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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., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Supravalvar aortic stenosis (SVAS) is a characteristic feature of Williams-Beuren syndrome (WBS). Its severity varies: ~20% of people with Williams-Beuren syndrome have SVAS requiring surgical intervention, whereas ~35% have no appreciable SVAS. The remaining individuals have SVAS of intermediate severity. Little is known about genetic modifiers that contribute to this variability., Methods and Results: We performed genome sequencing on 473 individuals with Williams-Beuren syndrome and developed strategies for modifier discovery in this rare disease population. Approaches include extreme phenotyping and nonsynonymous variant prioritization, followed by gene set enrichment and pathway-level association tests. We next used GTEx v8 and proteomic data sets to verify expression of candidate modifiers in relevant tissues. Finally, we evaluated overlap between the genes/pathways identified here and those ascertained through larger aortic disease/trait genome-wide association studies. We show that SVAS severity in Williams-Beuren syndrome is associated with increased frequency of common and rarer variants in matrisome and immune pathways. Two implicated matrisome genes ( ACAN and LTBP4 ) were uniquely expressed in the aorta. Many genes in the identified pathways were previously reported in genome-wide association studies for aneurysm, bicuspid aortic valve, or aortic size., Conclusions: Smaller sample sizes in rare disease studies necessitate new approaches to detect modifiers. Our strategies identified variation in matrisome and immune pathways that are associated with SVAS severity. These findings suggest that, like other aortopathies, SVAS may be influenced by the balance of synthesis and degradation of matrisome proteins. Leveraging multiomic data and results from larger aorta-focused genome-wide association studies may accelerate modifier discovery for rare aortopathies like SVAS.

Congenital diaphragmatic hernia (CDH) is a relatively common and genetically heterogeneous structural birth defect associated with high mortality and morbidity. We describe eight unrelated families with an X-linked condition characterized by diaphragm defects, variable anterior body-wall anomalies, and/or facial dysmorphism. Using linkage analysis and exome or genome sequencing, we found that missense variants in plastin 3 (PLS3), a gene encoding an actin bundling protein, co-segregate with disease in all families. Loss-of-function variants in PLS3 have been previously associated with X-linked osteoporosis (MIM: 300910), so we used in silico protein modeling and a mouse model to address these seemingly disparate clinical phenotypes. The missense variants in individuals with CDH are located within the actin-binding domains of the protein but are not predicted to affect protein structure, whereas the variants in individuals with osteoporosis are predicted to result in loss of function. A mouse knockin model of a variant identified in one of the CDH-affected families, c.1497G>C (p.Trp499Cys), shows partial perinatal lethality and recapitulates the key findings of the human phenotype, including diaphragm and abdominal-wall defects. Both the mouse model and one adult human male with a CDH-associated PLS3 variant were observed to have increased rather than decreased bone mineral density. Together, these clinical and functional data in humans and mice reveal that specific missense variants affecting the actin-binding domains of PLS3 might have a gain-of-function effect and cause a Mendelian congenital disorder., Competing Interests: Declaration of interests M.L. is currently an employee of, and holds equity in, Illumina Inc. J.R.L. has stock ownership in 23andMe and is a paid consultant for Genome International., (Copyright © 2023 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

QTc prolongation (≥ 460 ms), according to Bazett formula (QTcB), has been identified to be increased in Williams syndrome (WS) and suggested as a potential cause of increased risk of sudden cardiac death. The Bazett formula tends to overestimate QTc in higher heart rates. We performed a retrospective chart review of WS patients with ≥ 1 electrocardiogram (EKG) with sinus rhythm, no evidence of bundle branch blocks, and measurable intervals. A total of 280 EKGs from 147 patients with WS were analyzed and 123 EKGs from 123 controls. The QTc was calculated using Bazett formula. The average QTcB for individuals with WS and controls was 444 ± 24 ms and 417 ± 26 ms, respectively (p < 0.001). In our WS cohort 34.4% had at least 1 EKG with a QTcB ≥ 460 ms. The mean heart rate (HR) from patients with WS was significantly higher than controls (96 bpm vs 76 bpm, p < 0.001). Linear regression showed that HR contributed 27% to QTcB prolongation in the patients with WS. Patients with WS have a mean QTcB in the normal range but higher than controls, and a higher than expected frequency of QTc ≥ 460 ms compared to the general population. HR is also higher in WS and contributes modestly to the WS QTcB prolongation. Future studies are needed to assess if these findings contribute risk to sudden cardiac death but in the interim we recommend routine EKG testing, especially when starting QTc prolonging medications., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Williams syndrome (WS) is a neurodevelopmental disorder associated with several medical and psychiatric comorbidities., Objective: To describe the clinical presentation and treatment course of functional neurological symptom disorder (FNSD) in 3 adult patients with WS., Methods: This report describes the clinical presentation and long-term follow-up of 3 individuals with WS and FNSD who experienced a range of clinical presentations and responses to treatment. The literature on the clinical assessment and treatment of FNSD as it applies to patients with neurodevelopmental disorders is reviewed., Results: FNSD treatment strategies used in the general population were successfully adapted for these 3 patients. Literature on the diagnosis and treatment of FNSD in patients with neurodevelopmental disorders is lacking., Conclusions: FNSD may be more common in individuals with WS than previously appreciated, and future studies describing the prevalence, clinical presentation, risk factors, and treatment of FNSD in WS are needed., (Copyright © 2021 Academy of Consultation-Liaison Psychiatry. Published by Elsevier Inc. All rights reserved.)

The purpose of the study was to characterize repetitive phenomena in Williams syndrome (WS). The parents of 60 subjects with WS completed the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) or Children's Y-BOCS, the Yale Global Tic Severity Scale, the Stereotyped Behavior Scale, and the Spence Children's Anxiety Scale-Parent Version. Nineteen males and 41 females participated in the study. Six subjects (10%) had obsessions only, six (10%) had compulsions only, and eleven (18%) had at least one obsession and at least one compulsion. None of the subjects had tics. Fifty subjects (83.3%) endorsed at least one stereotypy. Increased anxiety was associated with increased severity of obsessions, but not severity of compulsions or stereotypies., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Williams syndrome (WS) is a relatively rare microdeletion disorder that occurs in as many as 1:7,500 individuals. WS arises due to the mispairing of low-copy DNA repetitive elements at meiosis. The deletion size is similar across most individuals with WS and leads to the loss of one copy of 25-27 genes on chromosome 7q11.23. The resulting unique disorder affects multiple systems, with cardinal features including but not limited to cardiovascular disease (characteristically stenosis of the great arteries and most notably supravalvar aortic stenosis), a distinctive craniofacial appearance, and a specific cognitive and behavioural profile that includes intellectual disability and hypersociability. Genotype-phenotype evidence is strongest for ELN, the gene encoding elastin, which is responsible for the vascular and connective tissue features of WS, and for the transcription factor genes GTF2I and GTF2IRD1, which are known to affect intellectual ability, social functioning and anxiety. Mounting evidence also ascribes phenotypic consequences to the deletion of BAZ1B, LIMK1, STX1A and MLXIPL, but more work is needed to understand the mechanism by which these deletions contribute to clinical outcomes. The age of diagnosis has fallen in regions of the world where technological advances, such as chromosomal microarray, enable clinicians to make the diagnosis of WS without formally suspecting it, allowing earlier intervention by medical and developmental specialists. Phenotypic variability is considerable for all cardinal features of WS but the specific sources of this variability remain unknown. Further investigation to identify the factors responsible for these differences may lead to mechanism-based rather than symptom-based therapies and should therefore be a high research priority.

Introduction : Williams syndrome (WS) is a neurogenetic disorder characterized by a hyper-social personality, intellectual disability, and multiple medical co-morbidities. Psychiatric co-morbidities are also common. Since medical co-morbidities are common in this population, the risk-benefit of the use of psychiatric medications must be carefully considered and monitoring for safety and tolerability is needed. Areas covered : We review the cognitive profile and common medical co-morbidities in WS. We then discuss the common presentations of psychiatric disorders and review the available evidence on the use of psychiatric medications in WS. No prospective psychiatric medication trials have been conducted. We highlight the side effect profile of common psychiatric medications as they pertain to WS. Expert opinion : Psychiatric disorders can have a major effect on the quality of life of individuals with WS. The lack of long-term safety data and high likelihood of medical co-morbidities in WS make the judicious use of psychiatric medications more challenging; however, they can play an important role in decreasing distress and improving functioning. We provide recommendations for first- and second-line classes of medications based on our clinical experience and consideration of adverse effect profiles, as well as safety monitoring parameters at baseline and periodically.

Purpose of Review: Williams syndrome is a multisystem disorder caused by a microdeletion on chromosome 7q. Throughout infancy, childhood, and adulthood, abnormalities in body composition and in multiple endocrine axes may arise for individuals with Williams syndrome. This review describes the current literature regarding growth, body composition, and endocrine issues in Williams syndrome with recommendations for surveillance and management by the endocrinologist, geneticist, or primary care physician., Recent Findings: In addition to known abnormalities in stature, calcium metabolism, and thyroid function, individuals with Williams syndrome are increasingly recognized to have low bone mineral density, increased body fat, and decreased muscle mass. Furthermore, recent literature identifies a high prevalence of diabetes and obesity starting in adolescence, and, less commonly, a lipedema phenotype in both male and female individuals. Understanding of the mechanisms by which haploinsufficiency of genes in the Williams syndrome-deleted region contributes to the multisystem phenotype of Williams syndrome continues to evolve., Summary: Multiple abnormalities in growth, body composition, and endocrine axes may manifest in individuals with Williams syndrome. Individuals with Williams syndrome should have routine surveillance for these issues in either the primary care setting or by an endocrinologist or geneticist., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Williams-Beuren syndrome (WBS) is a multisystem disorder caused by a hemizygous deletion on 7q11.23 encompassing 26-28 genes. An estimated 2-5% of patients have "atypical" deletions, which extend in the centromeric and/or telomeric direction from the WBS critical region. To elucidate clinical differentiators among these deletion types, we evaluated 10 individuals with atypical deletions in our cohort and 17 individuals with similarly classified deletions previously described in the literature. Larger deletions in either direction often led to more severe developmental delays, while deletions containing MAGI2 were associated with infantile spasms and seizures in patients. In addition, head size was notably smaller in those with centromeric deletions including AUTS2. Because children with atypical deletions were noted to be less socially engaged, we additionally sought to determine how atypical deletions relate to social phenotypes. Using the Social Responsiveness Scale-2, raters scored individuals with atypical deletions as having different social characteristics to those with typical WBS deletions (p = .001), with higher (more impaired) scores for social motivation (p = .005) in the atypical deletion group. In recognizing these distinctions, physicians can better identify patients, including those who may already carry a clinical or FISH WBS diagnosis, who may benefit from additional molecular evaluation, screening, and therapy. In addition to the clinical findings, we note mild endocrine findings distinct from those typically seen in WBS in several patients with telomeric deletions that included POR. Further study in additional telomeric deletion cases will be needed to confirm this observation., (Published 2020. This article is a U.S. Government work and is in the public domain in the USA.)

Objective: To evaluate the occurrence and estimate the frequency of macrocytosis in Williams-Beuren syndrome (WBS)., Study Design: Complete blood count (CBC) data from 179 subjects with WBS aged 1-69 were collected, with common parameters assessed for trends. Z-transformed mean corpuscular volume (MCV) was compared with each laboratory's reference range as well as with control data from the National Health and Nutrition Examination Survey (NHANES) 2013-2014 data archives., Results: Just over a third (35%) subjects had at least one recorded incidence of macrocytosis. In comparisons of CBC parameters with an expected population mean, MCV and MCH were greater than, while Hct and RDW were lower than, expected values. The distribution of erythrocyte MCV is shifted to the right in WBS compared to controls, as was the mean value. Despite this, anemia was absent, except in a single medically complex WBS subject. Though there was a paucity of data available of variables that could potentially cause an elevated MCV, no obvious etiology could be elucidated., Conclusions: Mild macrocytosis without anemia affects a moderate subset of WBS patients, leading to a rightward shift in the MCV distribution curve. Providers encountering isolated mild macrocytosis in WBS can consider observation over further workup., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Co-morbid anxiety disorders, including generalized anxiety disorder (GAD), are highly prevalent among individuals with Williams syndrome (WS). However, reports of the pharmacologic treatment of only a limited number of previous anxiety disorders in WS have appeared in the literature. Here, we review the case histories of three adolescents/young adults with WS and the treatment course of co-morbid GAD with buspirone. Treatment with buspirone was well-tolerated and resulted in sustained response in all three cases. Common medical disorders in WS are highlighted with regards to safe and appropriate pharmacologic treatment of GAD. Buspirone's generally benign side effect profile is a major benefit of its use for treating GAD in individuals with WS.

Objective: We assessed body composition, bone mineral density (BMD), glucose and lipids in Williams syndrome (WS), a rare microdeletion disorder., Design: Individuals with WS had outpatient assessment at Massachusetts General Hospital. Controls were selected from the National Health and Nutrition Examination Survey (NHANES 2005-2006)., Patients: A total of 22 individuals with WS, each matched by age, sex and race to four NHANES controls., Measurements: Blood sampling, oral glucose tolerance test, dual-energy X-ray absorptiometry scan., Results: WS and control groups were 59% female and 29 ± 8 years old. Compared to controls, individuals with WS were shorter but had similar body weight, with more fat and less lean mass. Per cent body fat was higher in WS even after adjusting for BMI (+2.1% [95% CI 0.4, 3.9%]). Four WS patients had abnormal lower extremity fat accumulation resembling lipedema. HbA1c (+0.5% [0.2, 0.7]) and 2-hour glucose (+68 mg/dL [44, 93]) were higher in WS vs controls, differences which persisted after adjusting for BMI. Fasting glucose was comparable between groups. LDL (-18 mg/dL [-35, -2]) and triglycerides (-45 mg/dL [-87, -2]) were significantly lower in WS. Whole-body BMD was significantly lower (-0.15 g/cm 2 [-0.20, -0.11]) in WS, and this remained true controlling for height (-0.06 g/cm 2 [-0.11, -0.02]). Vitamin D was <30 ng/mL in 81% of those with WS., Conclusions: On average, adults with WS have increased fat, decreased lean mass, impaired glucose homeostasis and reduced BMD. Clinical efforts to build muscle and bone mass, and to ensure vitamin D sufficiency, are warranted. Genotype-phenotype research efforts are also warranted., (© 2018 John Wiley & Sons Ltd.)

Descriptions of individuals with Williams syndrome (WS) and co-morbid major depressive disorder (MDD) with psychotic features have not appeared in the literature. In addition to reviewing previous reports of psychotic symptoms in persons with WS, this paper introduces clinical histories and therapeutic management strategies for three previously unreported adults with WS diagnosed with co-morbid MDD with psychotic features. Co-morbid medical disorders common in WS are highlighted with regard to safe and appropriate pharmacological treatment. The importance of assessment for co-morbid MDD with psychotic features in individuals with WS is emphasized.

Williams-Beuren syndrome (WBS) is a chromosomal microdeletion syndrome typically presenting with intellectual disability, a unique personality, a characteristic facial appearance, and cardiovascular disease. Several clinical features of WBS are thought to be due to haploinsufficiency of elastin (ELN), as the ELN locus is included within the WBS critical region at 7q11.23. Emphysema, a disease attributed to destruction of pulmonary elastic fibers, has been reported in patients without WBS who have pathogenic variants in ELN but only once (in one patient) in WBS. Here we report a second adult WBS patient with emphysema where the diagnosis of WBS was established subsequent to the discovery of severe bullous emphysema. Haploinsufficiency of ELN likely contributed to this pulmonary manifestation of WBS. This case emphasizes the contribution of rare genetic variation in cases of severe emphysema and provides further evidence that emphysema should be considered in patients with WBS who have respiratory symptoms, as it may be under-recognized in this patient population., (© 2017 Wiley Periodicals, Inc.)

Objective: To evaluate the timing, trajectory, and implications of hypercalcemia in Williams-Beuren syndrome (WBS) through a multicenter retrospective study., Study Design: Data on plasma calcium levels from 232 subjects with WBS aged 0-67.1 years were compared with that in controls and also with available normative data. Association testing was used to identify relevant comorbidities., Results: On average, individuals with WBS had higher plasma calcium levels than controls, but 86.7% of values were normal. Nonpediatric laboratories overreport hypercalcemia in small children. When pediatric reference intervals were applied, the occurrence of hypercalcemia dropped by 51% in infants and by 38% in toddlers. Across all ages, 6.1% of the subjects had actionable hypercalcemia. In children, actionable hypercalcemia was seen in those aged 5-25 months. In older individuals, actionable hypercalcemia was often secondary to another disease process. Evidence of dehydration, hypercalciuria, and nephrocalcinosis were common in both groups. Future hypercalcemia could not be reliably predicted by screening calcium levels. A subgroup analysis of 91 subjects found no associations between hypercalcemia and cardiovascular disease, gastrointestinal complaints, or renal anomalies. Analyses of electrogradiography data showed an inverse correlation of calcium concentration with corrected QT interval, but no acute life-threatening events were reported., Conclusions: Actionable hypercalcemia in patients with WBS occurs infrequently. Although irritability and lethargy were commonly reported, no mortality or acute life-threatening events were associated with hypercalcemia and the only statistically associated morbidities were dehydration, hypercalciuria, and nephrocalcinosis., Competing Interests: The authors declare no conflicts of interest., (Published by Elsevier Inc.)

Williams syndrome (WS), also referred to as Williams-Beuren syndrome (WBS), is a relatively rare genetic disorder affecting ∼1/10,000 persons. Since the disorder is caused by a micro-deletion of ∼1.5 Mb, it is not surprising that the manifestations of WS are extremely broad, involving most body systems. In this paper, we primarily focus on the musculoskeletal aspects of WS as these findings have not been the subject of a comprehensive review. We review the MSK features commonly seen in individuals with WS, along with related sensory and neurological issues interacting with and compounding underlying MSK abnormalities. We end by providing perspective, particularly from the vantage point of a physical therapist, on therapeutic interventions to address the most common MSK and related features seen in WS. Clin. Anat. 29:578-589, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Individuals with Williams syndrome (WS) often experience significant anxiety. A promising approach to anxiety intervention has emerged from cognitive studies of attention bias to threat. To investigate the utility of this intervention in WS, this study examined attention bias to happy and angry faces in individuals with WS (N = 46). Results showed a significant difference in attention bias patterns as a function of IQ and anxiety. Individuals with higher IQ or higher anxiety showed a significant bias toward angry, but not happy faces, whereas individuals with lower IQ or lower anxiety showed the opposite pattern. These results suggest that attention bias interventions to modify a threat bias may be most effectively targeted to anxious individuals with WS with relatively high IQ.

Zinc finger protein, FOG2 family member 2 (ZFPM2) (previously named FOG2) gene defects result in the highly morbid congenital diaphragmatic hernia (CDH) in humans and animal models. In a cohort of 275 CDH patient exomes, we estimated the prevalence of damaging ZFPM2 mutations to be almost 5%. Genetic analysis of a multigenerational family identified a heritable intragenic ZFPM2 deletion with an estimated penetrance of 37.5%, which has important implications for genetic counseling. Similarly, a low penetrance ZFPM2 frameshift mutation was observed in a second multiplex family. Isolated CDH was the predominant phenotype observed in our ZFPM2 mutation patients. Findings from the patients described herein indicate that ZFPM2 point mutations or deletions are a recurring cause of CDH., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Williams syndrome is a relatively rare genetic disorder caused by the hemizygous microdeletion of a region in chromosome 7q11.23. Individuals with Williams syndrome typically present with a highly social, overfriendly, and empathic personality. Comorbid medical and neuropsychiatric disorders are common. Reports of effective pharmacological treatment of associated neuropsychiatric disorders are limited. The authors describe the successful treatment of interfering anger, aggression, and hair-pulling with N-acetylcysteine in a 19-year-old woman with Williams syndrome. The neuropsychiatric symptoms emerged 1 week following an upper gastrointestinal endoscopy, for which fentanyl, midazolam, and propofol were used as anesthetics. The patient's treatment course and hypothesized mechanisms underlying the clinical presentation and symptom resolution are described., (© The Author(s) 2014.)

Previous examination in a small number of individuals with Williams syndrome (also referred to as Williams-Beuren syndrome) has shown subtly softer skin and reduced deposition of elastin, an elastic matrix protein important in tissue recoil. No quantitative information about skin elasticity in individuals with Williams syndrome is available; nor has there been a complete report of dermatologic findings in this population. To fill this knowledge gap, 94 patients with Williams syndrome aged 7-50 years were recruited as part of the skin and vascular elasticity (WS-SAVE) study. They underwent either a clinical dermatologic assessment by trained dermatologists (2010 WSA family meeting) or measurement of biomechanical properties of the skin with the DermaLab™ suction cup (2012 WSA family meeting). Clinical assessment confirmed that soft skin is common in this population (83%), as is premature graying of the hair (80% of those 20 years or older), while wrinkles (92%), and abnormal scarring (33%) were detected in larger than expected proportions. Biomechanical studies detected statistically significant differences in dP (the pressure required to lift the skin), dT (the time required to raise the skin through a prescribed gradient), VE (viscoelasticity), and E (Young's modulus) relative to matched controls. The RT (retraction time) also trended longer but was not significant. The biomechanical differences noted in these patients did not correlate with the presence of vascular defects also attributable to elastin insufficiency (vascular stiffness, hypertension, and arterial stenosis) suggesting the presence of tissue specific modifiers that modulate the impact of elastin insufficiency in each tissue., (© 2014 Wiley Periodicals, Inc.)

Congenital diaphragmatic hernia (CDH) is a common and severe birth defect. Despite its clinical significance, the genetic and developmental pathways underlying this disorder are incompletely understood. In this study, we report a catalog of variants detected by a whole exome sequencing study on 275 individuals with CDH. Predicted pathogenic variants in genes previously identified in either humans or mice with diaphragm defects are enriched in our CDH cohort compared with 120 size-matched random gene sets. This enrichment was absent in control populations. Variants in these critical genes can be found in up to 30.9% of individuals with CDH. In addition, we filtered variants by using genes derived from regions of recurrent copy number variations in CDH, expression profiles of the developing diaphragm, protein interaction networks expanded from the known CDH-causing genes, and prioritized genes with ultrarare and highly disruptive variants, in 11.3% of CDH patients. These strategies have identified several high priority genes and developmental pathways that likely contribute to the CDH phenotype. These data are valuable for comparison of candidate genes generated from whole exome sequencing of other CDH cohorts or multiplex kindreds and provide ideal candidates for further functional studies. Furthermore, we propose that these genes and pathways will enhance our understanding of the heterogeneous molecular etiology of CDH.

Williams syndrome is caused by the deletion of 26 to 28 genes, including elastin, on human chromosome 7. Elastin insufficiency leads to the cardiovascular hallmarks of this condition, namely focal stenosis and hypertension. Extrapolation from the Eln(+/-) mouse suggests that affected people may also have stiff vasculature, a risk factor for stroke, myocardial infarction, and cardiac death. NCF1, one of the variably deleted Williams genes, is a component of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex and is involved in the generation of oxidative stress, making it an interesting candidate modifier for vascular stiffness. Using a case-control design, vascular stiffness was evaluated by pulse wave velocity in 77 Williams cases and matched controls. Cases had stiffer conducting vessels than controls (P<0.001), with increased stiffness observed in even the youngest children with Williams syndrome. Pulse wave velocity increased with age at comparable rates in cases and controls, and although the degree of vascular stiffness varied, it was seen in both hypertensive and normotensive Williams participants. Use of antihypertensive medication and extension of the Williams deletion to include NCF1 were associated with protection from vascular stiffness. These findings demonstrate that vascular stiffness is a primary vascular phenotype in Williams syndrome and that treatment with antihypertensives or agents inhibiting oxidative stress may be important in managing patients with this condition, potentially even those who are not overtly hypertensive.

Objective: Patients with elastin deficiency attributable to gene mutation (supravalvular aortic stenosis) or chromosomal microdeletion (Williams syndrome) are characterized by obstructive arteriopathy resulting from excessive smooth muscle cell (SMC) proliferation, mural expansion, and inadequate vessel size. We investigated whether rapamycin, an inhibitor of the cell growth regulator mammalian target of rapamycin (mTOR) and effective against other SMC proliferative disorders, is of therapeutic benefit in experimental models of elastin deficiency., Approach and Results: As previously reported, Eln(-/-) mice demonstrated SMC hyperplasia and severe stenosis of the aorta, whereas Eln(+/-) mice exhibited a smaller diameter aorta with more numerous but thinner elastic lamellae. Increased mTOR signaling was detected in elastin-deficient aortas of newborn pups that was inhibited by maternal administration of rapamycin. mTOR inhibition reduced SMC proliferation and aortic obstruction in Eln(-/-) pups and prevented medial hyperlamellation in Eln(+/-) weanlings without compromising aortic size. However, rapamycin did not prolong the survival of Eln(-/-) pups, and it retarded the somatic growth of juvenile Eln(+/-) and Eln(+/+) mice. In cell cultures, rapamycin inhibited prolonged mTOR activation and enhanced proliferation of SMC derived from patients with supravalvular aortic stenosis and with Williams syndrome., Conclusions: mTOR inhibition may represent a pharmacological strategy to treat diffuse arteriopathy resulting from elastin deficiency.

Healthcare providers often share difficult or life-altering news with their patients yet this challenging and delicate process is frequently met with dissatisfaction by those receiving this news. Articles and guidelines exist to aid providers in sharing diagnoses such as Down syndrome, but relatively few have focused on rare genetic conditions often diagnosed years after birth. For this reason, we sought to learn about the experience of receiving a diagnosis from parents of children with Williams syndrome. We asked members of the Williams Syndrome Association to complete an anonymous online survey about recollections related to the diagnostic process. Responses, both close-ended and open-ended, were received from 600 families across the United States. Analysis revealed a high proportion of families (59.91%) with at least some negative recollections about the experience (and nearly half of those with negative recollections denied recalling anything positive). Factors influencing a more positive overall perception of the experience included receiving written information about Williams syndrome and seeing a genetic counselor. Analysis of open-ended responses identified additional positive and negative themes; for example, nearly one quarter of respondents expressed a desire to be given hope when receiving the diagnosis. Based on these analyses, we offer several specific recommendations for improving the diagnostic process in the future., (Copyright © 2013 Wiley Periodicals, Inc.)

Chromosome 8p23.1 is a common hotspot associated with major congenital malformations, including congenital diaphragmatic hernia (CDH) and cardiac defects. We present findings from high-resolution arrays in patients who carry a loss (n = 18) or a gain (n = 1) of sub-band 8p23.1. We confirm a region involved in both diaphragmatic and heart malformations. Results from a novel CNVConnect algorithm, prioritizing protein-protein interactions between products of genes in the 8p23.1 hotspot and products of previously known CDH causing genes, implicated GATA4, NEIL2, and SOX7 in diaphragmatic defects. Sequence analysis of these genes in 226 chromosomally normal CDH patients, as well as in a small number of deletion 8p23.1 patients, showed rare unreported variants in the coding region; these may be contributing to the diaphragmatic phenotype. We also demonstrated that two of these three genes were expressed in the E11.5-12.5 primordial mouse diaphragm, the developmental stage at which CDH is thought to occur. This combination of bioinformatics and expression studies can be applied to other chromosomal hotspots, as well as private microdeletions or microduplications, to identify causative genes and their interaction networks., (Copyright © 2012 Wiley Periodicals, Inc.)

Advances in genetic epidemiology have increased understanding of common, polygenic preventable diseases such as type 2 diabetes. As genetic risk testing based on this knowledge moves into clinical practice, we propose that genetic counselors will need to expand their roles and adapt traditional counseling techniques for this new patient set. In this paper, we present a genetic counseling intervention developed for a clinical trial [Genetic Counseling/Lifestyle Change for Diabetes Prevention, ClinicalTrials.gov identifier: NCT01034319] designed to motivate behavioral changes for diabetes prevention. Seventy-two phenotypically high-risk participants received counseling that included their diabetes genetic risk score, general education about diabetes risk factors, and encouragement to participate in a diabetes prevention program. Using two validated genetic counseling scales, participants reported favorable perceived control and satisfaction with the counseling session. Our intervention represents one model for applying traditional genetic counseling principles to risk testing for polygenetic, preventable diseases, such as type 2 diabetes.

Congenital diaphragmatic defects (CDDs) are a common group of birth defects, yet we presently know little about their pathogenesis. No systematic study documenting the detailed morphology of CDD has been performed, and current classification schemata of diaphragm phenotypes incompletely capture the location and extent of diaphragmatic involvement. To define the range of CDD anatomy, diaphragmatic pathology was reviewed from an examination of 181 autopsy records of children with CDDs at Children's Hospital Boston between 1927 and 2006. Defects were classified according to several parameters, including type (communicating versus noncommunicating) and location (anterior, posterior, etc.). The information permitted development of a phenotyping worksheet for prospective use on patients undergoing diaphragmatic repair at Children's Hospital Boston or MassGeneral Hospital for Children. Fifty-three patients who died between 1990 and 2006 had a total of 63 defects. Thirty-nine had a "classic" CDD phenotype (64% posterolateral, 18% hemidiaphragmatic aplasia, and 18% anterior). The remaining 19 defects, not fitting classical descriptions, were located in the posteromedial, anterolateral, or lateral regions of the diaphragm. Prospective data collected during surgical repair revealed posterolateral defects in 34 of 41 cases that demonstrated wide phenotypic variability in size, location, shape, type, and extent of organ displacement. Congenital diaphragmatic defects display significant phenotypic variation. Because rigorous anatomic evaluation and documentation are important steps towards elucidating the developmental biology of these disorders, we suggest establishment of a new and more precise classification using the model presented herein.

Congenital diaphragmatic hernia (CDH) is a common (1 in 3,000 live births) major congenital malformation that results in significant morbidity and mortality. The discovery of CDH loci using standard genetic approaches has been hindered by its genetic heterogeneity. We hypothesized that gene expression profiling of developing embryonic diaphragms would help identify genes likely to be associated with diaphragm defects. We generated a time series of whole-transcriptome expression profiles from laser captured embryonic mouse diaphragms at embryonic day (E)11.5 and E12.5 when experimental perturbations lead to CDH phenotypes, and E16.5 when the diaphragm is fully formed. Gene sets defining biologically relevant pathways and temporal expression trends were identified by using a series of bioinformatic algorithms. These developmental sets were then compared with a manually curated list of genes previously shown to cause diaphragm defects in humans and in mouse models. Our integrative filtering strategy identified 27 candidates for CDH. We examined the diaphragms of knockout mice for one of the candidate genes, pre-B-cell leukemia transcription factor 1 (Pbx1), and identified a range of previously undetected diaphragmatic defects. Our study demonstrates the utility of genetic characterization of normal development as an integral part of a disease gene identification and prioritization strategy for CDH, an approach that can be extended to other diseases and developmental anomalies.

Background: Congenital diaphragmatic hernia (CDH) is a major birth defect that occurs when abdominal organs herniate through a diaphragmatic opening into the thoracic cavity and is associated with high mortality (>50%). The etiology of CDH is not well understood., Methods: Using data from the National Birth Defects Prevention Study, we examined associations between CDH and maternal periconceptional exposure (1 month before through the third month of pregnancy) to cigarette smoking and alcohol. Interview reports of exposures were provided by mothers of CDH (n = 503) and unaffected control (n = 6703) infants delivered from October 1997 through December 2005. Any exposure (yes/no), as well as quantity (average number of cigarettes or drinks), type (active/passive smoking; beer, wine, distilled spirits), and duration (e.g., number of months exposed) were examined. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were calculated for all CDH cases combined, selected subtypes (Bochdalek, Morgagni, not otherwise specified), and phenotypes (infants with/without additional major birth defects)., Results: The aOR for any smoking was nonsignificantly elevated for all CDH cases combined. Odds of any smoking was significant for isolated Bochdalek CDH (aOR, 1.9; 95% CI, 1.2-3.0). The aORs associated with all measures of alcohol consumption were near unity for each CDH category examined. Stratification of smoking exposure by alcohol consumption and stratification of alcohol consumption by smoking exposure did not appreciably change the aORs., Conclusions: These findings identified periconceptional smoking exposure as a potential risk factor for CDH. Future studies need to confirm our findings and explore possible pathways accounting for the teratogenic effect of smoking., (Copyright © 2010 Wiley-Liss, Inc.)

Cytogenetic and molecular cytogenetic studies demonstrate association between congenital diaphragmatic hernia (CDH) and chromosome 1q41q42 deletions. In this study, we screened a large CDH cohort (N=179) for microdeletions in this interval by the multiplex ligation-dependent probe amplification (MLPA) technique, and also sequenced two candidate genes located therein, dispatched 1 (DISP1) and homo sapiens H2.0-like homeobox (HLX). MLPA analysis verified deletions of this region in two cases, an unreported patient with a 46,XY,del(1)(q41q42.13) karyotype and a previously reported patient with a Fryns syndrome phenotype [Kantarci et al., 2006]. HLX sequencing showed a novel but maternally inherited single nucleotide variant (c.27C>G) in a patient with isolated CDH, while DISP1 sequencing revealed a mosaic de novo heterozygous substitution (c.4412C>G; p.Ala1471Gly) in a male with a left-sided Bochdalek hernia plus multiple other anomalies. Pyrosequencing demonstrated the mutant allele was present in 43%, 12%, and 4.5% of the patient's lymphoblastoid, peripheral blood lymphocytes, and saliva cells, respectively. We examined Disp1 expression at day E11.5 of mouse diaphragm formation and confirmed its presence in the pleuroperitoneal fold, as well as the nearby lung which also expresses Sonic hedgehog (Shh). Our report describes the first de novo DISP1 point mutation in a patient with complex CDH. Combining this finding with Disp1 embryonic mouse diaphragm and lung tissue expression, as well as previously reported human chromosome 1q41q42 aberrations in patients with CDH, suggests that DISP1 may warrant further consideration as a CDH candidate gene., (Copyright © 2010 Wiley-Liss, Inc.)

A standard oral glucose tolerance test (OGTT) was administered to 28 adults with Williams syndrome (WS). Three quarters of the WS subjects showed abnormal glucose curves, meeting diagnostic criteria for either diabetes or the pre-diabetic state of impaired glucose tolerance. Fasting mean glucose and median insulin levels did not differ significantly in the total WS cohort versus age-gender-BMI matched controls, though the glucose area under the curve was greater in the WS subjects. HbA1c levels were not as reliable as the OGTT in diagnosing the presence of diabetes. Given the high prevalence of impaired glucose regulation, adults with WS should be screened for diabetes, and when present should be treated in accordance with standard medical practice. Hemizygosity for a gene mapping to the Williams syndrome chromosome region (WSCR) is likely the major factor responsible for the high frequency of diabetes in WS. Syntaxin-1A is a prime candidate gene based on its location in the WSCR, its role in insulin release, and the presence of abnormal glucose metabolism in mouse models with aberrantly expressed Stx-1a.

Williams-Beuren syndrome (WBS) is caused by a submicroscopic deletion on chromosome 7q11.23 that encompasses the entire elastin (ELN) gene. Elastin, a key component of elastic fibers within the lung, is progressively destroyed in emphysema. Defects in the elastin gene have been associated with increased susceptibility towards developing chronic obstructive pulmonary disease (COPD) and emphysema in both humans and mice. We postulate that hemizygosity at the elastin gene locus may increase susceptibility towards the development of COPD and emphysema in subjects with WBS. We describe an adult subject with WBS who was a lifelong non-smoker and was found to have moderate emphysema. We also examined the pulmonary function of a separate cohort of adolescents and young adults with WBS. Although no significant spirometric abnormalities were identified, a significant proportion of subjects reported respiratory symptoms. Thus, while significant obstructive disease does not appear to be common in relatively young adults with WBS, subclinical emphysema and lung disease may exist which possibly could worsen with advancing age. Further investigation may elucidate the pathogenesis of non-smoking-related emphysema., ((c) 2010 Wiley-Liss, Inc.)

Mutations in the gene LRP2 have recently been identified as the cause of Donnai-Barrow and Facio-oculo-acoustico-renal (DB/FOAR) syndrome. More than two dozen cases, the first reported more than 30 years ago by Holmes, have been published. Summarizing available information, we highlight the cardinal features of the disorder found in >or=90% of published cases. These features include: agenesis of the corpus callosum, developmental delay, enlarged anterior fontanelle, high myopia, hypertelorism, proteinuria, and sensorineural hearing loss. Congenital diaphragmatic hernia and omphalocele are reported in only half of the patients. There is no evidence for genotype-phenotype correlation, though the sample size is too small to preclude this with certainty. Although several conditions to consider in the differential diagnosis are highlighted, the diagnosis of DB/FOAR syndrome should not be difficult to establish as its constellation of findings is strikingly characteristic.

Donnai-Barrow syndrome [Faciooculoacousticorenal (FOAR) syndrome; DBS/FOAR] is a rare autosomal recessive disorder resulting from mutations in the LRP2 gene located on chromosome 2q31.1. We report a unique DBS/FOAR patient homozygous for a 4-bp LRP2 deletion secondary to paternal uniparental isodisomy for chromosome 2. The propositus inherited the mutation from his heterozygous carrier father, whereas the mother carried only wild-type LRP2 alleles. This is the first case of DBS/FOAR resulting from uniparental disomy (UPD) and the fourth published case of any paternal UPD 2 ascertained through unmasking of an autosomal recessive disorder. The absence of clinical symptoms above and beyond the classical phenotype in this and the other disorders suggests that paternal chromosome 2 is unlikely to contain imprinted genes notably affecting either growth or development. This report highlights the importance of parental genotyping in order to give accurate genetic counseling for autosomal recessive disorders., (2008 Wiley-Liss, Inc.)

Cardiovascular abnormalities, especially structural congenital heart defects, commonly occur in malformation syndromes and genetic disorders. Individuals with syndromes comprise a significant proportion of those affected with selected congenital heart defects such as complete atrioventricular canal, interrupted arch type B, supravalvar aortic stenosis, and pulmonary stenosis. As these individuals age, they contribute to the growing population of adults with special health care needs. Although most will require longterm cardiology follow-up, primary care providers, geneticists, and other specialists should be aware of (1) the type and frequency of cardiovascular abnormalities, (2) the range of clinical outcomes, and (3) guidelines for prospective management and treatment of potential complications. This article reviews fundamental genetic, cardiac, medical, and reproductive issues associated with common genetic syndromes that are frequently associated with a cardiovascular abnormality. New data are also provided about the cardiac status of adults with a 22q11.2 deletion and with Down syndrome.

Williams-Beuren syndrome (WBS) is a microdeletion disorder caused by heterozygous loss of approximately 1.5-Mb pairs of DNA from chromosome 7. Patients with WBS have a characteristic constellation of medical and cognitive findings, with a hallmark feature of generalized arteriopathy presenting as stenoses of elastic arteries and hypertension. Human and mouse studies establish that defects in the elastin gene, leading to elastin haploinsufficiency, underlie the arteriopathy. In this review we describe potential links between elastin expression and arteriopathy, possible explanations for disease variability, and current treatment options and their limitations, and we propose several new directions for the development of nonsurgical preventative therapies based on insights from elastin biology.

Background: Congenital diaphragmatic hernia (CDH) is a severe birth defect where there is an opening in the diaphragm through which a portion of the abdominal contents protrudes into the thoracic cavity. The etiologies of CDH remain unknown, although experimental animal data suggest dietary factors might play a role. This study examined whether maternal nutrient intakes were associated with delivering infants with CDH., Methods: We analyzed infants with isolated CDH who were born from 1997 to 2003 and recruited into the National Birth Defects Prevention Study (NBDPS), a multisite, population-based case-control study. Exposure data were obtained from telephone interviews, which were completed within 24 months after delivery, and were available for 377 case mothers and 5,008 control mothers. A food frequency questionnaire was used to derive nutrient intakes during the year before pregnancy., Results: A crude OR of 0.6 (95% CI: 0.3-1.0) was observed for higher intake of choline. Elevated ORs (1.4 to 1.7) were found for lower intakes of choline, cysteine, methionine, and protein. Among women who took vitamin supplements, higher intakes of B vitamins (i.e., folate, vitamin B1, B2, B6, and B12), minerals (i.e., calcium, iron, magnesium, and zinc), and vitamin E were inversely associated with CDH (ORs from 0.7-0.3). Moreover, among women who did not take vitamin supplements, lower intakes of calcium, retinol, selenium, vitamin B12, and vitamin E had positive associations with CDH (ORs from 1.4 to 2.1)., Conclusions: Our observations contribute to a limited body of evidence suggesting a woman's periconceptional diet might be associated with CDH in her offspring., ((c) 2007 Wiley-Liss, Inc.)