Comparison of the Accuracy in Provisional Diagnosis of 22q11.2 Deletion and Williams Syndromes by Facial Photos in Thai Population Between De-Identified Facial Program and Clinicians.

Introduction: There are more than 6000 genetic syndromes, therefore the recognition of facial patterns may present a challenge for clinicians. The 22q11.2 deletion syndrome (22q11.2 DS) and Williams syndrome (WS) are two different genetic syndromes but share some common phenotypic traits and subtle facial dysmorphisms. Therefore, any tool that would help clinicians recognize genetic syndromes would likely result in a more accurate diagnosis. Methods: The syndrome identification accuracy was compared between 2 different facial analysis algorithms (DeepGestalt and GestaltMatcher) of the Face2Gene (F2G) tool and a group of 9 clinicians with different levels of expertise before and after using F2G for a cohort of 64 Thai participants' frontal facial photos divided into 3 groups of 22q11.2 DS, WS and unaffected controls. Results: The higher accuracy from the DeepGestalt algorithm than from clinicians was demonstrated, especially when comparing between the two syndromes. The accuracy was highest when clinicians use the tool combined with their own decision-making process. The tool's second algorithm, GestaltMatcher revealed clear separation among these three groups of photos. Discussion: The result of F2G outperforming clinicians was not surprising. However, the highest increase in accuracy was with nondysmorphology clinicians using F2G. Conclusion: Face2Gene would be a useful tool to help clinicians in facial recognition of genetic syndromes, before ordering specific tests to confirm the definite diagnosis.

Spatial exploration and navigation in Down syndrome and Williams syndrome.

We know little about the ability to explore and navigate large-scale space for people with intellectual disability (ID). In this cross-syndrome study, individuals with Down syndrome (DS), individuals with Williams syndrome (WS) and typically developing children (TD; aged 5-11 years) explored virtual environments with the goal of learning where everything was within the environment (Experiment 1) or to find six stars (Experiment 2). There was little difference between the WS and DS groups when the goal was simply to learn about the environment with no specific destination to be reached (Experiment 1); both groups performed at a level akin to a subset of TD children of a similar level of non-verbal ability. The difference became evident when the goal of the task was to locate targets in the environment (Experiment 2). The DS group showed the weakest performance, performing at or below the level of a subset of TD children at a similar level of non-verbal ability, whilst the WS group performed at the level of the TD subset group. The DS, WS and TD group also demonstrated different patterns of exploration behavior. Exploration behaviour in DS was weak and did not improve across trials. In WS, exploration behavior changed across trials but was atypical (the number of revisits increased with repeated trials). Moreover, transdiagnostic individual difference analysis (Latent Profile Analysis) revealed five profiles of exploration and navigation variables, none of which were uniquely specific to DS or to WS. Only the most extreme profile of very poor navigators was specific to participants with DS and WS. Interestingly, all other profiles contained at least one individual with DS and at least one individual with WS. This highlights the importance of investigating heterogeneity in the performance of individuals with intellectual disability and the usefulness of a data-driven transdiagnostic approach to identifying behavioral profiles.

Peripheral Auditory Pathway and ABR Characterization in Adults with Williams Syndrome.

Introduction Williams syndrome (WS) is a genetic disorder caused by a microdeletion in chromosome 7, affecting ∼ 28 genes. Studies have demonstrated conductive losses seemingly related to the absence of the elastin gene and mild to profound sensorineural losses due to cochlear fragility. Objective To characterize and compare the peripheral auditory system and auditory brainstem response (ABR) of adults with WS and neurotypical adults matched by age and gender. Methods We conducted a cross-sectional observational study with 30 individuals of both sexes, aged 18 to 37 years - 15 of them with WS (study group) and 15 with neither the syndrome nor hearing complaints (control group), matched for sex and age. The subjects underwent pure-tone and speech audiometry, acoustic immittance, transient-evoked otoacoustic emissions (TEOAEs), and ABR. Results Early-onset sensorineural hearing loss was found in 53.3% of the study sample, mostly mild, occurring above 3 kHz. The TEOAEs were absent in 53.3% of assessed subjects; for those in whom they were present, the signal-to-noise responses were significantly lower than in the control group. In the ABR, increased absolute latencies were observed in waves I and III. Conclusion Individuals with WS have early and progressive cochlear impairments, mainly affecting the basal region of the cochlea. They may have low brainstem changes which seem to begin in adulthood.

Generation of two induced pluripotent stem cell lines from patients with Williams syndrome.

Williams syndrome (WS) is a relatively rare genetic disorder. It arises from a microdeletion in chromosome 7q11.23, resulting in the loss of one copy of more than 20 genes. Disorders in multiple systems, including cardiovascular and nervous systems, occur in patients with WS. Here, we generated two human induced pluripotent stem cell (iPSC) lines from WS patients. Both lines expressed pluripotency markers at gene and protein levels. They possessed normal karyotypes and the potential to differentiate into three germ layers. They serve as a useful tool to study disease mechanism, test drugs, and identify promising therapeutics for patients with WS.

Human Genetics of Semilunar Valve and Aortic Arch Anomalies.

Lesions of the semilunar valve and the aortic arch can occur either in isolation or as part of well-described clinical syndromes. The polygenic cause of calcific aortic valve disease will be discussed including the key role of NOTCH1 mutations. In addition, the complex trait of bicuspid aortic valve disease will be outlined, both in sporadic/familial cases and in the context of associated syndromes, such as Alagille, Williams, and Kabuki syndromes. Aortic arch abnormalities particularly coarctation of the aorta and interrupted aortic arch, including their association with syndromes such as Turner and 22q11 deletion, respectively, are also discussed. Finally, the genetic basis of congenital pulmonary valve stenosis is summarized, with particular note to Ras-/mitogen-activated protein kinase (Ras/MAPK) pathway syndromes and other less common associations, such as Holt-Oram syndrome.

Brazilian growth charts for Williams-Beuren Syndrome at ages 2 to 18 years

Abstract Objective: To develop growth charts for weight-for-age, height-for-age, and body mass index (BMI)-for-age for both genders aged 2 to 18 years for Brazilian patients with Williams-Beuren Syndrome (WBS). Methods: This is a multicenter, retrospective, and longitudinal study, data were collected from the medical records of boys and girls with a confirmed diagnosis of WBS in three large university centers in the state of Sao Paulo, Brazil. Growth charts stratified by gender and age in years were developed using LMSchartmaker Pro software. The LMS (Lambda Mu Sigma) method was used to model the charts. The quality of the settings was checked by worm plots. Results: The first Brazilian growth charts for weight-for-age, height-for-age, and BMI-for-age stratified by gender were constructed for WBS patients aged 2 to 18 years. Conclusion: The growth charts developed in this study can help to guide family members and to improve the health care offered by health professionals.

Caregiver-reported barriers to care for children and adults with Williams Syndrome.

Individuals with Williams syndrome (WS) may experience a variety of medical, behavioral, and educational concerns. The primary objective of this study was to assess barriers to health care for patients with WS, primarily using the Barriers to Care Questionnaire (BCQ), and to assess whether various demographic factors are correlated with these barriers. A REDCap survey was distributed using the Williams Syndrome Association Research Registry. 319 caregivers of individuals with WS in the United States completed the BCQ. On the BCQ, lower scores indicate more barriers to care. Younger age was associated with lower scores for both the pragmatics and the skills subscales while lower income levels and increased distances to providers knowledgeable about WS were consistently associated with lower total BCQ scores.

Case report: Development of central precocious puberty in a girl with late-diagnosed simple virilizing congenital adrenal hyperplasia complicated with Williams syndrome.

Congenital adrenal hyperplasia (CAH) and Williams Syndrome (WS; MIM # 194050) are distinct genetic conditions characterized by unique clinical features. 21-Hydroxylase deficiency (21-OHD; MIM #201910), the most common form of CAH, arises from mutations in the CYP21A2 gene, resulting in virilization of the external genitalia in affected females, early puberty in males, and short stature. Williams syndrome, caused by a microdeletion of 7q11.23, presents with distinctive facial features, intellectual disability, unique personality traits, early puberty, and short stature. This case report describe the clinical features of a 4-year-old girl referred due to progressive virilization and developmental delay. Genetic analysis confirmed concurrent CAH and WS, identifying a novel mutation in the CYP21A2 gene (c.1442T>C). Following corticosteroid therapy initiation, the patient developed central precocious puberty. This case report delves into the pubertal change patterns in a patient affected by overlapping genetic conditions, providing valuable insights in to the intricate clinical manifestation and management of these rare complex disorders.

Congenital heart defects and postoperative follow-up of patients with Williams syndrome as a single center experience and review of the cases from Türkiye.

BACKGROUND: Cardiovascular system involvement is quite common and the leading cause of morbidity and mortality in patients with Williams syndrome (WS), most of whom need surgery. The present study aimed to provide a detailed evaluation of the features of surgical procedures and outcomes of patients with WS given as single-center experience, and additionally to make a detailed review from Türkiye. MATERIALS AND METHODS: Thirty-five children with WS diagnosed between the years 1992 and 2021 were evaluated retrospectively including cardiovascular data, surgical treatment features, and outcomes. A total of six articles from Türkiye were evaluated. RESULTS: A total of 35 patients with Williams Syndrome (24 male) with a median age of cardiologic diagnosis of 6 months (range, 2 days-6 years) were evaluated. The cardiac defects of the patients with WS were found as supravalvular aortic stenosis (SVAS) (n=30, 85%) and peripheral pulmonary stenosis (PPS) (n=21, 65%). Additional cardiac anomalies were seen in 71% patients. The rate of SVAS and PPS surgery in all patients with WS was 77.1%. The median surgical age of the patients was 2.5 years (range, 7 months-15.5 years). No patients died due to surgery. But one patient died because of ventricular tachycardia due to anesthesia at the beginning of angiography. A total of 138 (63% male) patients with WS were evaluated from the articles published in Türkiye. Of 138 patients, 64.4% had SVAS, 52.1% had PPS, and 39.8% had additional cardiac anomaly. The median follow-up period ranged from 17 months to 18 years, and six (4.3%) patients died in the early postoperative period. CONCLUSION: Cardiovascular system involvement is extremely common and is the leading cause of morbidity and mortality in patients with WS, often requiring surgical intervention. As seen in our study including 35 patients with WS and in publications from Türkiye, SVAS in patients with WS generally requires surgery, especially in the first year of life. PPS, on the other hand, requires surgery less frequently than SVAS, and pulmonary stenosis appears to decrease over time.

Numerical study of hemodynamic flow in the aortic vessel of Williams syndrome patient with congenital heart disease.

Congenital arterial stenosis such as supravalvar aortic stenosis (SVAS) are highly prevalent in Williams syndrome (WS) and other arteriopathies pose a substantial health risk. Conventional tools for severity assessment, including clinical findings and pressure gradient estimations, often fall short due to their susceptibility to transient physiological changes and disease stage influences. Moreover, in the pediatric population, the severity of these and other congenital heart defects (CHDs) often restricts the applicability of invasive techniques for obtaining crucial physiological data. Conversely, evaluating CHDs and their progression requires a comprehensive understanding of intracardiac blood flow. Current imaging modalities, such as blood speckle imaging (BSI) and four-dimensional magnetic resonance imaging (4D MRI) face limitations in resolving flow data, especially in cases of elevated flow velocities. To address these challenges, we devised a computational framework employing zero-dimensional (0D) lumped parameter models coupled with patient-specific reconstructed geometries pre- and post-surgical intervention to execute computational fluid dynamic (CFD) simulations. This framework facilitates the analysis and visualization of intricate blood flow patterns, offering insights into geometry and flow dynamics alterations impacting cardiac function. In this study, we aim to assess the efficacy of surgical intervention in correcting an extreme aortic defect in a patient with WS, leading to reductions in wall shear stress (WSS), maximum velocity magnitude, pressure drop, and ultimately a decrease in cardiac workload.

Identification of Prostaglandin I2 Synthase Rare Variants in Patients With Williams Syndrome and Severe Peripheral Pulmonary Stenosis.

BACKGROUND: Peripheral pulmonary stenosis (PPS) is a condition characterized by the narrowing of the pulmonary arteries, which impairs blood flow to the lung. The mechanisms underlying PPS pathogenesis remain unclear. Thus, the aim of this study was to investigate the genetic background of patients with severe PPS to elucidate the pathogenesis of this condition. METHODS AND RESULTS: We performed genetic testing and functional analyses on a pediatric patient with PPS and Williams syndrome (WS), followed by genetic testing on 12 patients with WS and mild-to-severe PPS, 50 patients with WS but not PPS, and 21 patients with severe PPS but not WS. Whole-exome sequencing identified a rare PTGIS nonsense variant (p.E314X) in a patient with WS and severe PPS. Prostaglandin I2 synthase (PTGIS) expression was significantly downregulated and cell proliferation and migration rates were significantly increased in cells transfected with the PTGIS p.E314X variant-encoding construct when compared with that in cells transfected with the wild-type PTGIS-encoding construct. p.E314X reduced the tube formation ability in human pulmonary artery endothelial cells and caspase 3/7 activity in both human pulmonary artery endothelial cells and human pulmonary artery smooth muscle cells. Compared with healthy controls, patients with PPS exhibited downregulated pulmonary artery endothelial prostaglandin I2 synthase levels and urinary prostaglandin I metabolite levels. We identified another PTGIS rare splice-site variant (c.1358+2T>C) in another pediatric patient with WS and severe PPS. CONCLUSIONS: In total, 2 rare nonsense/splice-site PTGIS variants were identified in 2 pediatric patients with WS and severe PPS. PTGIS variants may be involved in PPS pathogenesis, and PTGIS represents an effective therapeutic target.

Using a community engaged research approach to develop the social skills training program for adults with Williams syndrome.

This article describes the development of a distance-delivered social skills training program for adults with Williams syndrome (SSTP-WS) through a community engaged approach. Throughout six phases of development, the research team received input from adults with Williams syndrome, caregivers, service providers, educators, and researchers on (a) the need for a training program and topics to be addressed (Phase 1), (b) an initial draft of the SSTP-WS (Phase 3), (c) the intervention pilot study (Phase 5), and (d) feedback to provide context for the results of the study (Phase 6). The development of the SSTP-WS resulted in an intervention aligned with the Williams syndrome community's values and needs that supports the unique cognitive and behavioral phenotypes and social characteristics of this low incidence disability population.

Genetic Testing for Supravalvar Aortic Stenosis: What to Do When It Is Not Williams Syndrome.

BACKGROUND: We aimed to describe the frequency and yield of genetic testing in supravalvar aortic stenosis (SVAS) following negative evaluation for Williams-Beuren syndrome (WS). METHODS AND RESULTS: This retrospective cohort study included patients with SVAS at our institution who had a negative evaluation for WS from May 1991 to September 2021. SVAS was defined as (1) peak supravalvar velocity of ≥2 meters/second, (2) sinotubular junction or ascending aortic Z score <-2.0, or (3) sinotubular junction Z score <-1.5 with family history of SVAS. Patients with complex congenital heart disease, aortic valve disease as the primary condition, or only postoperative SVAS were excluded. Genetic testing and diagnoses were reported. Of 162 patients who were WS negative meeting inclusion criteria, 61 had genetic testing results available (38%). Chromosomal microarray had been performed in 44 of 61 and was nondiagnostic for non-WS causes of SVAS. Sequencing of 1 or more genes was performed in 47 of 61. Of these, 39 of 47 underwent ELN sequencing, 20 of 39 (51%) of whom had a diagnostic variant. Other diagnoses made by gene sequencing were Noonan syndrome (3 PTPN11, 1 RIT1), Alagille syndrome (3 JAG1), neurofibromatosis (1 NF1), and homozygous familial hypercholesterolemia (1 LDLR1). Overall, sequencing was diagnostic in 29 of 47 (62%). CONCLUSIONS: When WS is excluded, gene sequencing for SVAS is high yield, with the highest yield for the ELN gene. Therefore, we recommend gene sequencing using a multigene panel or exome analysis. Hypercholesterolemia can also be considered in individuals bearing the stigmata of this disease.

Specificity of Early Childhood Hyperphagia Profiles in Neurogenetic Conditions.

Hyperphagia is highly penetrant in Prader-Willi syndrome (PWS) and has increasingly been reported in other neurogenetic conditions (NGC). The Hyperphagia Questionnaire (HQ) was completed by caregivers of 4-8-year-olds with PWS (n = 17), Angelman syndrome (AS; n = 22), Williams syndrome (WS; n = 25), or low-risk controls (LRC; n = 35). All NGC groups were significantly elevated in HQ Total and Behavior scores compared to LRC. Only AS and WS were significantly elevated in the Drive domain, and only PWS in the Severity domain. After controlling for externalizing behavior, HQ Total scores were higher for PWS relative to other groups. Hyperphagic symptoms may not differentiate PWS from other NGCs in early childhood. However, hyperphagic phenotypes may be most severe in PWS. Further investigation of these profiles may inform etiology and syndrome-specific treatments.

Case Report: Rapid and progressive left ventricular endocardial calcification in an infant with Williams syndrome.

Williams syndrome (WS) is characterized by a range of clinical features, including cardiovascular disease, distinctive facial traits, neurobehavioral disorders, and a condition known as transient infantile hypercalcemia. Among these, endocardial calcification represents a non-specific response to severe, etiologically diverse myocardial injuries. In this report, we document a unique case involving an infant with WS who exhibited rapidly progressive arterial stenosis and left ventricular endocardial calcification, associated with a novel heterozygous deletion. While arterial stenosis is the most frequently observed cardiovascular issue in WS, instances of endocardial calcification during infancy are exceedingly rare and have not previously been reported in the context of WS.

Cognitive strengths in neurodevelopmental disorders, conditions and differences: A critical review.

Neurodevelopmental disorders are traditionally characterised by a range of associated cognitive impairments in, for example, sensory processing, facial recognition, visual imagery, attention, and coordination. In this critical review, we propose a major reframing, highlighting the variety of unique cognitive strengths that people with neurodevelopmental differences can exhibit. These include enhanced visual perception, strong spatial, auditory, and semantic memory, superior empathy and theory of mind, along with higher levels of divergent thinking. Whilst we acknowledge the heterogeneity of cognitive profiles in neurodevelopmental conditions, we present a more encouraging and affirmative perspective of these groups, contrasting with the predominant, deficit-based position prevalent throughout both cognitive and neuropsychological research. In addition, we provide a theoretical basis and rationale for these cognitive strengths, arguing for the critical role of hereditability, behavioural adaptation, neuronal-recycling, and we draw on psychopharmacological and social explanations. We present a table of potential strengths across conditions and invite researchers to systematically investigate these in their future work. This should help reduce the stigma around neurodiversity, instead promoting greater social inclusion and significant societal benefits.

Neuronal deletion of Gtf2i results in developmental microglial alterations in a mouse model related to Williams syndrome.

Williams syndrome (WS) is a genetic neurodevelopmental disorder caused by a heterozygous microdeletion, characterized by hypersociability and unique neurocognitive abnormalities. Of the deleted genes, GTF2I has been linked to hypersociability in WS. We have recently shown that Gtf2i deletion from forebrain excitatory neurons, referred to as Gtf2i conditional knockout (cKO) mice leads to multi-faceted myelination deficits associated with the social behaviors affected in WS. These deficits were potentially mediated also by microglia, as they present a close relationship with oligodendrocytes. To study the impact of altered myelination, we characterized these mice in terms of microglia over the course of development. In postnatal day 30 (P30) Gtf2i cKO mice, cortical microglia displayed a more ramified state, as compared with wild type (controls). However, postnatal day 4 (P4) microglia exhibited high proliferation rates and an elevated activation state, demonstrating altered properties related to activation and inflammation in Gtf2i cKO mice compared with control. Intriguingly, P4 Gtf2i cKO-derived microglial cells exhibited significantly elevated myelin phagocytosis in vitro compared to control mice. Lastly, systemic injection of clemastine to P4 Gtf2i cKO and control mice until P30, led to a significant interaction between genotypes and treatments on the expression levels of the phagocytic marker CD68, and a significant reduction of the macrophage/microglial marker Iba1 transcript levels in the cortex of the Gtf2i cKO treated mice. Our data thus implicate microglia as important players in WS, and that early postnatal manipulation of microglia might be beneficial in treating inflammatory and myelin-related pathologies.

Pragmatic skills in people with Williams syndrome: the perception of families.

BACKGROUND: One of the most challenging linguistic areas in people with Williams Syndrome throughout their evolutionary stage is the development of pragmatic skills. The research conducted so far highlights specific problems concerning adaptation to the linguistic context and interlocutors, language comprehension, as well as other aspects interfering with verbal communication. However, until now, most scientific evidence has been based on personal assessments of this group. In a complementary manner, the goal of this study was to discover the level of pragmatic skills of people with Williams Syndrome from the point of view of the families. The sample consisted of 34 families belonging to the Williams Syndrome Association of Spain. The assessment instrument was the pragmatic awareness questionnaire, which includes 26 items related to different aspects that are part of the pragmatic area on a Likert-type scale. RESULTS: The results indicate that, families consider there to be a regular to low level in all the areas assessed. The strong points seem to lie in the paralinguistic aspects, while the weakest factors are those related to the understanding of figurative language. CONCLUSIONS: Therefore, it is necessary to continue insisting on the importance of language intervention in this group throughout its development to improve its level of linguistic competence.

Loss of GTF2I promotes neuronal apoptosis and synaptic reduction in human cellular models of neurodevelopment.

Individuals with Williams syndrome (WS), a neurodevelopmental disorder caused by hemizygous loss of 26-28 genes at 7q11.23, characteristically portray a hypersocial phenotype. Copy-number variations and mutations in one of these genes, GTF2I, are associated with altered sociality and are proposed to underlie hypersociality in WS. However, the contribution of GTF2I to human neurodevelopment remains poorly understood. Here, human cellular models of neurodevelopment, including neural progenitors, neurons, and three-dimensional cortical organoids, are differentiated from CRISPR-Cas9-edited GTF2I-knockout (GTF2I-KO) pluripotent stem cells to investigate the role of GTF2I in human neurodevelopment. GTF2I-KO progenitors exhibit increased proliferation and cell-cycle alterations. Cortical organoids and neurons demonstrate increased cell death and synaptic dysregulation, including synaptic structural dysfunction and decreased electrophysiological activity on a multielectrode array. Our findings suggest that changes in synaptic circuit integrity may be a prominent mediator of the link between alterations in GTF2I and variation in the phenotypic expression of human sociality.

Buspirone for the treatment of anxiety in Williams syndrome: a retrospective chart review study.

BACKGROUND: Williams syndrome (WS) is a rare genetic disorder associated with a high prevalence of anxiety disorders. Evidence-based pharmacologic treatments for anxiety in WS are lacking. The purpose of this study is to provide naturalistic data on the use of buspirone for the treatment of anxiety in WS. RESEARCH DESIGN AND METHODS: Medical records of 24 individuals with Williams syndrome (ages 7-47 years) and anxiety who received treatment with buspirone were reviewed. Treatment response to buspirone was rated by assigning a retrospective Clinical Global Impression Improvement subscale (CGI-I) score. RESULTS: Twenty-three of 24 (96%) patients completed at least a 16-week treatment course with buspirone. Sixteen patients (67%; 95% CI 47%, 82%) were treatment responders (CGI-I ≤ 2). Only 1 (4%) patient discontinued buspirone due to a treatment-emergent side effect (nausea and vomiting). The most common side effect was nausea (13%). Twenty (84%) patients remained on buspirone at the time of their most recent follow-up visit. CONCLUSIONS: In this retrospective study, the majority of patients responded to a 16-week course of buspirone. Prospective studies are warranted to further assess the efficacy and tolerability of buspirone for anxiety in WS.