic regions of other nonhuman primates. However, such duplications are not present in the mouse.

Long deletions of the Williams syndrome region on chromosome 7 result in more severe mental retardation

Williams syndrome (WS) is characterized by dysmorphic facial features, mental retardation, elastin arteriopathy, a specific cognitive profile, and a unique personality. It is caused by a ∼ 1.5 Mb deletion in chromosome 7ql1.23, bounded by markers D7S1778 and D7S489A. We report four individuals with WS who have longer deletions in the telomeric direction. The individuals with longer deletions had the classic WS phenotype, but had more severe mental retardation than those with the common WS deletion. The mean (Kaufman Brief Intelligence Test) IQ for 47 individuals with WS (age range 5 years - 47 years) with the classic deletion was 71.13 (SD=14.02), while the mean IQ for those with longer deletions was 47.0 (SD=5.48). the difference between the two groups was significant, t=3.39 (p=.001). These findings suggest that gene(s) telomeric to the classic WS region may play an important role in normal cognitive development.