Williams Syndrome Research Articles

Supplemental Material for Reliability of Teleneuropsychological Assessment of People With Williams Syndrome

Supplemental Material for Reliability of Teleneuropsychological Assessment of People With Williams Syndrome

The experiences of children with Williams syndrome and their nondisabled siblings of their relationship

AbstractObjectiveThis study explored sibling relationships from the perspective of children with Williams syndrome (WS) and their nondisabled (ND) siblings.BackgroundWS, a genetic condition with a profile that can include intellectual disabilities, hypersociability and anxiety, might be predicted to impact sibling relationships, but this has not been qualitatively explored from the children's perspective.MethodsThirty‐nine children (6–17 years; 20 male, 19 female) participated: 20 sibling dyads in which one child had WS and the other was ND (one child with WS did not participate). Children were interviewed about experiences of their relationship. Data were analyzed with reflexive thematic analysis.ResultsSiblings described multifaceted relationships, in which love and positivity were overtly evident and embedded in the reciprocity of sibling expertise and support. Children skillfully navigated the spaces and boundaries of their relationship across home, school, and friendship contexts, with parent support. ND siblings' knowledge of WS supported interactions, relationships, and advocacy, but some children with WS felt their sibling lacked knowledge of the challenges of WS.ConclusionsThe WS profile was woven through multidimensional relationships.ImplicationsFindings have implications for how parents are supported to help siblings navigate relationships and learn about WS, and how schools support WS sibling relationships.

Characteristics of early cognitive development in children with Williams syndrome: a prospective cohort study

To investigate the early cognitive development characteristics of children with Williams syndrome (WS) at different age stages. From September 2018 to June 2023, 106 children diagnosed with WS at the Department of Pediatric Health Care, Children's Hospital, Zhejiang University School of Medicine, aged 1 to <5 years, were prospectively enrolled. All children underwent Gesell developmental diagnostic assessments to analyze the cognitive development characteristics of WS children across different age groups. The average age of the 106 WS children was (3.1±1.2) years; 58 were male, and 48 were female. There were no significant differences in developmental levels between males and females in the five domains of gross motor skills, fine motor skills, language, personal-social skills, and adaptive behavior (P>0.05). The incidence rates of mild, moderate, severe, and profound developmental disabilities among children of different age groups showed no significant differences (P>0.05). Comparisons of developmental levels in gross motor skills, language, personal-social skills, and adaptive behavior among different age groups were also not statistically significant (P>0.05). With the increase of age, the developmental level of fine motor skills showed a decreasing trend (P<0.05). There were no significant differences in verbal IQ and non-verbal IQ within each age group of WS children (P>0.05). The overall developmental level of WS children stabilizes with age, and their early language abilities do not significantly exceed their non-verbal abilities.

Unexpected and atypical clinical presentation of myocardial infarction in infants and children: complex pathogenesis of progressive and lethal disease.

Myocardial infarction is rare in children but frequently occurs unexpectedly with atypical presentation. It can cause a progressive lethal course unless prompt treatment is initiated. Paediatric cases of myocardial infarction diagnosed by the presence of ischaemic myocardial insults and symptomatic ventricular dysfunction were reviewed retrospectively. Eighteen patients (5 days to 14 years of age; median 3 months) with myocardial infarction were studied. The aetiology was variable, including congenital coronary anomalies: anomalous left coronary artery from pulmonary artery (five patients), pulmonary atresia with intact ventricular septum with right ventricle-dependent coronary circulation (four), anomalous aortic origin of left coronary artery (three), and Williams syndrome with supravalvar aortic stenosis (one). Two acquired coronary anomalies occurred in one patient with undiagnosed Kawasaki disease with complete thrombotic obstruction of the left coronary artery and another with post-transplant cardiac allograft microangiopathy. Three patients developed thromboembolic coronary artery incidents in normal coronary anatomy. Fourteen patients were less than 1 year of age (78%). Electrocardiographic abnormalities were noted in all patients. Four patients required extracorporeal membrane oxygenation support for severe ventricular dysfunction, none of whom survived. Five patients underwent heart transplant. Five patients died during the same hospitalisation, and one patient died after discharge (overall mortality 33%). Transplant-free survival was 39%. Most myocardial infarction occurred in infants who presented with abrupt onset of non-specific clinical manifestations with progressively deteriorating haemodynamic status resulting in poor transplant-free survival rate. Early diagnosis and treatment are essential to prevent catastrophic outcomes.

Behaviour and Psychopathology in Preschool Children with William Syndrome and the Effects of Age, Sex and Cognition.

The current study compared the prevalence of cognitive and psychopathological impairments among 24 preschool children with Williams syndrome (WS) (aged 2.20 to 5.97years) and 53 controls without WS and screened for developmental or psychological diagnoses (aged 2.21 to 5.89years) matched on chronological age and sex distribution. Associations between sex, chronological age, early development and psychopathology were also investigated. The Child Behavior Checklist-Preschool Version (CBCL) and the Mullen Scales of Early Learning were administered. Higher reported rates of Attention Problems, Emotional Reactivity, Somatic Complaints, Withdrawal, Affective Problems and Total Problems were found in preschool children with WS. There were no significant group differences in prevalence rates of all other CBCL domains. Attention Problems were the most prevalent psychopathology in preschool children with WS (33% falling in the clinically significant range), followed by Affective Problems (29% in clinically significant range), then Anxiety Problems (17%) or Attention Deficit/Hyperactivity Problems (17%). Among children without WS, the highest prevalence rates of psychopathology were for Attention Problems (4% falling in the clinically significant range), Aggressive Behaviour (4%), Sleep Problems (4%) and Oppositional Defiant Problems (4%). There were no significant associations between sex or chronological age and CBCL-reported psychopathology for either group. In addition, there were no significant relationships between CBCL ratings and verbal ability, nonverbal ability or overall developmental level in either group. Findings highlight variations in the pattern of psychopathology among preschool children with WS compared to those without WS, which needs to be considered in clinical management and future research.

A Rare Co-occurrence of Williams Syndrome and 𝘛𝘕𝘒2 Gene-Related Epilepsy

A Rare Co-occurrence of Williams Syndrome and 𝘛𝘕𝘒2 Gene-Related Epilepsy

Examining of Social-Emotional and Moral Characteristics of a Child with Williams Syndrome and a Typically Developing Peer

Introduction: This paper compared the social-emotional and moral developmental characteristics of a boy with Williams syndrome and a typically developing girl. Method: The sample consisted of two eighth graders and their mothers. Participants were recruited using purposive criterion sampling. This qualitative study adopted a holistic multiple-case design because it compared the interrelated social-emotional and moral developmental characteristics of two different profiles of children. Findings: Data were collected using the Social-Emotional and Character Development Scale (SECDS), semi-structured interview questions, spontaneous conversations, and observations. The quantitative data were analyzed using descriptive analysis, while the qualitative data were analyzed using content analysis. The results show that the boy with Williams syndrome is more successful than his typically developing peer in making plans and helping others, but less successful in making eye contact, making friends, and following rules in the absence of authority. The typically developing girl has better internal control in following rules, behaving politely and respectfully, and exhibiting moral behaviors because she wants to. The findings show that both children have relatively developed social-emotional and moral characteristics. Discussion: The fact that the boy with Williams syndrome was more successful in expressing his wants and needs, planning and organizing, helping, maintaining communication with strangers, and choosing positive behaviors compared to his typically developing peer; behaving according to people's opinions, having approval anxiety, making decisions, self-regulation, following rules in the absence of authority, peer relations, adaptation, understanding people's feelings, and having difficulty in distinguishing good and bad intentions were in line with the literature. The fact that the typically developing girl exhibited more extreme social actions such as initiating communication; making eye contact for a long time; apologizing for misbehaviors; following rules with internal control and exhibiting positive behaviors provided different information from the literature. These results provide a new and different perspective to the results that children with Williams syndrome exhibit more social behaviors than their typically developing peers.

RFC2 may contribute to the pathogenicity of Williams syndrome revealed in a zebrafish model

Williams syndrome (WS) is a rare multisystemic disorder caused by recurrent microdeletions on 7q11.23, characterized by intellectual disability, distinctive craniofacial and dental features, and cardiovascular problems. Previous studies have explored the roles of individual genes within these microdeletions in contributing to WS phenotypes. Here, we report five patients with WS with 1.4 Mb–1.5 Mb microdeletions that include RFC2, as well as one patient with a 167 kb microdeletion involving RFC2 and six patients with intragenic variants within RFC2. To investigate the potential involvement of RFC2 in WS pathogenicity, we generate a rfc2 knockout (KO) zebrafish using CRISPR-Cas9 technology. Additionally, we generate a KO zebrafish of its paralog gene, rfc5, to better understand the functions of these RFC genes in development and disease. Both rfc2 and rfc5 KO zebrafish exhibit similar phenotypes reminiscent of WS, including small head and brain, jaw and dental defects, and vascular problems. RNA-seq analysis reveals that genes associated with neural cell survival and differentiation are specifically affected in rfc2 KO zebrafish. In addition, heterozygous rfc2 KO adult zebrafish demonstrate an anxiety-like behavior with increased social cohesion. These results suggest that RFC2 may contribute to the pathogenicity of Williams syndrome, as evidenced by the zebrafish model.

Overuse of familiar phrases by individuals with Williams syndrome masks differences in language processing.

We investigated whether individuals with Williams Syndrome (WS) produce language with a bias towards statistical properties of word combinations rather than grammatical rules, resulting in an overuse of holistically stored, familiar phrases. We analysed continuous speech samples from English children with WS (n = 12), typically developing (TD) controls matched on chronological age (n = 15) and TD controls matched on language age (n = 14). Alongside word count, utterance length, grammatical complexity, and morphosyntactic errors, we measured familiarity of expressions by computing collocation strength of each word combination. The WS group produced stronger collocations than both control groups. Moreover, the WS group produced fewer complex sentences, shorter utterances, and more frequent function words than chronological-age matched controls. Language in WS may appear more typical than it is because familiar, holistically processed expressions mask grammatical and other difficulties.

Characterization of the Prenatal Ultrasound Phenotype Associated With 7q11.23 Microduplication Syndrome and Williams-Beuren Syndrome.

This study aimed to characterize the intrauterine phenotype of fetuses with 7q11.23 microduplication syndrome and Williams-Beuren syndrome (WBS) to provide insight into prenatal genotype and phenotype correlations in the 7q11.23 region. Seven fetuses with 7q11.23 microduplication syndrome and sixteen with WBS were diagnosed via array comparative genomic hybridization (array CGH) or copy number variation sequencing (CNV-seq) at our center. Clinical data were also systematically collected and analyzed, including intrauterine phenotype, pregnancy outcome, and inheritance. In our cases, the most common prenatal ultrasound feature of 7q11.23 microduplication syndrome was cardiovascular defects; less frequent features included choroid plexus cysts, anencephaly, bilateral pyelectasis, and cervical lymphatic hygroma. On the other hand, WBS was mainly associated with cardiovascular defects and intrauterine growth retardation. Other clinical phenotypes included hypoechoic frontal horn of the right lateral ventricle, crossed fused renal ectopia, hyperechogenic bowel, hyperechogenic right thoracic cavity, and hyperechogenic hepatic parenchyma/intrahepatic duct wall. Our study describes a series of new ultrasound features identified prenatally in fetuses with 7q11.23 microduplications and microdeletions with the intent of expanding the prenatal phenotype associated with copy number variants in this chromosomal region. Additional studies are needed to clearly delineate specific prenatal features associated with these rare genetic entities.

Clinical Care for Cardiovascular Disease in Patients With Williams-Beuren Syndrome.

Williams-Beuren syndrome (WBS) is a congenital multisystem disorder affecting the cardiovascular, central nervous, and musculoskeletal systems. Cardiovascular abnormalities, which consist principally of vascular stenoses, occur in approximately 80% of people with WBS and are the predominant cause of early morbidity and mortality. Supravalvar aortic stenosis and peripheral pulmonary artery stenosis are the most common stenotic lesions in WBS, though other stenoses often occur, including stenoses of the coronary arteries. Approximately one-third of people with WBS undergo cardiovascular interventions. The risk of sudden cardiac death is markedly higher than the general population, with most events occurring in the periprocedural period. Because of the rarity of WBS and the often-complex nature of the cardiovascular abnormalities, most physicians, including cardiologists, have limited experience in caring for patients with WBS. Further, heretofore, clinical cardiovascular management guidelines based on international expert consensus have not been available. This state-of-the-art review provides a comprehensive synopsis of the cardiovascular abnormalities in WBS and presents clinical management guidelines based on the authors' expert consensus.

Identifying individuals at risk for surgical supravalvar aortic stenosis by polygenic risk score with graded phenotyping.

In a previous pathway-based, extreme phenotype study, we identified 1064 variants associated with supravalvar aortic stenosis (SVAS) severity in people with Williams syndrome (WS) and either no SVAS or surgical SVAS. Here, we use those variants to develop and test polygenic risk scores (PRS). We used the clumping and thresholding (CT) approach on the full 1064 variants and a 427-variant subset that was part of 13 biologically relevant pathways identified in the previous study. We also used a lasso approach on the full set. We were able to achieve an area under the curve (AUC) of >0.99 for the two CT PRS methods, using only 622 and 320 variants respectively when 2/3 of the initial 217 participants data were used for training and 1/3 for testing. The lasso performed less well. We then evaluated the performance of those PRS variant sets on an additional group of 138 patients with WS with intermediate severity SVAS and found a misclassification rate of <10% between the surgical and intermediate groups, suggesting potential for clinical utility of the score.

Diagnosing william-beuren syndrome in a patient with primary hyperparathyroidism

Diagnosing william-beuren syndrome in a patient with primary hyperparathyroidism

Excessive noise explains the impaired visually-guided navigation abilities in adults with Williams syndrome: a computational approach

Excessive noise explains the impaired visually-guided navigation abilities in adults with Williams syndrome: a computational approach

The Genetic Architecture of Congenital Heart Disease in Neonatal Intensive Care Unit Patients-The Experience of University Medical Centre, Ljubljana.

Congenital heart disease (CHD) is the most commonly detected congenital anomaly and affects up to 1% of all live-born neonates. Current guidelines support the use of chromosomal microarray analysis (CMA) and next-generation sequencing (NGS) as diagnostic approaches to identify genetic causes. The aim of our study was to evaluate the diagnostic yield of CMA and NGS in a cohort of neonates with both isolated and syndromic CHD. The present study included 188 infants under 28 days of age with abnormal echocardiography findings hospitalized at the Department of Neonatology, UMC Ljubljana, between January 2014 and December 2023. Phenotypic data were obtained for each infant via retrospective medical chart review. We established the genetic diagnosis of 22 distinct syndromes in 17% (32/188) of neonates. The most frequent genetic diagnoses in diagnosed cases were 22q11.2 microdeletion and CHARGE syndromes, followed by Noonan syndrome and Williams syndrome. In addition, we detected variants of uncertain significance in 4.8% (9/188) of neonates. Timely genetic diagnosis is important for the detection of syndrome-related comorbidities, prognosis, reproductive genetic risks and, when appropriate, genetic testing of other family members.

Optimization and evaluation of facial recognition models for Williams-Beuren syndrome.

The results showed that facial recognition technology can be used to accurately diagnose patients with WBS. Facial recognition models based on VGG-19BN can play a crucial role in its clinical diagnosis. Their performance can be improved by expanding the size of the training dataset, optimizing the CNN architectures applied, and modifying them with a variable cosine learning rate. • The facial gestalt of WBS, often described as "elfin," includes a broad forehead, periorbital puffiness, a flat nasal bridge, full cheeks, and a small chin. • Recent studies have demonstrated the potential of deep convolutional neural networks for facial recognition as a diagnostic tool for WBS. • This study develops six models of facial recognition, EfficientNet-b3, ResNet-50, VGG-16, VGG-16BN, VGG-19, and VGG-19BN, to improve WBS diagnosis. • The VGG-19BN model achieved the best performance, with an accuracy of 95.10% and specificity of 93.42%. The facial recognition model based on VGG-19BN can play a crucial role in the clinical diagnosis of WBS.

The role of social motivation in sharing and fairness: insights from Williams syndrome

BackgroundSharing and fairness are important prosocial behaviors that help us navigate the social world. However, little is known about how and whether individuals with Williams Syndrome (WS) engage in these behaviors. The unique phenotype of individuals with WS, consisting of high social motivation and limited social cognition, can also offer insight into the role of social motivation in sharing and fairness when compared to typically developing (TD) individuals. The current study used established experimental paradigms to examine sharing and fairness in individuals with WS and TD individuals.MethodsWe compared a sample of patients with WS to TD children (6-year-olds) matched by mental age (MA) on two experimental tasks: the Dictator Game (DG, Experiment 1, N = 17 WS, 20 TD) with adults modeling giving behaviors used to test sharing and the Inequity Game (IG, Experiment 2, N = 14 WS, 17 TD) used to test fairness.ResultsResults showed that the WS group behaved similarly to the TD group for baseline giving in the DG and in the IG, rejecting disadvantageous offers but accepting advantageous ones. However, after viewing an adult model giving behavior, the WS group gave more than their baseline, with many individuals giving more than half, while the TD group gave less. Combined these results suggest that social motivation is sufficient for sharing and, in particular, generous sharing, as well as the self-focused form of fairness. Further, individuals with WS appear capable of both learning to be more generous and preventing disadvantageous outcomes, a more complex profile than previously known.ConclusionsIn conclusion, the present study provides a snapshot into sharing and fairness-related behaviors in WS, contributing to our understanding of the intriguing social-behavioral phenotype associated with this developmental disorder.

Developmental process of the understanding of linguistic register in children: A comparison of typically developing children, autistic children, and children with Williams syndrome.

Although the developmental process of linguistic register-the appropriate manner of speech as determined by the listener and social situation-has been gradually clarified in typically developing (TD) children, research on the mechanism and developmental process of register acquisition in atypically developing children are insufficient. This study compared the developmental process of understanding linguistic register among TD children, autistic children, and those with Williams syndrome (WS), and examined the contributions of social cognition and motivation to the acquisition of linguistic register. Two experiments were designed to assess the recognition of which linguistic register to use when communicating with different listeners and of the listener's feelings according to the speakers' use of register. The results revealed that the process of understanding register-listener associations was nearly identical among all groups of children and their understanding improved with age. Conversely, their understanding of the effect of register selection on the listener's feelings varied. Importantly, as TD children mature, they become aware that adult listeners may feel negatively when spoken to in an inappropriate register, whereas autistic children and those with WS do not exhibit the same awareness. Thus, our results suggest that atypical social cognition and motivation do not disturb the understanding of register-listener associations. However, social cognition and motivation play important roles in understanding the effect of register selection on the listener's feelings. These findings provide a significant contribution to clarifying the mechanism of linguistic register acquisition.

7p22.3 microdeletion: a case study of a patient with congenital heart defect, neurodevelopmental delay and epilepsy

BackgroundChromosome 7 has regions enriched with low copy repeats (LCRs), which increase the likelihood of chromosomal microdeletion disorders. Documented microdeletion disorders on chromosome 7 include both well-known Williams syndrome and more rare cases. It is noteworthy that most cases of various microdeletions are characterized by phenotypic signs of neuropsychological developmental disorders, which, however, have a different genetic origin. The localization of the microdeletions, the genes included in the region, as well as the structural features of the sequences of these genes have a cumulative influence on the phenotypic characteristics of the individuals for each specific case and the severity of the manifestations of disorders. The consideration of these features and their detailed analysis is important for a correct and comprehensive assessment of the disease.ResultsThe article describes a clinical case of 7p22.3 microdeletion in a patient with congenital heart defect and neurological abnormalities - epilepsy, combined with moderate mental and motor developmental delay.ConclusionsThrough detailed genetic analyses, we are improving the clinical description of the rare 7p22.3 microdeletion and thus creating a basis for future genetic counseling and research into targeted therapies.

Conditional learning abilities in Down syndrome and Williams syndrome

ABSTRACT We investigated whether individuals with Down (DS) or Williams (WS) syndrome are capable of conditional learning, a hippocampus-dependent process enabling flexible reasoning, using three touch-screen tasks: a visual learning task to assess unconditional learning (A > B and C > D), a 3-item conditional learning task (A > B, B > C), and a 5-item conditional learning task (A > B, B > C, C > D, D > E) to further assess transitive inference abilities. We compared the performance of individuals with DS or WS to typically developing 3–12-year-old children and 20–30-year-old adults. Most participants exhibited unconditional learning, but only 12% of individuals with DS, 15% of individuals with WS, and 42% of children exhibited conditional learning, as compared to 95% of young adults; only adults demonstrated transitive inference. Our findings indicate that conditional learning and transitive inference, which depend on brain structures impacted in these disorders, including the hippocampus and the prefrontal cortex, are beyond reach for most individuals with DS and WS.