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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.

Although the uneven neuropsychological profile of William Syndrome (WS) is well established, less is known about social perception and how profile characteristics may affect the ability to predict other’s intentions, a main hallmark of social cognition. This study aimed at examining the neuropsychological profile, including social perception, of adolescents and adults with WS, and at verifying which neuropsychological outcome might account for their social prediction ability. Twenty-six individuals with WS were administered a comprehensive neuropsychological assessment, and a virtual reality scenario designed to assess social prediction in a dynamic, everyday life-like context. We found that social perception was a relative strength of the profile, although a dissociation emerged between impaired verbal ToM and relatively spared low-level components. Peaks and valleys were reported in other domains consistently with the expected profile. Both spatial and facial memory were significantly associated with the performance at the social prediction task. Results clarified that social perception per se should not be considered as typically impaired in WS. Weaknesses and strengths in specific abilities, particularly spatial and facial memory, might affect the ability to understand others’ intentions in WS beyond domain-specific mechanisms. These findings might inform future syndrome-specific rehabilitative interventions. [ABSTRACT FROM AUTHOR]

Objective Background Methods Results Conclusions Implications This study explored sibling relationships from the perspective of children with Williams syndrome (WS) and their nondisabled (ND) siblings.WS, 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.Thirty‐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.Siblings 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.The WS profile was woven through multidimensional relationships.Findings have implications for how parents are supported to help siblings navigate relationships and learn about WS, and how schools support WS sibling relationships. [ABSTRACT FROM AUTHOR]

Purpose: This study describes participant diversity in Williams syndrome (WS) intervention studies. Methods: A literature search was conducted to identify prospective treatment studies including participants with WS. Data was extracted on the reporting of and information provided on age, sex, cognitive ability, socioeconomic status, race, and ethnicity. Results: Eleven eligible articles were identified. Reporting rates of demographic factors varied considerably, with the highest rates for age and sex (100%) and the lowest reporting rates for race (18%) and ethnicity (9%). Combining demographic data from the two studies that reported on race and/or ethnicity (n = 33), 88% of participants were White. The combined participant mean age was 20.9 years. Conclusion: There is a low frequency of reporting on several demographic factors including socioeconomic status, race, and ethnicity in WS intervention studies. There is a need for increased representation of racial and ethnic minority groups, older participants, and more cognitively impaired patients in WS research. [ABSTRACT FROM AUTHOR]

The LIM domain kinases (LIMKs) are important actin cytoskeleton regulators. These proteins, LIMK1 and LIMK2, are nodes downstream of Rho GTPases and are the key enzymes that phosphorylate cofilin/actin depolymerization factors to regulate filament severing. They therefore perform an essential role in cascades that control actin depolymerization. Signaling of the LIMKs is carefully regulated by numerous inter‐ and intra‐molecular mechanisms. In this review, we discuss recent findings that improve the understanding of LIM domain kinase regulation mechanisms. We also provide an up‐to‐date review of the role of the LIM domain kinases, their architectural features, how activity is impacted by other proteins, and the implications of these findings for human health and disease. [ABSTRACT FROM AUTHOR]

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Purpose: The aim of this study was to explore relations between speech sound disorder severity and selective mutism in a group of children with 7q11.23 duplication syndrome (Dup7), a genetic condition predisposing children to childhood apraxia of speech (CAS) and other speech sound disorders and to anxiety disorders, including selective mutism and social anxiety disorder. Method: Forty-nine children aged 4-17 years with genetically confirmed Dup7 completed the Goldman-Fristoe Test of Articulation-Second Edition (GFTA-2), the Expressive Vocabulary Test-Second Edition (EVT-2), and the Differential Ability Scales-Second Edition (DAS-II). Parents completed the Anxiety Disorders Interview Schedule-Parent (ADIS-P). Results: Mean standard scores (SSs) were 65.67 for the GFTA-2, 92.73 for the EVT-2, and 82.69 for the DAS-II General Conceptual Ability (GCA; similar to IQ). Standard deviations for all measures were larger than for the general population. GFTA-2 SS was significantly correlated with both EVT-2 SS and DAS-II GCA. Based on the ADIS-P, 22 participants (45%) were diagnosed with selective mutism and 29 (59%) were diagnosed with social anxiety disorder. No significant differences in performance on any of the measures were found either between the group with a selective mutism diagnosis and the group that did not have selective mutism or between the group with a selective mutism and/or social anxiety disorder diagnosis and the group that did not have either disorder. Conclusions: For children with Dup7, neither the diagnosis of selective mutism nor the diagnosis of selective mutism and/or social anxiety disorder was related to severity of speech sound disorder, expressive vocabulary ability, or overall intellectual ability. Accordingly, treatment for speech sound disorder alone is unlikely to lead to remission of selective mutism or social anxiety disorder. Instead, selective mutism and/or social anxiety disorder should be treated directly. Further research is needed to determine if these findings generalize to other populations, such as children with idiopathic CAS. [ABSTRACT FROM AUTHOR]

A heterozygous microdeletion of chromosome 7q11.23 causes the rare neuropsychiatric developmental disorder Williams-Beuren Syndrome. The syndrome is more difficult to diagnose before birth than after, even though the syndrome often manifests prenatally as intrauterine growth restriction and cardiovascular defects on prenatal ultrasonography. The potentially poor prognosis of affected individuals highlights the need to improve prenatal diagnosis of the syndrome. This review summarizes recent advances in our understanding of the genetics of Williams-Beuren Syndrome and its manifestations on prenatal ultrasonography, which may facilitate its early detection and inform prenatal genetic counseling. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. Lay Summary: The significance of this study is its determination that autistic children and children with Williams syndrome (WS), who show atypical social cognition and motivation, are still able to make the associations of which linguistic register to use when communicating with different people. However, they show difficulty in comprehending the effect that their register selection has on the listener's feelings. These findings have implications for understanding how linguistic register is acquired in childhood to aid in further research and supporting persons with atypical communication. [ABSTRACT FROM AUTHOR]

Abstract Although the uneven neuropsychological profile of William Syndrome (WS) is well established, less is known about social perception and how profile characteristics may affect the ability to predict other’s intentions, a main hallmark of social cognition. This study aimed at examining the neuropsychological profile, including social perception, of adolescents and adults with WS, and at verifying which neuropsychological outcome might account for their social prediction ability. Twenty-six individuals with WS were administered a comprehensive neuropsychological assessment, and a virtual reality scenario designed to assess social prediction in a dynamic, everyday life-like context. We found that social perception was a relative strength of the profile, although a dissociation emerged between impaired verbal ToM and relatively spared low-level components. Peaks and valleys were reported in other domains consistently with the expected profile. Both spatial and facial memory were significantly associated with the performance at the social prediction task. Results clarified that social perception per se should not be considered as typically impaired in WS. Weaknesses and strengths in specific abilities, particularly spatial and facial memory, might affect the ability to understand others’ intentions in WS beyond domain-specific mechanisms. These findings might inform future syndrome-specific rehabilitative interventions.

Abstract 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.

Background: Radio-Tartaglia syndrome or RATARS is an unfamiliar disease caused by a heterozygous mutation of the SPEN gen in the 1p36 chromosome. Clinically, it is represented by global developmental delay and intellectual disability; however, it can also be associated with other relevant comorbidities that embark on the cardiovascular, gastrointestinal, musculoskeletal, integumentary as well as endocrinological systems. Case Report: A 3-year-old pediatric male patient from Venezuela is referred to genetic counseling due to neurodevelopmental delay, microcephaly and dysmorphisms. The initial diagnostic impression consisted of Williams syndrome. Further studies revealed mild supravalvular stenosis, but no important changes in brain imaging or laboratory analysis. The patient’s diagnosis was later replaced with RATARS after a complete exome sequencing revealed heterozygous SPEN pathogenic genes. Conclusion: The diagnostic process of RATARS must become a pillar of further investigation given its uncertainty when clinically diagnosed hence the necessity of a clear confirmation through exome sequencing. This case report highlights the importance of genetic testing in patients with neurodevelopmental delay due to a possible but uncommon correlation with rare diseases such as RATARS.

Nop Khongthon,1 Midi Theeraviwatwong,1 Khunton Wichajarn,2 Kitiwan Rojnueangnit3 1Medical Students, Faculty of Medicine, Thammasat University, Pathumthani, Thailand; 2Department of Pediatrics, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand; 3Department of Pediatrics, Faculty of Medicine, Thammasat University, Pathumthani, ThailandCorrespondence: Kitiwan Rojnueangnit, Division of Genetics, Department of Pediatrics, Faculty of Medicine, Thammasat University, 99/209 Moo 18 Phahonyothin Road, Klong-Luang, Pathumthani, 12120, Thailand, Tel +66-2-926-9514, Email rkitiwan@tu.ac.thIntroduction: 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.Keywords: 22q11.2 deletion syndrome, Williams syndrome, accuracy, GestaltMatcher, Face2Gene

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. [ABSTRACT FROM AUTHOR]

Introduction: Williams-Beuren syndrome is a contiguous gene syndrome caused by microdeletion of the locus 7q11.23. It is a clinically recognizable condition whose cardinal features include growth deficiency, variable degrees of neurodevelopmental disorders, congenital cardiac defects, outgoing personality, and typical facies. Case Series Presentation: This retrospective study analyzed 38 consecutive patients in a single center for rare diseases, diagnosed by Preus criteria modified by the Sugayama scoring system, comprising 17 male and 21 female individuals aged 1 month to 55 years. Cases were divided into two groups concerning (a) exclusive clinical diagnosis or (b) clinical diagnosis followed by a laboratory cytogenetic or cytogenomic test; except for hypertension, no significant difference was seen among both groups. The most frequent findings were intellectual deficiency, developmental delay, typical facies, and overfriendliness, all above 80% of the total sample. On the other hand, supravalvar aortic stenosis was found in only 32.4%, while other congenital heart diseases were seen in 56.7% of the sample. Unusual features included one individual with 13 pairs of ribs, another with unilateral microphthalmia, and three with unilateral renal agenesis. Comorbidities comprised 9 cases of hypothyroidism and 1 case each of precocious puberty, segmental vitiligo, type 1 diabetes mellitus, and congenital adrenal hyperplasia. Conclusion: Preus criteria modified by the Sugayama scoring system are still efficient and helpful for clinical diagnosis. This is the second report on microphthalmia and the first study describing the association between vitiligo, type 1 diabetes mellitus, and congenital adrenal hyperplasia in individuals with Williams-Beuren syndrome. [ABSTRACT FROM AUTHOR]

Background: Chromosome 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. Results: The 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. Conclusions: Through 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. [ABSTRACT FROM AUTHOR]

S-Adenosyl-L-methionine (SAM)-mediated methylation of biomolecules controls their function and regulates numerous vital intracellular processes. Analogs of SAM with a reporter group in place of the S-methyl group are widely used to study these processes. However, many of these analogs are chemically unstable that largely limits their practical application. We have developed a new compound, SAM-Ph, which contains an H-phosphinic group (-P(O)(H)OH) instead of the SAM carboxylic group. SAM-PH is significantly more stable than SAM, retains functional activity in catechol-O-methyltransferase and methyltransferase WBSCR27 reactions. The last is associated with Williams-Beuren syndrome. Rac-SAM-PH was synthesized chemically, while (R,S)-SAM-PH and its analogs were prepared enzymatically either from H-phosphinic analogs of methionine (Met-PH) or H-phosphinic analog of S-adenosyl-L-homocysteine (SAH-Ph) using methionine adenosyltransferase 2A or halide methyltransferases, respectively. SAH-PH undergoes glycoside bond cleavage in the presence of methylthioadenosine nucleosidase like natural SAH. Thus, SAM-PH and its analogs are promising new tools for investigating methyltransferases and incorporating reporter groups into their substrates. [ABSTRACT FROM AUTHOR]

Aphasia is an acquired neurogenic language disorder that is often caused by stroke in adulthood. However, how does aphasia present, and how can it be effectively treated, in a neurodivergent adult with pre-existing differences in language or cognition? To confirm our intuitions that there are few published cases of aphasia resulting from stroke in adults with either Williams syndrome or autism, we searched for articles from 1990 to 2022 across multiple publication databases. For Williams syndrome, the search revealed two cases of aphasia, but few details were provided. No clear adult cases of autism with aphasia were found, though two potential cases were discovered. Despite the paucity of cases, we discuss how researchers and clinicians might meet the specific needs of these populations in relation to the assessment and treatment of aphasia. [ABSTRACT FROM AUTHOR]

This study examined the similarities/differences between the social phenotypes of Williams syndrome (WS) and autism spectrum disorder (ASD). As cultural norms may affect symptom evaluation, this study administered the Social Responsiveness Scale-2 to Japanese individuals with WS (n = 78, 4.4–44.0 years) and ASD (n = 75, 4.7–55.4 years). The scores for Social Motivation and Social Communication were significantly more severe in the ASD than WS group. Overall, the similarities and differences between the social phenotypes of the syndromes were consistent with the findings of a recent study conducted in the UK, except for the social awareness subscale score. This highlights the importance of cross-cultural investigations of WS and ASD. [ABSTRACT FROM AUTHOR]

Genetic disorders affect over 6% of the global population and pose substantial obstacles to healthcare systems. Early identification of these rare facial genetic disorders is essential for managing related medical complexities and health issues. Many people consider the existing screening techniques inadequate, often leading to a diagnosis several years after birth. This study evaluated the efficacy of deep learning-based classifier models for accurately recognizing dysmorphic characteristics using facial photos. This study proposes a multi-class facial syndrome classification framework that encompasses a unique combination of diseases not previously examined together. The study focused on distinguishing between individuals with four specific genetic disorders (Down syndrome, Noonan syndrome, Turner syndrome, and Williams syndrome) and healthy controls. We investigated how well fine-tuning a few well-known convolutional neural network (CNN)-based pre-trained models—including VGG16, ResNet-50, ResNet152, and VGG-Face—worked for the multi-class facial syndrome classification task. We obtained the most encouraging results by adjusting the VGG-Face model. The proposed fine-tuned VGG-Face model not only demonstrated the best performance in this study, but it also performed better than other state-of-the-art pre-trained CNN models for the multi-class facial syndrome classification task. The fine-tuned model achieved both accuracy and an F1-Score of 90%, indicating significant progress in accurately detecting the specified genetic disorders. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Radio-Tartaglia syndrome or RATARS is an unfamiliar disease caused by a heterozygous mutation of the SPEN gen in the 1p36 chromosome. Clinically, it is represented by global developmental delay and intellectual disability; however, it can also be associated with other relevant comorbidities that embark on the cardiovascular, gastrointestinal, musculoskeletal, integumentary as well as endocrinological systems. Case Report: A 3-year-old pediatric male patient from Venezuela is referred to genetic counseling due to neurodevelopmental delay, microcephaly and dysmorphisms. The initial diagnostic impression consisted of Williams syndrome. Further studies revealed mild supravalvular stenosis, but no important changes in brain imaging or laboratory analysis. The patient’s diagnosis was later replaced with RATARS after a complete exome sequencing revealed heterozygous SPEN pathogenic genes. Conclusion: The diagnostic process of RATARS must become a pillar of further investigation given its uncertainty when clinically diagnosed hence the necessity of a clear confirmation through exome sequencing. This case report highlights the importance of genetic testing in patients with neurodevelopmental delay due to a possible but uncommon correlation with rare diseases such as RATARS. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Is the oxytocin-vasopressin (OT-AVP) system a part of the unseen force that subtly (in a clever and indirect way) directs our human fascination to ourselves? And is it possible that this fundamental drive is the inevitable handmaiden of the genetic selection for survival and reproduction that is played out at the level of the individual, the family and the society? Perhaps. But an equally intense biological drive to experience the unknown is intertwined and exists in the individual as “curiosity”. Both are essential for survival and success of the species. Curiously, the path to understanding ourselves, the joy of discovery and joining with others on this imperial journey to the OT-AVP system may itself be driven by the same system. I have been driven and inspired to understand “Us” for some unseen reason. This chapter relates how a driving curiosity and search for meaning led to the critical training and inspired mentorship essential for developing novel genetic, cellular and imaging technologies necessary for each advance toward this deeper understanding. Specifically, the chapter describes my recognition of human “Genetics” as the hub of medicine and the language of human neurobiology. We then set out the rationale for and sequential development of four technologies (dense whole genome arrays of genomic markers integrated with the recombination map; needed to genetically dissect and define the genetic contributions to the distinct features of brain and social behavior in Down syndrome and Williams syndrome. These include generation of 1) dense whole genome arrays of genomic markers integrated with the recombination and gene maps for defining rare cases of WS differing by one or more deleted genes, 2) analytic methods for parsing genetic contributions to standardized outcomes of cognitive and behavioral data, 3) technologies using multicolor and multi temporal fluorescence in situ hybridization to define the subcellular and neuroanatomic localization of candidate genes in the non-human primate (macaque) brain, and 4) an approach to integrating timed measures of blood neuropeptides and genomic DNA sequence variants with self-reported religious experience in devout members of the LDS church. Working across evolution and ontogeny at the cellular, neural systems and organismal levels, has led to a suspicion that a bit of the grand design may involve OT, AVP and their partners in the subtle and artful processes of the last one-half billion years that link survival of our species with our prized capacity for abstract thought and spirituality.

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.