Frequency of the 7q11.23 inversion polymorphism in transmitting parents of children with Williams syndrome and in the general population does not differ between North America and Europe

Inversion of the Williams syndrome (WS) region on chromosome 7q11.23 has previously been shown to occur at a higher frequency in the transmitting parents of children with WS than in the general population, suggesting that it predisposes to the WS deletion. Frohnauer et al. recently reported that the frequency of this inversion is not elevated in the parents of children with WS in Germany relative to the German general population. We have compared Frohnauer et al.'s data to those from three previously published studies (Hobart et al., Bayes et al., Osborne et al.), all of which reported a significantly higher rate of 7q11.23 inversion in transmitting parents than in the general population. Results indicated that Frohnauer et al.'s data are consistent with previously reported frequencies of 7q11.23 inversion in North America and Spain in both transmitting parents and the general population

Pragmatic Abilities of Children with Williams Syndrome: A Longitudinal Examination

Prior research has indicated that pragmatics is an area of particular weakness for individuals with Williams syndrome (WS). To further address this aspect of the WS social phenotype, we used an individual differences approach to consider both cross-sectional and longitudinal relations among different pragmatic abilities for 14 children with WS, taking into account individual differences in non-verbal reasoning abilities. We also considered the relations between pragmatic abilities and expressive vocabulary ability. Participants were tested at two time points: as 4-year-olds during a 30-min play session with their mothers (Time 1) and an average of 5.87 years later during a one-on-one conversation with a familiar researcher (Time 2). Children’s intellectual and expressive vocabulary abilities were assessed at both time points. Results indicated that the ability to verbally contribute information beyond what was required in response to a question (ExtendQ) was significantly related to the ability to verbally contribute new information in the absence of a question (ExtendS) both at age 4 years and during primary school. At age 4, both the ability to pair verbalizations with eye contact in triadic interactions (secondary intersubjectivity) and expressive vocabulary ability were related to both ExtendQ and ExtendS. Finally, both ExtendQ and the ability to pair verbalizations with eye contact (intersubjectivity) at age 4 years predicted ExtendQ at age 9–12 years. The theoretical implications of our findings and the importance of early pragmatic language intervention for children who have WS are discussed

Use of spelling rules in school-aged children with Williams syndrome

Purpose: Researchers evaluating children’s spelling abilities usually score their spellings dichotomously - as correct or incorrect. This type of scoring is not as informative as procedures that take into consideration the plausibility of children’s spellings (Treiman et al., 2016). We examined the spelling abilities of children and adolescents with Williams syndrome (WS), a genetic disorder associated with intellectual disability, to determine if their spellings were based on English orthographic rules. Method: Sixty-six 9–17-year-olds with WS (M=13.50 years, SD=3.14) completed the Wechsler Individual Achievement Test-III (Wechsler, 2009) Spelling subtest. Items 6 to 16 were scored using the Ponto software (Kessler, 2017) to determine the extent to which children’s spelling differed from the correct spelling (the “letter distance ). Letter distance is calculated based on the transformations needed to change the child’s spelling to the correct spelling. Each insertion or deletion is scored 1, and each substitution is scored 1.4. If the word is spelled correctly, its letter distance is 0. Letter distance scores for the child’s spellings were compared to letter distance scores for random spellings, using the Monte Carlo method. Improvement scores were obtained by dividing a child’s sum of letter distances by the sum of random letter distances. Results: Children spelled a median of 10 (MAD=1) of 11 words correctly. Their mean improvement score was 0.89 (SD=0.14), which was significantly better than expected if their spelling had been random, p \u3c .001. Conclusion: Children and adolescents with WS have at least some knowledge of English orthographic spelling rules.https://ir.library.louisville.edu/uars/1054/thumbnail.jp

Genome Rearrangements Detected by SNP Microarrays in Individuals with Intellectual Disability Referred with Possible Williams Syndrome

Intellectual disability (ID) affects 2-3% of the population and may occur with or without multiple congenital anomalies (MCA) or other medical conditions. Established genetic syndromes and visible chromosome abnormalities account for a substantial percentage of ID diagnoses, although for approximately 50% the molecular etiology is unknown. Individuals with features suggestive of various syndromes but lacking their associated genetic anomalies pose a formidable clinical challenge. With the advent of microarray techniques, submicroscopic genome alterations not associated with known syndromes are emerging as a significant cause of ID and MCA.High-density SNP microarrays were used to determine genome wide copy number in 42 individuals: 7 with confirmed alterations in the WS region but atypical clinical phenotypes, 31 with ID and/or MCA, and 4 controls. One individual from the first group had the most telomeric gene in the WS critical region deleted along with 2 Mb of flanking sequence. A second person had the classic WS deletion and a rearrangement on chromosome 5p within the Cri du Chat syndrome (OMIM:123450) region. Six individuals from the ID/MCA group had large rearrangements (3 deletions, 3 duplications), one of whom had a large inversion associated with a deletion that was not detected by the SNP arrays.Combining SNP microarray analyses and qPCR allowed us to clone and sequence 21 deletion breakpoints in individuals with atypical deletions in the WS region and/or ID or MCA. Comparison of these breakpoints to databases of genomic variation revealed that 52% occurred in regions harboring structural variants in the general population. For two probands the genomic alterations were flanked by segmental duplications, which frequently mediate recurrent genome rearrangements; these may represent new genomic disorders. While SNP arrays and related technologies can identify potentially pathogenic deletions and duplications, obtaining sequence information from the breakpoints frequently provides additional information

Rare and Low Frequency Genomic Variants Impacting Neuronal Functions Modify the Dup7q11.23 Phenotype

© 2021, The Author(s). Background: 7q11.23 duplication (Dup7) is one of the most frequent recurrent copy number variants (CNVs) in individuals with autism spectrum disorder (ASD), but based on gold-standard assessments, only 19% of Dup7 carriers have ASD, suggesting that additional genetic factors are necessary to manifest the ASD phenotype. To assess the contribution of additional genetic variants to the Dup7 phenotype, we conducted whole-genome sequencing analysis of 20 Dup7 carriers: nine with ASD (Dup7-ASD) and 11 without ASD (Dup7-non-ASD). Results: We identified three rare variants of potential clinical relevance for ASD: a 1q21.1 microdeletion (Dup7-non-ASD) and two deletions which disrupted IMMP2L (one Dup7-ASD, one Dup7-non-ASD). There were no significant differences in gene-set or pathway variant burden between the Dup7-ASD and Dup7-non-ASD groups. However, overall intellectual ability negatively correlated with the number of rare loss-of-function variants present in nervous system development and membrane component pathways, and adaptive behaviour standard scores negatively correlated with the number of low-frequency likely-damaging missense variants found in genes expressed in the prenatal human brain. ASD severity positively correlated with the number of low frequency loss-of-function variants impacting genes expressed at low levels in the brain, and genes with a low level of intolerance. Conclusions: Our study suggests that in the presence of the same pathogenic Dup7 variant, rare and low frequency genetic variants act additively to contribute to components of the overall Dup7 phenotype

LIM-kinase1 Hemizygosity Implicated in Impaired Visuospatial Constructive Cognition

AbstractTo identify genes important for human cognitive development, we studied Williams syndrome (WS), a developmental disorder that includes poor visuospatial constructive cognition. Here we describe two families with a partial WS phenotype; affected members have the specific WS cognitive profile and vascular disease, but lack other WS features. Submicroscopic chromosome 7q11.23 deletions cosegregate with this phenotype in both families. DNA sequence analyses of the region affected by the smallest deletion (83.6 kb) revealed two genes, elastin (ELN ) and LIM-kinase1 (LIMK1). The latter encodes a novel protein kinase with LIM domains and is strongly expressed in the brain. Because ELN mutations cause vascular disease but not cognitive abnormalities, these data implicate LIMK1 hemizygosity in impaired visuospatial constructive cognition

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

The regulatory function of social referencing in preschoolers with Down syndrome or Williams syndrome

Abstract Background An important developmental task is to learn to recognize another person as a source of information and to utilize this information as a method of learning about the surrounding world. This socially guided form of learning, referred to as social referencing, is critical for the development of children’s understanding of other people, themselves and their surrounding world. In the present project, the regulatory function of social referencing was examined in two genetic disorders that are characterized by differing patterns of socio-cognitive development: Down syndrome (DS) and Williams syndrome (WS). Methods Participants were 20 children with DS and 20 children with WS aged 42 to 71 months, matched on chronological age and gender. Each child participated in four studies: one study in which we examined performance in a social referencing paradigm and three studies in which we considered performance on tasks designed to tap each of three component abilities (initiating eye contact, gaze following and emotional responsivity) important for success in social referencing. Results The majority of children in both groups demonstrated positive behavioral responses regarding the stimulus in the Social Referencing task when the adult communicated a joyful message but did not regulate their own behavior in accordance with the adult’s expression of fear. Between-group differences were observed in both conditions, with most differences indicating more advanced socio-communicative competence for children with DS than for children with WS even though the overall intellectual abilities and receptive language abilities of the children with WS were significantly higher than were those of the children with DS. The results of follow-up studies indicated that children with DS were more likely to initiate eye contact (unsolicited) and to follow another person’s gaze in triadic situations than were children with WS. Neither group regulated their behavior in response to expressions of fear. Conclusions These findings provide new insight into the development of the social cognitive phenotypes associated with DS and WS. These social cognitive differences found during the preschool years likely contribute to the differing phenotypes observed later in life between individuals with DS and individuals with WS