Innate frequency-discrimination hyperacuity in Williams-Beuren syndrome mice.

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.

The 7q11.23 Protein DNAJC30 Interacts with ATP Synthase and Links Mitochondria to Brain Development.

Despite the known causality of copy-number variations (CNVs) to human neurodevelopmental disorders, the mechanisms behind each gene's contribution to the constellation of neural phenotypes remain elusive. Here, we investigated the 7q11.23 CNV, whose hemideletion causes Williams syndrome (WS), and uncovered that mitochondrial dysfunction participates in WS pathogenesis. Dysfunction is facilitated in part by the 7q11.23 protein DNAJC30, which interacts with mitochondrial ATP-synthase machinery. Removal of Dnajc30 in mice resulted in hypofunctional mitochondria, diminished morphological features of neocortical pyramidal neurons, and altered behaviors reminiscent of WS. The mitochondrial features are consistent with our observations of decreased integrity of oxidative phosphorylation supercomplexes and ATP-synthase dimers in WS. Thus, we identify DNAJC30 as an auxiliary component of ATP-synthase machinery and reveal mitochondrial maladies as underlying certain defects in brain development and function associated with WS.

Loss of Baz1b in mice causes perinatal lethality, growth failure, and variable multi-system outcomes.

BAZ1B is one of 25-27 coding genes deleted in canonical Williams syndrome, a multi-system disorder causing slow growth, vascular stenosis, and gastrointestinal complaints, including constipation. BAZ1B is involved in (among other processes) chromatin organization, DNA damage repair, and mitosis, suggesting reduced BAZ1B may contribute to Williams syndrome symptoms. In mice, loss of Baz1b causes early neonatal death. 89.6% of Baz1b-/- mice die within 24 h of birth without vascular anomalies or congenital heart disease (except for patent ductus arteriosus). Some (<50%) Baz1b-/- were noted to have prolonged neonatal cyanosis, patent ductus arteriosus, or reduced lung aeration, and none developed a milk spot. Meanwhile, 35.5% of Baz1b+/- mice die over the first three weeks after birth. Surviving Baz1b heterozygotes grow slowly (with variable severity). 66.7% of Baz1b+/- mice develop bowel dilation, compared to 37.8% of wild-type mice, but small bowel and colon transit studies were normal. Additionally, enteric neuron density appeared normal in Baz1b-/- mice except in distal colon myenteric plexus, where neuron density was modestly elevated. Combined with several rare phenotypes (agnathia, microphthalmia, bowel dilation) recovered, our work confirms the importance of BAZ1B in survival and growth and suggests that reduced copy number of BAZ1B may contribute to the variability in Williams syndrome phenotypes.

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.

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.

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.

Transposons in the Williams-Beuren Syndrome Critical Region are Associated with Social Behavior in Assistance Dogs.

A strong signature of selection in the domestic dog genome is found in a five-megabase region of chromosome six in which four structural variants derived from transposons have previously been associated with human-oriented social behavior, such as attentional bias to social stimuli and social interest in strangers. To explore these genetic associations in more phenotypic detail-as well as their role in training success in a specialized assistance dog program-we genotyped 1001 assistance dogs from Canine Companions for Independence®, including both successful graduates and dogs released from the training program for behaviors incompatible with their working role. We collected phenotypes on each dog using puppy-raiser questionnaires, trainer questionnaires, and both cognitive and behavioral tests. Using Bayesian mixed models, we found strong associations (95% credibility intervals excluding zero) between genotypes and certain behavioral measures, including separation-related problems, aggression when challenged or corrected, and reactivity to other dogs. Furthermore, we found moderate differences in the genotypes of dogs who graduated versus those who did not; insertions in GTF2I showed the strongest association with training success (ß = 0.23, CI95% = - 0.04, 0.49), translating to an odds-ratio of 1.25 for one insertion. Our results provide insight into the role of each of these four transposons in canine sociability and may inform breeding and training practices for working dog organizations. Furthermore, the observed importance of the gene GTF2I supports the emerging consensus that variation in GTF2I genotypes and expression have important consequences for social behavior broadly.

In individuals with Williams syndrome, dysregulation of methylation in non-coding regions of neuronal and oligodendrocyte DNA is associated with pathology and cortical development.

Williams syndrome (WS) is a neurodevelopmental disorder caused by a heterozygous micro-deletion in the WS critical region (WSCR) and is characterized by hyper-sociability and neurocognitive abnormalities. Nonetheless, whether and to what extent WSCR deletion leads to epigenetic modifications in the brain and induces pathological outcomes remains largely unknown. By examining DNA methylation in frontal cortex, we revealed genome-wide disruption in the methylome of individuals with WS, as compared to typically developed (TD) controls. Surprisingly, differentially methylated sites were predominantly annotated as introns and intergenic loci and were found to be highly enriched around binding sites for transcription factors that regulate neuronal development, plasticity and cognition. Moreover, by utilizing enhancer-promoter interactome data, we confirmed that most of these loci function as active enhancers in the human brain or as target genes of transcriptional networks associated with myelination, oligodendrocyte (OL) differentiation, cognition and social behavior. Cell type-specific methylation analysis revealed aberrant patterns in the methylation of active enhancers in neurons and OLs, and important neuron-glia interactions that might be impaired in individuals with WS. Finally, comparison of methylation profiles from blood samples of individuals with WS and healthy controls, along with other data collected in this study, identified putative targets of endophenotypes associated with WS, which can be used to define brain-risk loci for WS outside the WSCR locus, as well as for other associated pathologies. In conclusion, our study illuminates the brain methylome landscape of individuals with WS and sheds light on how these aberrations might be involved in social behavior and physiological abnormalities. By extension, these results may lead to better diagnostics and more refined therapeutic targets for WS.

Gastrointestinal manifestations in Williams syndrome: A prospective analysis of an adult and pediatric cohort.

Williams syndrome (WS) is a multi-system condition caused by the deletion of 25-27 coding genes on human chromosome 7. Irritability, gastrointestinal (GI) reflux and slow growth are commonly reported in infants with WS, but less data exist regarding GI concerns in older children and adults with the condition. This study evaluates 62 individuals with WS (31 children aged 3-17, and 31 adults aged 18-62) as well as 36 pediatric and adult controls to assess current and historical rates of common GI symptoms. Data were evaluated using a regression model including age, sex, self-reported race, and diagnosis. Symptoms including food intolerance, reflux, dysphagia, choking/gagging, vomiting, constipation, bloating, diarrhea, hematochezia, rectal prolapse, abdominal pain, and weight loss are more common in those with WS relative to controls. In addition, people with WS utilize more GI medications, specialty care, procedures, and supplemental feeds. Among those with WS, symptoms were present at similar rates in children and adults, except for diverticular disease, which was not noted until adulthood. GI symptoms are frequent in people with WS and serve as a significant source of morbidity.

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.

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

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

Development of a Low Cost Semiquantitative Polymerase Chain Reaction Assay for Molecular Diagnosis of Williams Syndrome.

BACKGROUND: Williams Beuren Syndrome (WBS) is a well-recognized and common genetic cause of congenital heart defects, developmental delay, hypercalcemia, and characteristic facial features. It is caused by a 1.5 - 1.8 Mb heterozygous deletion of chromosome 7q11.23 with loss of around 28 coding genes. The aim of this study was to develop a low-cost, semi-quantitative PCR (sqPCR) method to detect the chromosome 7q11.23 deletion. METHODS: Twenty-four suspected WBS cases were recruited following ethical clearance and informed consent. Blood was obtained, DNA extracted and spectrophotometrically quantified using standard methods. To detect the deletion by dosage analysis, a target region within a gene located in the WBS commonly deleted region of 7q11.23 was amplified together with a control region in a duplex sqPCR assay. The control region was telomeric to the WBS commonly deleted region and was located in chromosome 7q31.2. The two target regions within the deleted region namely a locus within ELN and a marker in the intergenic region between FZD9 and FKBP6 and designated IFF, were amplified in separate duplex sqPCR assays. The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene was used as the control for normalization. Included in the assay were a non-deleted and deleted individuals' samples. RESULTS: Nineteen patients were identified to have the deletion while five did not. All 24 patients' results were confirmed by whole exome sequencing and 11 also by fluorescence in-situ hybridization (FISH). CONCLUSIONS: The data obtained indicates the sqPCR assay developed in this study to be an accurate and reliable diagnostic test for WBS. Most Sri Lankan patients with WBS are diagnosed clinically, as many parents of affected WBS children are unable to afford currently available molecular diagnostic testing. This low cost sqPCR test is therefore likely to benefit Sri Lankan WBS patients, by enabling genetic testing for confirming or refuting a clinical diagnosis of WBS and may be of use in other low and middle income countries.

Parallel deletion and duplication at 7q11.23 in a silent carrier for two reciprocal syndromic disorders.

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.

Mosaic Williams syndrome: A case report.

Williams syndrome (WS) is a well-known genetic disorder caused by heterozygous microdeletions of the 7q11.23 chromosome region. The main clinical features of the syndrome are characteristic facial dysmorphisms, cardiovascular and endocrine anomalies, short stature, mild-to-moderate intellectual disability, and a recognizable cognitive and behavioral profile. Differently from large chromosomal imbalances and aneuploidies, mosaicism has only rarely been found in microdeletion syndromes, and mosaic cases with WS phenotype have never been reported. We here describe a 51-year-old female patient with the typical clinical features of WS, whose chromosomal microarray analysis and fluorescence in situ hybridization disclosed a 54%-68% germline mosaicism for 7q11.23 deletion.

Biallelic GTF2IRD1 variants in brothers with profound neurodevelopmental disorder: A possible novel disorder involving a critical gene for Williams syndrome.

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.

Celiac disease prevalence and predisposing-HLA in a cohort of 93 Williams-Beuren syndrome patients.

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.

Ocular features in Williams-Beuren syndrome: a review of the literature.

PURPOSE OF REVIEW: The current review will discuss the pathophysiology, work-up and clinical relevance of the ocular phenotype in Williams-Beuren syndrome in detail. RECENT FINDINGS: Few case reports, case series and retrospective studies reported the ophthalmic features in Williams-Beuren syndrome, focusing on specific aspects of the ocular involvement. Recently, novel retinal findings have been described in association with the disease. SUMMARY: Numerous ocular features have been described in Williams-Beuren syndrome. Some of them, such as the stellate pattern of the iris or the retinal arteriolar tortuosity may be helpful for the diagnosis but have no significant clinical implications; others, such as strabismus and refractive errors require early treatment to reduce the risk of irreversible visual impairment. Finally, some features, such as a broad foveal pit and thinner retina still have unknown significance and require further longitudinal and multimodal studies.

Antenatal ultrasound features of isolated recurrent copy number variation in 7q11.23 (Williams syndrome and 7q11.23 duplication syndrome).

OBJECTIVE: We aimed to gather fetal cases carrying a 7q11.23 copy number variation (CNV) and collect precise clinical data to broaden knowledge of antenatal features in these syndromes. METHODS: We retrospectively recruited unrelated cases with 7q11.23 deletion, known as Williams-Beuren syndrome (WBS), or 7q11.23 duplication who had prenatal ultrasound findings. We collected laboratory and clinical data, fetal ultrasound, cardiac ultrasound and fetal autopsy reports from 18 prenatal diagnostic centers throughout France. RESULTS: 40 fetuses with WBS were collected and the most common features were intra-uterine growth retardation (IUGR) (70.0%, 28/40), cardiovascular defects (30.0%, 12/40), polyhydramnios (17.5%, 7/40) and protruding tongue (15.0%, 6/40). Fetal autopsy reports were available for 11 cases and were compared with ultrasound prenatal features. Four cases of fetuses with 7q11.23 microduplication were collected and prenatal ultrasound signs were variable and often isolated. CONCLUSION: This work strengthens the fact that 7q11.23 CNVs are associated with a broad spectrum of antenatal presentations. IUGR and cardiovascular defects were the most frequent ultrasound signs. By reporting the biggest series of antenatal WBS, we aim to better delineate distinctive signs in fetuses with 7q11.23 CNVs.

Sudden Cardiac Arrest During a Sedated Cardiac Magnetic Resonance Study in a Nonsyndromic Child with Evolving Supravalvar Aortic Stenosis Due to Familial ELN Mutation.

Supravalvar aortic stenosis (SVAS) is a less common but clinically important form of left ventricular outflow tract obstruction, and commonly associated with Williams syndrome (WS). SVAS outside of WS may also occur sporadically or in a familial form, often with identifiable mutations in the elastin (ELN) gene. While risk of sudden cardiac death in patients with SVAS has been extensively described in the context of WS, less is known about risk in patients with isolated SVAS. We report a case of a nonsyndromic two-year-old boy with evolving manifestations of SVAS who developed sudden cardiac arrest and death during a sedated cardiac magnetic resonance imaging study. A strong family history of SVAS was present and targeted genetic testing identified an ELN gene mutation in the boy's affected father and other paternal relatives. We review risk factors found in the literature for SCA in SVAS patients and utilize this case to raise awareness of the risk of cardiac events in these individuals even in the absence of WS or severe disease. This case also underscores the importance of genetic testing, including targeted panels specifically looking for ELN gene mutations, in all patients with SVAS even in the absence of phenotypic concerns for WS or other genetic syndromes.

Dysfunctional Mitochondria in the Cardiac Fibers of a Williams-Beuren Syndrome Mouse Model.

Williams-Beuren syndrome (WBS) is a rare neurodevelopmental disorder that, together with a rather characteristic neurocognitive profile, presents a strong cardiovascular phenotype. The cardiovascular features of WBS are mainly related to a gene dosage effect due to hemizygosity of the elastin (ELN) gene; however, the phenotypic variability between WBS patients indicates the presence of important modulators of the clinical impact of elastin deficiency. Recently, two genes within the WBS region have been linked to mitochondrial dysfunction. Numerous cardiovascular diseases are related to mitochondrial dysfunction; therefore, it could be a modulator of the phenotype present in WBS. Here, we analyze mitochondrial function and dynamics in cardiac tissue from a WBS complete deletion (CD) model. Our research reveals that cardiac fiber mitochondria from CD animals have altered mitochondrial dynamics, accompanied by respiratory chain dysfunction with decreased ATP production, reproducing alterations observed in fibroblasts from WBS patients. Our results highlight two major factors: on the one hand, that mitochondrial dysfunction is probably a relevant mechanism underlying several risk factors associated with WBS disease; on the other, the CD murine model mimics the mitochondrial phenotype of WBS and could be a great model for carrying out preclinical tests on drugs targeting the mitochondria.