Williams-Beuren Syndrome (WBS) is a rare genetic condition caused by a chromosomal microdeletion at 7q11.23. It is a multi-system disorder characterized by distinct facies, intellectual disability, and supravalvar aortic stenosis. 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) risk. A recently introduced method for HRV analysis called \'heart rate fragmentation\' (HRF) correlates with adverse cardiovascular events and death in studies where HRV failed to identify high-risk subjects. Some argue that HRF quantifies non-autonomic cardiovascular modulators. We, therefore, sought to apply HRF analysis to a WBS cohort to: 1) determine if those with WBS show differences in HRF compared to healthy controls and 2) determine if HRF correlates with traditional HRV measures in those with WBS. Similar to studies of those with CAD and atherosclerosis, we found significantly higher HRF in those with WBS compared to healthy controls. In general, HRF shows minimal correlation with traditional HRV metrics, suggesting that HRF may quantify some non-autonomic modulators of sudden death risk in those with WBS. We also introduce a new metric inspired by the HRF methodology, Significant Acute Rate Drop (SARD), which may permit vagal activity detection more directly. HRF and SARD increase the ability of non-invasive HRV measures to identify those at greatest risk for sudden cardiac death both in those with WBS as well as populations more broadly.

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.
CONCLUSIONS: 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.
BACKGROUND: • 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.
BACKGROUND: • 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.

UNASSIGNED: Williams-Beuren syndrome (WBS) is a rare genetic disorder with delays in language and cognitive development, but, with increased awareness of clinical features and a reliable diagnostic test, WBS is becoming more widely recognized in childhood. Adaptive behavior skills and/or maladaptive behavior are important for the prognosis of individuals with WBS. The aim of this study was to investigate the clinical and developmental characteristics of patients with WBS and further increase awareness about it by evaluating the adaptive skills and maladaptive behaviors of the patients.
UNASSIGNED: The data of WBS patients followed-up at the Developmental Behavioral Pediatrics Unit were reviewed. Patient data on perinatal and postnatal history, developmental stages, physical and neurological examination findings were collected. The International Guide for Monitoring Child Development (GMCD) was administered to each child. In addition, semistructured interviews were conducted with the parents using the Vineland Adaptive Behavior Scales, Second edition (Vineland-II).
UNASSIGNED: A total of 12 patients diagnosed with WBS via detection of the 7q11.23 deletion, of whom 6 were girls, were retrospectively reviewed. The mean age at the time of review was 54.6 ± 32.5 months. The mean age at first presentation to the Developmental Behavioral Pediatrics Outpatient Clinic was 15 ± 11.5 months. In the first developmental evaluation using the GMCD, there was a delay in fine and gross motor domains in 6 patients, in the language domains in 4 patients, and in all of the domains in 2 patients. Findings with Vineland-II showed socialization and communication domains as strengths, but the daily living skills and motor skills domains were weaknesses. In terms of maladaptive behavior, the patients tended to frequently have behavioral problems, neurodevelopmental disease, anxiety disorders, eating problems, and sleeping problems.
UNASSIGNED: This retrospective review of 12 patients indicated a general delay in overall development, and confirmed impairment in both adaptive and maladaptive functioning in WBS.

OBJECTIVE: Williams-Beuren syndrome (WBS) is a rare genetic disease characterized by psychomotor delay, cardiovascular, musculoskeletal, and endocrine problems. Retinal involvement, which is not well characterized, has also been described. The purpose of this cross-sectional study is to describe the characteristics in optical coherence tomography (OCT) and OCT-angiography (OCTA) of patients with WBS.
METHODS: We included patients with WBS confirmed by genetic analysis. The patients underwent OCT (30° × 25°, 61 B-scans) and OCTA (10° × 10° and 20° × 20°) examinations, all centered on the. Data on retinal thickness (total, inner and outer layers) and foveal morphology on OCT and vessel and perfusion density in OCTA (VD and PD, respectively) were collected. These data were compared with an age-matched control group.
RESULTS: 22 eyes of 22 patients with WBS (10 females, mean age 31.5 years) were included. Retinal thickness (and specifically inner retinal layers) in OCT was significantly reduced in all sectors (central, parafoveal, and perifoveal) compared to the control group (p < 0.001 in all sectors). Fovea in WBS eyes was broader and shallower than controls. The PD and VD in both 10 and 20 degrees of fields in OCTA was significantly reduced in patients with WBS, in all vascular plexa (all p < 0.001).
CONCLUSIONS: This study is the first to quantify and demonstrate retinal structural and microvascular alterations in patients with WBS. Further studies with longitudinal data will reveal the potential clinical relevance of these alterations.

Partial deletions at chromosome 7q11.23 are causative for the autosomal-dominant Williams-Beuren syndrome (WBS), whereas the partial duplication of this region leads to the 7q11.23 duplication syndrome. Both syndromes are highly penetrant and occur with a frequency of 1:7500-10,000 (WBS) and 1:13,000-20,000 (7q11.23 duplication syndrome). They are associated with multiple organ defects, intellectual disability, and typical facial dysmorphisms showing broad phenotypic variability. The 7q11.23 region is susceptible to chromosomal rearrangements due to flanking segmental duplications and regions of long repetitive DNA segments. Here, we report on a family with two children affected by WBS and clinically unaffected parents. Interestingly, metaphase fluorescence in situ hybridization (FISH) revealed a deletion on 7q11.23 in the father. Intensive genetic testing, using interphase FISH, whole genome sequencing and optical genome mapping led to the confirmation of a 1.5 Mb deletion at one 7q11.23 allele and the identification of a reciprocal 1.8 Mb duplication at the other allele. This finding is highly important regarding genetic counseling in this family. The father is a silent carrier for two syndromic disorders, thus his risk to transmit a disease-causing allele is 100%. To the best of our knowledge we, here, report on the first case in which the phenotype of a microdeletion/microduplication syndrome was compensated by its reciprocal counterpart.

Williams-Beuren syndrome (WBS) (Online Mendelian Inheritance in Man #194050) is a rare genetic multisystem disorder resulting from a chromosomal microdeletion at 7q11.23. The condition is characterized by distinct facies, intellectual disability, and supravalvar aortic stenosis. Those with WBS have an increased risk of sudden death, but mechanisms underlying this phenotype are incompletely understood.
The aim of this study was to quantify and compare autonomic activity as reflected by heart rate variability (HRV) measures in a cohort of individuals with WBS (n = 18) and age- and sex-matched control subjects (n = 18).
We performed HRV analysis on 24-hour electrocardiography recordings using nonlinear, time and frequency domain analyses on a cohort of subjects with WBS and age- and sex-matched control subjects enrolled in a prospective cross-sectional study designed to characterize WBS disease natural history.
WBS subjects demonstrated diminished HRV (reflected by the SD of the NN intervals [P = 0.0001], SD of the average NN interval for 5-minute intervals over 24 hours [P < 0.0001], average of the 5-minute SDs of NN intervals for 24 hours [P = 0.0002], root mean square of successive differences of NN intervals [P = 0.0004], short axis of the Poincaré plot (SD1) [P < 0.0001], and long axis of the Poincaré plot [P < 0.0001]) and indirect markers of parasympathetic activity (reflected by the percent of NN intervals different from previous by 50% or more of local average [P < 0.0007], root mean square of successive differences of NN intervals [P = 0.0004], natural log high-frequency power [P = 0.0038], and SD1 [P < 0.0001]). Additional parameters were also significantly different, including natural log very low-frequency power (decreased; P = 0.0002), natural log low-frequency power (decreased; P = 0.0024), and SD1 divided by the long axis of the Poincaré plot (decreased; P < 0.0001).
Individuals with WBS demonstrate significant HRV abnormalities consistent with diminished autonomic reserve. Future studies will be needed to determine the relationship between autonomic dysregulation observed and sudden death risk seen in these patients. (Impact of Elastin Mediated Vascular Stiffness on End Organs; NCT02840448).

GTF2IRD1, a gene on chromosome 7 which encodes a transcription factor, is of significant clinical interest due to its heterozygous loss as part of the classical deletion associated with Williams-Beuren syndrome (WBS). However, biallelic variants in GTF2IRD1 alone as part of an autosomal recessive disease have not been previously reported. Here, we present two full brothers with variants in trans of GTF2IRD1 at c.1231C > T (p.Arg411Trp) and c.2632C > G (p.Leu878Val). A detailed clinical phenotype is described, which includes severe neurodevelopmental disability, facial dysmorphology, and pectus excavatum. Importantly, out of eight full siblings, only these two brothers harboring both variants in trans present with the profound described phenotype. We present the possibility that these brothers represent the identification of a new syndrome characterized by biallelic variants in GTF2IRD1, which may also have important implications for the molecular etiology of WBS.

Williams-Beuren syndrome is considered to be at increased risk for celiac disease, as for recent literature data and celiac disease guidelines, despite pathogenic mechanisms are still unclear. Our study analyzed the prevalence of autoimmune disorders, HLA DQ2 and/or DQ8 haplotypes, of transglutaminase antibodies and of diagnosis of celiac disease in a cohort of 93 Williams-Beuren syndrome\'s patients (mean age 21.26 years). Our study showed an increased prevalence of celiac disease equal to 10.8% (10/93 patients). We did not find a significant different frequency of predisposing HLA in subjects with Williams-Beuren syndrome compared to literature data in the general population (49.5% vs. 42.9%, with p > .1), nor a susceptibility to autoimmunity. This suggests that the increased prevalence of celiac disease in Williams-Beuren syndrome cannot be ascribed to HLA haplotype and may be related to other factors that still need to be identified in these patients.

Williams-Beuren syndrome (WBS) is a rare disorder caused by hemizygous microdeletion of ∼27 contiguous genes. Despite neurodevelopmental and cognitive deficits, individuals with WBS have spared or enhanced musical and auditory abilities, potentially offering an insight into the genetic basis of auditory perception. Here, we report that the mouse models of WBS have innately enhanced frequency-discrimination acuity and improved frequency coding in the auditory cortex (ACx). Chemogenetic rescue showed frequency-discrimination hyperacuity is caused by hyperexcitable interneurons in the ACx. Haploinsufficiency of one WBS gene, Gtf2ird1, replicated WBS phenotypes by downregulating the neuropeptide receptor VIPR1. VIPR1 is reduced in the ACx of individuals with WBS and in the cerebral organoids derived from human induced pluripotent stem cells with the WBS microdeletion. Vipr1 deletion or overexpression in ACx interneurons mimicked or reversed, respectively, the cellular and behavioral phenotypes of WBS mice. Thus, the Gtf2ird1-Vipr1 mechanism in ACx interneurons may underlie the superior auditory acuity in WBS.

BACKGROUND: There are a few literature reports of prenatal ultrasound manifestations of Williams-Beuren syndrome. We aimed to explore the prenatal diagnosis of Williams-Beuren syndrome by ultrasound and chromosomal microarray analysis and describe the prenatal ultrasound performance of this syndrome.
METHODS: In this retrospective study, we reported eight cases of Williams-Beuren syndrome diagnosed at our prenatal diagnostic center from 2016 to 2021. We systematically reviewed clinical data from these cases, including indications for invasive testing, sonographic findings, QF-PCR results, chromosomal microarray analysis results, and pregnancy outcomes.
RESULTS: In this study, the common ultrasound features were ventricular septal defect (37.5%), intrauterine growth retardation (25%), and aortic coarctation (25%). Moreover, all patients were found to have a common deletion in the Williams-Beuren syndrome chromosome region at the 7q11.23 locus, which contained the elastin gene. Deletion sizes ranged from 1.42 to 2.07 Mb. Seven parents asked for termination of pregnancy, and one patient was lost to follow-up.
CONCLUSIONS: This study is the most extensive prenatal study using chromosomal microarray analysis technology for detailed molecular analysis of Williams-Beuren syndrome cases. We reported three cases combined with first-reported ultrasound manifestations. Case 1 was concomitant with multicystic dysplastic kidney and duodenal atresia combined with case 3. Notably, case 4 was combined with multiple cardiovascular malformations: Tetralogy of Fallot, right aortic arch, and supravalvar aortic stenosis. These manifestations expand the intrauterine ultrasound phenotype of Williams-Beuren syndrome in previous literature reports.