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The human chromosome 7 homologs from the orangutan (Pongo), gorilla (Gorilla), and chimpanzee (Pan) are illustrated. Horizontal arrows indicate the approximate chromosome band of the major inversions that have accompanied their speciation. Experiments using BACs from the closely flanking duplicated regions (BACs 239C10, 204, and 611E3) for FISH revealed duplicated sequences located at or close to all inversion breakpoints, illustrated by the colored dots. The gene for elastin (ELN) mapped to the subtelomeric band of Pongo, and was close to the initial inversion breakpoint as well as all subsequent inversions of chromosome 7 through primate evolution.
Source publication
Williams syndrome (WMS) is a most compelling model of human cognition, of human genome organization, and of evolution. Due to a deletion in chromosome band 7q11.23, subjects have cardiovascular, connective tissue, and neurodevelopmental deficits. Given the striking peaks and valleys in neurocognition including deficits in visual-spatial and global...
Contexts in source publication
Context 1
... have been two inversions in the higher primate homologues of human chromosome 7. The results, summarized in Figure 4, revealed that the region of 7q11.2 deleted in WMS has been involved in both of these evolutionary breakage and inversion events. The probes for both the duplicated and single-copy regions generated signals in the chromosome bands involved in the region of the inversions occurring between the orangutan and gorilla, and then again between the gorilla and the chimpanzee. ...
Context 2
... is based on the lack of these features (e.g., facies, hoarse voice) in individuals with elastin single-base mutations ( Li et al. 1997). Second, although a part of the visual-spatial deficit may be due to deletion of LIMK1 ( Frangiskakis et al., 1996), this is unlikely to be the major gene responsible as the ob- servation is not supported by three further cases that delete this gene as well as others ( Tassabehji et al., 1999; Figure 4). The strength of this inference is emphasized by one of the cases being an engineering student. ...
Citations
... The WS group was recruited through Williams Syndrome Australia Limited and Williams Syndrome New Zealand. The WS diagnosis was confirmed via microarray analysis which detected the 7q11.23 microdeletion [30,31]. WS children were screened for a history of psychological, neurodevelopmental, neurological, and major sensory impairments that were unrelated to their WS, and no child was excluded from the study based on these criteria. ...
Williams Syndrome (WS) involves high rates of psychopathology across the lifespan. However, little is known about the early, longitudinal trajectory of internalising/externalising symptoms or the association between these and the family environment in WS. WS (n = 16; aged 2 years, 2 months to 9 years, 5 months) and typically developing or TD (n = 46; aged 2 years, 2 months to 11 years, 1 month) children were assessed on two occasions over 2.5 years utilising parent report questionnaires—the Child Behaviour Checklist and the Family Environment Scale. No statistically significant changes were found in CBCL/psychopathology profiles across timepoints, on average, for either WS or TD children. However, reliable change scores showed WS children had considerable variability in CBCL scores over time. Cross-sectionally, the WS group showed higher scores (reflecting more psychopathology) compared to TD controls at both time points across most CBCL subscales, with elevated overall psychopathology problems identified in 56–68% of WS children (versus 8% in TD controls). Psychopathology was not associated with sex, chronological age, or cognitive ability in WS. Conflict in the family environment was positively associated with higher Attention Problems at Time 1 in the WS group, whilst the TD group showed associations between family conflict and total psychopathology problems at both time points and between family cohesion and total psychopathology problems at Time 2. Family environment did not differ between groups, except for lower engagement in intellectual and cultural activities in WS. Findings highlight variable Internalising and Externalising Problems in young WS children over time, with greater biological than environmental contributions to psychopathology in WS.
... 23, who have aided in understanding the contribution of specific sub-regions to the phenotypes of these disorders. Although rare, studies of individuals with atypical rearrangements over the last 20 years have highlighted the importance of genes at the telomeric end of 7q11.23 in contributing to aspects of the WBS cognitive profile [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] . ...
Williams-Beuren syndrome (WBS) and 7q11.23 duplication syndrome (Dup7) are rare neurodevelopmental disorders caused by deletion and duplication of a 1.5 Mb region that includes at least five genes with a known role in epigenetic regulation. We have shown that CNV of this chromosome segment causes dose-dependent, genome-wide changes in DNA methylation, but the specific genes driving these changes are unknown. We measured genome-wide whole blood DNA methylation in six participants with atypical CNV of 7q11.23 (three with deletions and three with duplications) using the Illumina HumanMethylation450k array and compared their profiles with those from groups of individuals with classic WBS or classic Dup7 and with typically developing (TD) controls. Across the top 1000 most variable positions we found that only the atypical rearrangements that changed the copy number of GTF2IRD1 and/or GTF2I (coding for the TFII-IRD1 and TFII-I proteins) clustered with their respective syndromic cohorts. This finding was supported by results from hierarchical clustering across a selection of differentially methylated CpGs, in addition to pyrosequencing validation. These findings suggest that CNV of the GTF2I genes at the telomeric end of the 7q11.23 interval is a key contributor to the large changes in DNA methylation that are seen in blood DNA from our WBS and Dup7 cohorts, compared to TD controls. Our findings suggest that members of the TFII-I protein family are involved in epigenetic processes that alter DNA methylation on a genome-wide level.
... Health issues (e.g., gastroesophageal reflux) are prominent and associated with self-injury and low mood [123] • Social anxiety [44][45][46] and intolerance of uncertainty [47] • Familiarity and social context [49] • Age-related increase in social withdrawal, self-injury and low mood [51][52][53] Williams syndrome (WS) Microdeletion of 26-28 genes on chromosome 7q11.23 [124] Typically, degree of ID severity is in the borderline to moderate range [58] High motivation for social engagement, presenting as overly friendly and affectionate [55]. ...
Purpose of Review
Elevated prevalence of autism characteristics is reported in genetic syndromes associated with intellectual disability. This review summarises recent evidence on the behavioural heterogeneity of autism in the following syndromes: Fragile X, Cornelia de Lange, Williams, Prader-Willi, Angelman, Down, Smith-Magenis, and tuberous sclerosis complex. Key considerations for assessment and support are discussed.
Recent Findings
The profile and developmental trajectory of autism-related behaviour in these syndromes indicate some degree of syndrome specificity which may interact with broader behavioural phenotypes (e.g. hypersociability), intellectual disability, and mental health (e.g. anxiety). Genetic subtype and co-occurring epilepsy within syndromes contribute to increased significance of autism characteristics. Autism-related strengths and challenges are likely to be overlooked or misunderstood using existing screening/diagnostic tools and criteria, which lack sensitivity and specificity within these populations.
Summary
Autism characteristics are highly heterogeneous across genetic syndromes and often distinguishable from non-syndromic autism. Autism diagnostic assessment practices in this population should be tailored to specific syndromes. Service provisions must begin to prioritise needs-led support.
... The associated behavioral skills are comparable to those of individuals with other neurodevelopmental conditions with ID, although individuals with DS are usually characterized as having fewer maladaptive behaviors than cognitively-matched individuals (Chapman & Hesketh, 2000). WS is a rare genetic disorder (1 in 20,000 live births, Morris et al., 1988) notably characterized by mild to moderate ID (Korenberg et al., 2000), maladaptive behaviors, a gregarious personality, and high positive affect (Järvinen et al., 2013). Individuals with DS or WS are generally described as having difficulties with Theory of Mind (Neitzel & Penke, 2021;Tager-Flusberg & Sullivan, 2000), with some social competences in the domains of social awareness, social cognition, social communication, and restrictive repetitive behaviors (Channell, 2020;Fisher & Morin, 2017), and experience similar rates and types of victimization than autistic individuals (Fisher et al., 2013), reporting increased incidences of being bullied Jackson et al., 2014) and difficulties sustaining friendships (Iarocci et al., 2008;Järvinen et al., 2013). ...
Background:
Research has shown that autistic individuals seem to be more prone to develop gelotophobia (i.e., the fear of being laughed at) than typically developing individuals. The goals of the present study were to discover whether the high levels of gelotophobia found in autism in previous studies were replicated here, to expand the research to Down syndrome (DS) and Williams syndrome (WS), and to assess the relation between individual differences and social impairments, affective predispositions, and humor temperament.
Methods:
Questionnaires were distributed to parents of autistic individuals (N = 48), individuals with DS (N = 139), and individuals with WS (N = 43) aged between 5 and 25 years old.
Results:
Autistic individuals were shown to frequently experience at least a slight level of gelotophobia (45%), compared to only 6% of individuals with DS and 7% of individuals with WS. Interestingly, humorless temperament traits (i.e., seriousness and bad mood) manifested as the strongest predictors of gelotophobia. This relation even transcended group differences.
Conclusion:
The results confirm that gelotophobia seems to be particularly concerning for autistic individuals, whereas individuals with DS and WS seem to be more protected from developing such a fear. Moreover, it appears that gelotophobia seems to be more linked to high seriousness and irritability than diagnosis.
... Williams syndrome (WS) is a rare genetic disorder caused by deletions on chromosome 7q11.23 (Korenberg et al., 2000). People with WS have relatively good language skills but impaired visuospatial construction perception. ...
Background:
People with Williams syndrome (WS) are relatively proficient with lexical semantics; however, their contextual integration ability is impaired. Few studies have examined the cause of this deficiency.
Aims:
This study aimed to examine how people with WS process the integration of lexical words into contexts and determine whether this processing differs across syntactic categories.
Methods and procedures:
Cross-modal tasks with pictures and aurally presented sentences were employed. The semantic appropriateness of target word meanings represented by pictures with context were determined.
Outcomes and results:
People with WS responded to the figurative and literal nouns as appropriate interpretations significantly less often than the chronological age (CA)-matched controls; however, they responded to the literal verbs significantly more often than the mental age (MA)-matched controls. Furthermore, our findings suggest that people with WS displayed weaker contextual integration and asymmetric processing of nouns and verbs.
Conclusions and implications:
People with WS were not at the same lexical semantic knowledge developmental level as the CA controls and differed from the MA controls. They used less contextual information when processing syntactic categories compared to the typically developing controls. These might lead to the impaired integration of words into contexts. These findings confirm the neuroconstructivism theory.
... WS is a rare neurodevelopmental disorder, with a prevalence of 1 in 7500, caused by a hemizygous deletion of approximately 25 genes on the 7q11.23 chromosomal region Korenberg et al, [1] Stromme, Bjørnstad & Ramstad, [69] resulting in a phenotype comprised of medical, cognitive, affective, and neurophysiological impairments Bellugi et al, [2]. A core behavioral component of this syndrome is increased motivation for social interaction Open Access † Alice Gomez, Guillaume Lio and Angela Sirigu contributed equally to this work. ...
Background
Williams syndrome (WS) and Autism Spectrum Disorders (ASD) are neurodevelopmental conditions associated with atypical but opposite face-to-face interactions patterns: WS patients overly stare at others, ASD individuals escape eye contact. Whether these behaviors result from dissociable visual processes within the occipito-temporal pathways is unknown.
Using high-density electroencephalography, multivariate signal processing algorithms and a protocol designed to identify and extract evoked activities sensitive to facial cues, we investigated how WS (N = 14), ASD (N = 14) and neurotypical subjects (N = 14) decode the information content of a face stimulus.
Results
We found two neural components in neurotypical participants, both strongest when the eye region was projected onto the subject's fovea, simulating a direct eye contact situation, and weakest over more distant regions, reaching a minimum when the focused region was outside the stimulus face. The first component peaks at 170 ms, an early signal known to be implicated in low-level face features. The second is identified later, 260 ms post-stimulus onset and is implicated in decoding salient face social cues.
Remarkably, both components were found distinctly impaired and preserved in WS and ASD. In WS, we could weakly decode the 170 ms signal based on our regressor relative to facial features, probably due to their relatively poor ability to process faces’ morphology, while the late 260 ms component was highly significant. The reverse pattern was observed in ASD participants who showed neurotypical like early 170 ms evoked activity but impaired late evoked 260 ms signal.
Conclusions
Our study reveals a dissociation between WS and ASD patients and points at different neural origins for their social impairments.
... However, it cannot be ruled out that CNV size-related position effects, variants in the allele not deleted, epigenetic mechanisms, regulatory sequences, or other factors may affect a patient's phenotype [29]. Analysis of the molecular and phenotypic relationship between patient No. 6 and previous case reports [13,[30][31][32] with similar deletion positions and intellectual disability showed that the genes on the proximal side of the WBSCR also play an important role in the phenotype of patients with WBS. The BAZ1B, FZD9, and STX1A genes are particularly important in this regard, according to previous studies [9,[33][34][35][36][37]. ...
Genes associated with specific neurocognitive phenotypes in Williams–Beuren syndrome are still controversially discussed. This study identified nine patients with atypical deletions out of 111 patients with Williams–Beuren syndrome; these deletions included seven smaller deletions and two larger deletions. One patient had normal neurodevelopment with a deletion of genes on the distal side of the Williams–Beuren syndrome chromosomal region, including GTF2I and GTF2IRD1 . However, another patient retained these genes but showed neurodevelopmental abnormalities. By comparing the genotypes and phenotypes of patients with typical and atypical deletions and previous reports in the literature, we hypothesize that the BAZ1B , FZD9 , and STX1A genes may play an important role in the neurodevelopment of patients with WBS.
... Thus, the social interaction abnormality displayed by Scn2a Δ1898/+ mice correlates well with observations of humans with SCN2A variants and with the inappropriate social disinhibition observed in individuals with SCN2A mutations. Inappropriate social contact with strangers, often characterized as over-friendliness, is a feature of Williams syndrome (WS), a neurodevelopmental disorder caused by hemizygous deletion of 7q11.23 (28). A mouse model of WS shows increased social interaction and lack of habituation to a stranger mouse (29), suggestive of the phenotype we observed in the Scn2a Δ1898/+ mice. ...
SCN2A, encoding the neuronal voltage-gated Na+ channel NaV1.2, is one of the most commonly affected loci linked to autism spectrum disorders (ASDs). Most ASD-associated mutations in SCN2A are loss-of-function, but studies examining how such mutations affect neuronal function and whether Scn2a mutant mice display ASD endophenotypes have been inconsistent. We generated a protein truncation variant Scn2a mouse model (Scn2aΔ1898/+) by CRISPR that eliminates the NaV1.2 channel's distal intracellular C-terminal domain and analyzed the molecular and cellular consequences of this variant in a heterologous expression system, in neuronal culture, in brain slices, and in vivo. We also analyzed multiple behaviors in wild type and Scn2aΔ1898/+ mice and correlated behaviors with clinical data obtained in human subjects with SCN2A variants. Expression of the NaV1.2 mutant in a heterologous expression system revealed decreased NaV1.2 channel function and cultured pyramidal neurons isolated from Scn2aΔ1898/+ forebrain showed correspondingly reduced voltage-gated Na+ channel currents without compensation from other CNS voltage-gated Na+ channels. Na+ currents in inhibitory neurons were unaffected. Consistent with loss of voltage-gated Na+ channel currents, Scn2aΔ1898/+ pyramidal neurons displayed reduced excitability in forebrain neuronal culture and reduced excitatory synaptic input onto the pyramidal neurons in brain slices. Scn2aΔ1898/+ mice displayed several behavioral abnormalities, including abnormal social interactions that reflect behavior observed in humans with ASD and with harboring loss-of-function SCN2A variants. This model and its cellular electrophysiological characterizations provide a framework for tracing how a SCN2A loss-of-function variant leads to cellular defects that result in ASD-associated behaviors.
... [3][4][5][6][7][8][9][10][11][12] Interestingly, however, individuals with WS possess relatively intact expressive language and verbal skills, 13,14 as well as heightened sensitivity and emotional response to music. 2,15 One of the most striking phenotypes of individuals with WS is hypersociability and strong social motivation, [16][17][18] despite high non-social anxiety 19 and deficits in social cognition and awareness. 20 A substantial body of research indicates the neuropeptide oxytocin (OT) plays a key role in mediating the regulation of social behavior and cognition, fear conditioning and extinction, observational fear, 21 fear modulation via social memory 22 and anxiety in humans and rodents. ...
Williams Syndrome results in distinct behavioral phenotypes, which include learning deficits, anxiety, increased phobias, and hypersociability. While the underlying mechanisms driving this subset of phenotypes is unknown, oxytocin dysregulation is hypothesized to be involved as some studies have shown elevated blood oxytocin and altered oxytocin receptor expression in patients. A ‘Complete Deletion’ mouse, modeling the hemizygous deletion in Williams Syndrome, recapitulates many of the phenotypes present in humans. These Complete Deletion mice also exhibit impaired fear responses in the conditioned fear task. Here, we address whether oxytocin dysregulation is responsible for this impaired associative fear memory response. We show direct delivery of an oxytocin receptor antagonist to the central nervous system did not rescue the attenuated contextual or cued fear memory responses in Complete Deletion mice. Thus, increased oxytocin signaling is not acutely responsible for this phenotype. We also evaluated oxytocin receptor and serotonin transporter availability in regions related to fear learning, memory, and sociability using autoradiography in wild type and Complete Deletion mice. While no differences withstood correction, we identified regions that may warrant further investigation. There was a nonsignificant decrease in oxytocin receptor expression in the lateral septal nucleus, and nonsignificant lowered serotonin transporter availability in the striatum and orbitofrontal cortex. Together, these data suggest the fear conditioning anomalies in the Williams Syndrome mouse model are independent of any alterations in the oxytocinergic system caused by deletion of the Williams locus.
... Advances in molecular biology have enabled the scientific community to gain a clear insight of the genetic basis responsible for certain NDDs. For example, individuals with WS have similar genetic deficits in 95% of the cases (Korenberg et al., 2000). However, the genetic architecture of most NDDs is highly complex (Devlin and Scherer, 2012;Lesch, 2016;Deciphering Developmental Disorders Study, 2017), thus requiring the development of multiple genetic therapeutic approaches, to maximize the arsenal of possible treatments. ...
Genetic neurodevelopmental disorders are characterized by abnormal neurophysiological and behavioral phenotypes, affecting individuals worldwide. While the subject has been heavily researched, current treatment options relate mostly to alleviating symptoms, rather than targeting the altered genome itself. In this review, we address the neurogenetic basis of neurodevelopmental disorders, genetic tools that are enabling precision research of these disorders in animal models, and postnatal gene-therapy approaches for neurodevelopmental disorders derived from preclinical studies in the laboratory.
