An atypical deletion of the Williams-Beuren Syndrome interval implicates genes associated with defective visuospatial processing and autism

Journal of Medical Genetics (Impact Factor: 6.34). 03/2007; 44(2):136-43. DOI: 10.1136/jmg.2006.044537
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During a genetic study of autism, a female child who met diagnostic criteria for autism spectrum disorder, but also exhibited the cognitive-behavioural profile (CBP) associated with Williams-Beuren syndrome (WBS) was examined. The WBS CBP includes impaired visuospatial ability, an overly friendly personality, excessive non-social anxiety and language delay.
Using array-based comparative genomic hybridisation (aCGH), a deletion corresponding to BAC RP11-89A20 in the distal end of the WBS deletion interval was detected. Hemizygosity was confirmed using fluorescence in situ hybridisation and fine mapping was performed by measuring the copy number of genomic DNA using quantitative polymerase chain reaction.
The proximal breakpoint was mapped to intron 1 of GTF2IRD1 and the distal breakpoint lies 2.4-3.1 Mb towards the telomere. The subject was completely hemizygous for GTF2I, commonly deleted in carriers of the classic approximately 1.5 Mb WBS deletion, and GTF2IRD2, deleted in carriers of the rare approximately 1.84 Mb WBS deletion.
Hemizygosity of the GTF2 family of transcription factors is sufficient to produce many aspects of the WBS CBP, and particularly implicate the GTF2 transcription factors in the visuospatial construction deficit. Symptoms of autism in this case may be due to deletion of additional genes outside the typical WBS interval or remote effects on gene expression at other loci.

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    • "Patients with partial or atypical deletions ($0.2 Mb to $2.5 Mb) are of extreme importance for genotype-phenotype studies, due the substantial phenotypic variability among WBS. [Frangiskakis et al., 1996; Botta et al., 1999; Tassabehji et al., 1999, 2005; Gagliardi et al., 2003; Heller et al., 2003; Hirota et al., 2003; Karmiloff-Smith et al., 2003; Morris et al., 2003; Howald et al., 2006; Edelmann et al., 2007; van Hagen, 2007; Blyth et al., 2008; Dai et al., 2009; Schubert, 2009; Antonell et al., 2010; Ferrero et al., 2010]. Thus, the advent of genomic array technology has led directly to the appreciation of genomic number copy variation and the elevated complexity of CNVs, called Complex Chromosomal Rearrangements (CCRs) commonly characterized by multiple breakpoints and exchanges interspersed with regions of normal copy number [Zhang et al., 2009; Colnaghi et al., 2011]. "
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    ABSTRACT: Williams-Beuren syndrome (WBS) is caused by a hemizygous contiguous gene microdeletion of 1.55-1.84 Mb at 7q11.23 region. Approximately, 28 genes have been shown to contribute to classical phenotype of SWB with presence of dysmorphic facial features, supravalvular aortic stenosis (SVAS), intellectual disability, and overfriendliness. With the use of Microarray-based comparative genomic hybridization and other molecular cytogenetic techniques, is possible define with more accuracy partial or atypical deletion and refine the genotype-phenotype correlation. Here, we report on a rare genomic structural rearrangement in a boy with atypical deletion in 7q11.23 and XYY syndrome with characteristic clinical signs, but not sufficient for the diagnosis of WBS. Cytogenetic analysis of G-banding showed a karyotype 47,XYY. Analysis of DNA with the technique of MLPA (Multiplex Ligation-dependent Probe Amplification) using kits a combination of kits (P064, P036, P070, and P029) identified an atypical deletion on 7q11.23. In addition, high resolution SNP Oligonucleotide Microarray Analysis (SNP-array) confirmed the alterations found by MLPA and revealed others pathogenic CNVs, in the chromosomes 7 and X. The present report demonstrates an association not yet described in literature, between Williams-Beuren syndrome and 47,XYY. The identification of atypical deletion in 7q11.23 concomitant to additional pathogenic CNVs in others genomic regions allows a better comprehension of clinical consequences of atypical genomic rearrangements. © 2015 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 09/2015; DOI:10.1002/ajmg.a.37360 · 2.16 Impact Factor
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    • "The results of this analysis showed that AWSdel-01 was within or closer to (for visuo-motor integration and block design) the range of TD, AWSdel-02 was within the range of WS (clearly for visuo-motor integration and judgment of line orientation, though not for block design), and AWSdel-03 was within the range of TD (though in this case only for visuo-motor integration and not for judgment of line orientation or block design). Overall, these results implicate GTF2I and/or GTF2IRD1 as candidate genes contributing to altered IPS volumes and visuo-spatial function, in particular visuo-motor integration as consistent with previous animal [37] and human behavioral research [15], [38] (Figure 3). "
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    ABSTRACT: In this study of eight rare atypical deletion cases with Williams-Beuren syndrome (WS; also known as 7q11.23 deletion syndrome) consisting of three different patterns of deletions, compared to typical WS and typically developing (TD) individuals, we show preliminary evidence of dissociable genetic contributions to brain structure and human cognition. Univariate and multivariate pattern classification results of morphometric brain patterns complemented by behavior implicate a possible role for the chromosomal region that includes: 1) GTF2I/GTF2IRD1 in visuo-spatial/motor integration, intraparietal as well as overall gray matter structures, 2) the region spanning ABHD11 through RFC2 including LIMK1, in social cognition, in particular approachability, as well as orbitofrontal, amygdala and fusiform anatomy, and 3) the regions including STX1A, and/or CYLN2 in overall white matter structure. This knowledge contributes to our understanding of the role of genetics on human brain structure, cognition and pathophysiology of altered cognition in WS. The current study builds on ongoing research designed to characterize the impact of multiple genes, gene-gene interactions and changes in gene expression on the human brain.
    PLoS ONE 08/2014; 9(8):e104088. DOI:10.1371/journal.pone.0104088 · 3.23 Impact Factor
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    • "The roles played by most genes deleted in the WBSCR are largely unknown. However, deletion of the elastin gene (ELN) is clearly involved in the vascular anomalies [14], and the LIMK1, GTF2I and GTFIIRD1 genes have been implicated in cognitive developmental delay and visuospatial deficiency [3,7,15]. Recently, duplication of the WBSCR has been reported to be associated with intellectual disability, severe delay in expressive language and autism spectrum disorders, suggesting that specific genes within WBSCR can influence language and social development through gene–dosage effects [16-19]. "
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    ABSTRACT: Deletion of the Williams-Beuren syndrome (WBS) critical region (WBSCR), at 7q11.23, causes a developmental disorder commonly characterized by hypersociability and excessive talkativeness and often considered the opposite behavioral phenotype to autism. Duplication of the WBSCR leads to severe delay in expressive language. Gene--dosage effects on language development at 7q11.23 have been hypothesized. Molecular characterization of the WBSCR was performed by fluorescence in situ hybridization and high-resolution single-nucleotide polymorphism array in two individuals with severe autism enrolled in a genetic study of autism who showed typical WBS facial dysmorphism on systematic clinical genetic examination. The serotonin transporter promoter polymorphism (5-HTTLPR, locus SLC6A4) was genotyped. Platelet serotonin levels and urinary 6-sulfatoxymelatonin excretion were measured. Behavioral and cognitive phenotypes were examined. The two patients had common WBSCR deletions between proximal and medial low copy repeat clusters, met diagnostic criteria for autism and displayed severe impairment in communication, including a total absence of expressive speech. Both patients carried the 5-HTTLPR ss genotype and exhibited platelet hyperserotonemia and low melatonin production. Our observations indicate that behaviors and neurochemical phenotypes typically associated with autism can occur in patients with common WBSCR deletions. The results raise intriguing questions about phenotypic heterogeneity in WBS and regarding genetic and/or environmental factors interacting with specific genes at 7q11.23 sensitive to dosage alterations that can influence the development of social communication skills. Thus, the influence of WBSCR genes on social communication expression might be dramatically modified by other genes, such as 5-HTTLPR, known to influence the severity of social communication impairments in autism, or by environmental factors, such as hyperserotonemia, given that hyperserotonemia is found in WBS associated with autism but not in WBS without autism. In this regard, WBS provides a potentially fruitful model with which to develop integrated genetic, cognitive, behavioral and neurochemical approaches to study genotype--phenotype correlations, possible gene--environment interactions and genetic background effects. The results underscore the importance of considering careful clinical and molecular genetic examination of individuals diagnosed with autism.
    Molecular Autism 08/2013; 4(1):29. DOI:10.1186/2040-2392-4-29 · 5.41 Impact Factor
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