Noninvasive prenatal screening and diagnosis of two fetuses with Williams syndrome in a cohort of 19,607 pregnancies.

BACKGROUND: This study aimed to evaluate the efficiency of noninvasive prenatal screening (NIPS) technology in screening for microdeletions in the 7q11.23 region. METHODS: 19,607 pregnant women underwent NIPS in our hospital. Maternal peripheral cell-free foetal DNA (cffDNA) was routinely screened for aneuploidy by cffDNA enrichment and simultaneously analyzed for pathogenic copy number variants (CNVs). The Williams syndrome (WS) 7q11.23 region was targeted in this study. Chromosomal microarray analysis (CMA) was used to verify the screen-positive samples. RESULTS: The mean concentration of cffDNA before and after enrichment increased from 9.44% to 19.32%, with a statistically significant difference. Two out of 19,607 samples tested for CNVs were found to have a heterozygous deletion at the 7q11.23 region, indicating a high risk for WS. CMA results confirmed the 1.5 megabase (Mb) deletions at the 7q11.23 region in amniotic fluid samples. One of the two WS foetuses had a small left ventricle by ultrasound screening, and the other did not have a significant cardiovascular abnormality phenotype. CONCLUSIONS: NIPS screening for Williams syndrome can be achieved by enriching cell-free foetal DNA and improving bioinformatic analysis algorithms.

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

BACKGROUND: Sharing 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. METHODS: We 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. RESULTS: Results 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. CONCLUSIONS: In 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.

A case of Williams syndrome with Wolff-Parkinson-White syndrome.

INTRODUCTION: Williams syndrome (WS) cases have been reported to have with 25-100 times greater increased risk of sudden cardiac death (SCD). SCD has been reported in cases without any evidence of structural cardiovascular anomalies. Wolff-Parkinson-White (WPW) syndrome is characterized by short PR interval and delta wave. Ventricular preexcitations can develop paroxysmal reentrant tachycardia through Kent bundle or less frequent atrial fibrillation and in some cases with accessory pathway effective refractory period (APERP) under 250 ms considered as risky and may lead to SCD. WS associated with WPW has not been reported before. CASE REPORT: An 11-year-old male who had been followed up with WS was referred to pediatric cardiology outpatient clinic with the complaint of palpitation. Electrocardiographic examination showed short PR interval and delta wave in the ECG consistent with WPW. He underwent electrophysiological study (EPS). Basic measurements were performed, and APERP was found at 280 ms cycle atrial pacing. RF energy was delivered using a 4 mm tip nonirrigated radiofrequency (RF) ablation catheter where the best ventriculoatrial (VA) signals were received and the AP was abolished within few seconds. DISCUSSION AND CONCLUSIONS: Although, WPW cases are usually asymptomatic or related to SVT, the risk of SCD should not be ignored. Thus, all patients with WPW deserve an EPS for assessing the AP conduction properties. Due to the increased risk of SCD in patients with WS compared to general population, in the presence of concomitant WPW, these patients should be evaluated with EPS even if they do not have symptoms.

Williams-Beuren syndrome diagnosis in an infant with atypical chromosome 7 microdeletion.

This patient is an infant with Williams-Beuren syndrome (WBS) who was diagnosed at 2 months of age. He was born by caesarean section with a low birth weight (LBW) of 2.1 kg and was small for gestational age. His para 1+1 (1 alive) mother in her mid-30s had intrauterine growth restriction during pregnancy. On examination at birth, he appeared phenotypically normal, but at 2 weeks old, he had subtle phenotypic features of WBS of fused filtrum, ulnar deviation of fingers and wide anterior fontanelle, a systolic murmur and mild gaseous distension of the abdomen.All neonatal reflexes were normal. The author saw this patient at 6 months of age at the well-baby clinic for his 6-month vaccinations during which examination revealed periorbital fullness. Investigations including chromosomal microarray analysis confirmed the diagnosis of WBS. Laboratory tests were essentially normal except for raised creatinine, chloride and liver aspartate transaminase and viral serology that showed reactive cytomegalovirus antibody IgG, rubella antibody IgG, toxoplasma IgG and positive herpes simplex virus type 1 IgG. Echocardiography revealed mild pulmonary artery stenosis. ECG revealed right ventricular hypertrophy. Abdominal ultrasonography was normal and so was cranial sonography. This is a unique case of early diagnosis of WBS in an infant with atypical chromosome 7 deletion in Qatar, Middle East. The patient is undergoing further multidisciplinary follow-up.

Multiscale modeling uncovers 7q11.23 copy number variation-dependent changes in ribosomal biogenesis and neuronal maturation and excitability.

Copy number variation (CNV) at 7q11.23 causes Williams-Beuren syndrome (WBS) and 7q microduplication syndrome (7Dup), neurodevelopmental disorders (NDDs) featuring intellectual disability accompanied by symmetrically opposite neurocognitive features. Although significant progress has been made in understanding the molecular mechanisms underlying 7q11.23-related pathophysiology, the propagation of CNV dosage across gene expression layers and their interplay remains elusive. Here we uncovered 7q11.23 dosage-dependent symmetrically opposite dynamics in neuronal differentiation and intrinsic excitability. By integrating transcriptomics, translatomics, and proteomics of patient-derived and isogenic induced neurons, we found that genes related to neuronal transmission follow 7q11.23 dosage and are transcriptionally controlled, while translational factors and ribosomal genes are posttranscriptionally buffered. Consistently, we found phosphorylated RPS6 (p-RPS6) downregulated in WBS and upregulated in 7Dup. Surprisingly, p-4EBP was changed in the opposite direction, reflecting dosage-specific changes in total 4EBP levels. This highlights different dosage-sensitive dyregulations of the mTOR pathway as well as distinct roles of p-RPS6 and p-4EBP during neurogenesis. Our work demonstrates the importance of multiscale disease modeling across molecular and functional layers, uncovers the pathophysiological relevance of ribosomal biogenesis in a paradigmatic pair of NDDs, and uncouples the roles of p-RPS6 and p-4EBP as mechanistically actionable relays in NDDs.

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.

Symptoms of autism in Williams syndrome: a transdiagnostic approach.

Williams syndrome (WS) is associated with atypical social communication and cognition reminiscent of the behaviours observed in autism. Nonetheless, WS also differs significantly from autism, such as regarding social motivation, which is typically enhanced in WS and reduced in autism. This study sought to examine the conditions' transdiagnostic similarities and differences for autistic symptoms and social functioning, and their developmental trajectories, by comparing individuals with WS (n = 24) and those diagnosed with idiopathic autism (n = 24) and attention deficit hyperactivity disorder (ADHD; n = 24), aged 9 to 53 years, on measures of autism, social functioning, IQ and cooccurring psychiatric conditions. Although only 12.5% in the WS group met the criteria for an autism diagnosis, a majority exhibited distinct difficulties within social communication, social cognition, repetitive behaviours, and atypical sensory reactivity resembling autism. Conversely, elevated social motivation and a high number of social initiatives accompany these characteristics. No group differences in the developmental trajectories of autism symptoms were found. Our results demonstrate that autistic behaviours are more frequent in individuals with WS, than in individuals with idiopathic ADHD, and emphasize the need for clinical management of these behaviours.

Increased heart rate fragmentation in those with Williams-Beuren syndrome suggests nonautonomic mechanistic contributors to sudden death risk.

Williams-Beuren syndrome (WBS) is a rare genetic condition caused by a chromosomal microdeletion at 7q11.23. It is a multisystem disorder characterized by distinct facies, intellectual disability, and supravalvar aortic stenosis (SVAS). Those with WBS are at increased risk of sudden death, but mechanisms underlying this remain poorly understood. We recently demonstrated autonomic abnormalities in those with WBS that are associated with increased susceptibility to arrhythmia and sudden cardiac death (SCD). A recently introduced method for heart rate variability (HRV) analysis called "heart rate fragmentation" (HRF) correlates with adverse cardiovascular events (CVEs) and death in studies where heart rate variability (HRV) failed to identify high-risk subjects. Some argue that HRF quantifies nonautonomic cardiovascular modulators. We, therefore, sought to apply HRF analysis to a WBS cohort to determine 1) if those with WBS show differences in HRF compared with healthy controls and 2) if HRF helps characterize HRV abnormalities in those with WBS. Similar to studies of those with coronary artery disease (CAD) and atherosclerosis, we found significantly higher HRF (4 out of 7 metrics) in those with WBS compared with healthy controls. Multivariable analyses showed a weak-to-moderate association between HRF and HRV, suggesting that HRF may reflect HRV characteristics not fully captured by traditional HRV metrics (autonomic markers). We also introduce a new metric inspired by HRF methodology, significant acute rate drop (SARD), which may detect vagal activity more directly. HRF and SARD may improve on traditional HRV measures to identify those at greatest risk for SCD both in those with WBS and in other populations.NEW & NOTEWORTHY This work is the first to apply heart rate fragmentation analyses to individuals with Williams syndrome and posits that the heart rate fragmentation parameter W3 may enable detection and investigation of phenomena underlying the proarrhythmic short-long-short RR interval sequences paradigm known to precede ventricular fibrillation and ventricular tachycardia. It also forwards a novel method for quantifying sinus arrhythmia and sinus pauses that likely correlate with parasympathetic activity.

Approximating facial expression effects on diagnostic accuracy via generative AI in medical genetics.

Artificial intelligence (AI) is increasingly used in genomics research and practice, and generative AI has garnered significant recent attention. In clinical applications of generative AI, aspects of the underlying datasets can impact results, and confounders should be studied and mitigated. One example involves the facial expressions of people with genetic conditions. Stereotypically, Williams (WS) and Angelman (AS) syndromes are associated with a "happy" demeanor, including a smiling expression. Clinical geneticists may be more likely to identify these conditions in images of smiling individuals. To study the impact of facial expression, we analyzed publicly available facial images of approximately 3500 individuals with genetic conditions. Using a deep learning (DL) image classifier, we found that WS and AS images with non-smiling expressions had significantly lower prediction probabilities for the correct syndrome labels than those with smiling expressions. This was not seen for 22q11.2 deletion and Noonan syndromes, which are not associated with a smiling expression. To further explore the effect of facial expressions, we computationally altered the facial expressions for these images. We trained HyperStyle, a GAN-inversion technique compatible with StyleGAN2, to determine the vector representations of our images. Then, following the concept of InterfaceGAN, we edited these vectors to recreate the original images in a phenotypically accurate way but with a different facial expression. Through online surveys and an eye-tracking experiment, we examined how altered facial expressions affect the performance of human experts. We overall found that facial expression is associated with diagnostic accuracy variably in different genetic conditions.

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

Williams-Beuren syndrome (WBS) is a rare genetic disorder characterized by special facial gestalt, delayed development, and supravalvular aortic stenosis or/and stenosis of the branches of the pulmonary artery. We aim to develop and optimize accurate models of facial recognition to assist in the diagnosis of WBS, and to evaluate their effectiveness by using both five-fold cross-validation and an external test set. We used a total of 954 images from 135 patients with WBS, 124 patients suffering from other genetic disorders, and 183 healthy children. The training set comprised 852 images of 104 WBS cases, 91 cases of other genetic disorders, and 145 healthy children from September 2017 to December 2021 at the Guangdong Provincial People's Hospital. We constructed six binary classification models of facial recognition for WBS by using EfficientNet-b3, ResNet-50, VGG-16, VGG-16BN, VGG-19, and VGG-19BN. Transfer learning was used to pre-train the models, and each model was modified with a variable cosine learning rate. Each model was first evaluated by using five-fold cross-validation and then assessed on the external test set. The latter contained 102 images of 31 children suffering from WBS, 33 children with other genetic disorders, and 38 healthy children. To compare the capabilities of these models of recognition with those of human experts in terms of identifying cases of WBS, we recruited two pediatricians, a pediatric cardiologist, and a pediatric geneticist to identify the WBS patients based solely on their facial images. We constructed six models of facial recognition for diagnosing WBS using EfficientNet-b3, ResNet-50, VGG-16, VGG-16BN, VGG-19, and VGG-19BN. The model based on VGG-19BN achieved the best performance in terms of five-fold cross-validation, with an accuracy of 93.74% ± 3.18%, precision of 94.93% ± 4.53%, specificity of 96.10% ± 4.30%, and F1 score of 91.65% ± 4.28%, while the VGG-16BN model achieved the highest recall value of 91.63% ± 5.96%. The VGG-19BN model also achieved the best performance on the external test set, with an accuracy of 95.10%, precision of 100%, recall of 83.87%, specificity of 93.42%, and F1 score of 91.23%. The best performance by human experts on the external test set yielded values of accuracy, precision, recall, specificity, and F1 scores of 77.45%, 60.53%, 77.42%, 83.10%, and 66.67%, respectively. The F1 score of each human expert was lower than those of the EfficientNet-b3 (84.21%), ResNet-50 (74.51%), VGG-16 (85.71%), VGG-16BN (85.71%), VGG-19 (83.02%), and VGG-19BN (91.23%) models. CONCLUSION: 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. WHAT IS KNOWN: • 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. WHAT IS NEW: • 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.

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.

Why do individuals with Williams syndrome or Down syndrome fail the Weather Prediction Task?

Williams syndrome (WS) and Down syndrome (DS) are two neurodevelopmental disorders with distinct genetic origins characterized by mild to moderate intellectual disability. Individuals with WS or DS exhibit impaired hippocampus-dependent place learning and enhanced striatum-dependent spatial response learning. Here, we used the Weather Prediction Task (WPT), which can be solved using hippocampus- or striatum-dependent learning strategies, to determine whether individuals with WS or DS exhibit similar profiles outside the spatial domain. Only 10% of individuals with WS or DS solved the WPT. We further assessed whether a concurrent memory task could promote reliance on procedural learning to solve the WPT in individuals with WS but found that the concurrent task did not improve performance. To understand how the probabilistic cue-outcome associations influences WPT performance, and whether individuals with WS or DS can ignore distractors, we assessed performance using a visual learning task with differing reward contingencies, and a modified WPT with unpredictive cues. Both probabilistic feedback and distractors negatively impacted the performance of individuals with WS or DS. These findings are consistent with deficits in hippocampus-dependent learning and executive functions, and reveal the importance of congruent feedback and the minimization of distractors to optimize learning in these two populations.

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.

Contrasting neurofunctional correlates of face- and visuospatial-processing in children and adolescents with Williams syndrome: convergent results from four fMRI paradigms.

Understanding neurogenetic mechanisms underlying neuropsychiatric disorders such as schizophrenia and autism is complicated by their inherent clinical and genetic heterogeneity. Williams syndrome (WS), a rare neurodevelopmental condition in which both the genetic alteration (hemideletion of ~ twenty-six 7q11.23 genes) and the cognitive/behavioral profile are well-defined, offers an invaluable opportunity to delineate gene-brain-behavior relationships. People with WS are characterized by increased social drive, including particular interest in faces, together with hallmark difficulty in visuospatial processing. Prior work, primarily in adults with WS, has searched for neural correlates of these characteristics, with reports of altered fusiform gyrus function while viewing socioemotional stimuli such as faces, along with hypoactivation of the intraparietal sulcus during visuospatial processing. Here, we investigated neural function in children and adolescents with WS by using four separate fMRI paradigms, two that probe each of these two cognitive/behavioral domains. During the two visuospatial tasks, but not during the two face processing tasks, we found bilateral intraparietal sulcus hypoactivation in WS. In contrast, during both face processing tasks, but not during the visuospatial tasks, we found fusiform hyperactivation. These data not only demonstrate that previous findings in adults with WS are also present in childhood and adolescence, but also provide a clear example that genetic mechanisms can bias neural circuit function, thereby affecting behavioral traits.

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.

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.

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.

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.

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.