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Nature Reviews. Disease Primers Jun 2021Williams 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... (Review)
Review
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.
Topics: Cognition; Elastin; Humans; Transcription Factors; Williams Syndrome
PubMed: 34140529
DOI: 10.1038/s41572-021-00276-z -
Wiley Interdisciplinary Reviews.... Jan 2017Recent technological advances allow us to measure how the infant brain functions in ways that were not possible just a decade ago. Although methodological advances are... (Review)
Review
Recent technological advances allow us to measure how the infant brain functions in ways that were not possible just a decade ago. Although methodological advances are exciting, we must also consider how theories guide research: what we look for and how we explain what we find. Indeed, the ways in which research findings are interpreted affects the design of policies, educational practices, and interventions. Thus, the theoretical approaches adopted by scientists have a real impact on the lives of children with neurodevelopmental disorders (NDDs) and their families, as well as on the wider community. Here, we introduce and compare two theoretical approaches that are used to understand NDDs: the neuropsychological account and neuroconstructivism. We show how the former, adult account, is inadequate for explaining NDDs and illustrate this using the examples of Williams syndrome and specific language impairment. Neuroconstructivism, by contrast, focuses on the developing organism and is helping to change the way in which NDDs are investigated. Whereas neuropsychological static approaches assume that one or more 'modules' (e.g., visuospatial ability in Williams syndrome) are impaired while the rest of the system is spared (e.g., language in Williams syndrome), neuroconstructivism proposes that basic-level deficits have subtle cascading effects on numerous domains over development. Neuroconstructivism leads researchers to embrace complexity by establishing large research consortia to integrate findings at multiple levels (e.g., genetic, neural, cognitive, environmental) across developmental time. WIREs Cogn Sci 2017, 8:e1398. doi: 10.1002/wcs.1398 For further resources related to this article, please visit the WIREs website.
Topics: Brain; Brain Mapping; Electroencephalography; Humans; Magnetic Resonance Imaging; Models, Neurological; Neurodevelopmental Disorders; Neuropsychological Tests; Research Design; Williams Syndrome
PubMed: 27906503
DOI: 10.1002/wcs.1398 -
Matrix Biology : Journal of the... Oct 2018Elastic fibers provide recoil to tissues that undergo repeated deformation, such as blood vessels, lungs and skin. Composed of elastin and its accessory proteins, the... (Review)
Review
Elastic fibers provide recoil to tissues that undergo repeated deformation, such as blood vessels, lungs and skin. Composed of elastin and its accessory proteins, the fibers are produced within a restricted developmental window and are stable for decades. Their eventual breakdown is associated with a loss of tissue resiliency and aging. Rare alteration of the elastin (ELN) gene produces disease by impacting protein dosage (supravalvar aortic stenosis, Williams Beuren syndrome and Williams Beuren region duplication syndrome) and protein function (autosomal dominant cutis laxa). This review highlights aspects of the elastin molecule and its assembly process that contribute to human disease and also discusses potential therapies aimed at treating diseases of elastin insufficiency.
Topics: Aortic Stenosis, Supravalvular; Cutis Laxa; Elastin; Gene Dosage; Genetic Predisposition to Disease; Humans; Mutation; Williams Syndrome
PubMed: 29501665
DOI: 10.1016/j.matbio.2018.02.021 -
Medicina 2013
Topics: Chromosome Deletion; Humans; Williams Syndrome
PubMed: 23335714
DOI: No ID Found -
Genes Sep 2021The bromodomain adjacent to the zinc finger domain 1B (BAZ1B) or Williams syndrome transcription factor (WSTF) are just two of the names referring the same protein that... (Review)
Review
The bromodomain adjacent to the zinc finger domain 1B (BAZ1B) or Williams syndrome transcription factor (WSTF) are just two of the names referring the same protein that is encoded by the gene and is among the 26-28 genes that are lost from one copy of 7q11.23 in Williams syndrome (WS: OMIM 194050). Patients afflicted by this contiguous gene deletion disorder present with a range of symptoms including cardiovascular complications, developmental defects as well as a characteristic cognitive and behavioral profile. Studies in patients with atypical deletions and mouse models support BAZ1B hemizygosity as a contributing factor to some of the phenotypes. Focused analysis on BAZ1B has revealed this to be a versatile nuclear protein with a central role in chromatin remodeling through two distinct complexes as well as being involved in the replication and repair of DNA, transcriptional processes involving RNA Polymerases I, II, and III as well as possessing kinase activity. Here, we provide a comprehensive review to summarize the many aspects of BAZ1B function including its recent link to cancer.
Topics: Animals; Chromatin Assembly and Disassembly; DNA Repair; Humans; Neurogenesis; Transcription Factors; Williams Syndrome
PubMed: 34680936
DOI: 10.3390/genes12101541 -
Cell Oct 2022Williams-Beuren syndrome (WBS) is a rare disorder caused by hemizygous microdeletion of ∼27 contiguous genes. Despite neurodevelopmental and cognitive deficits,...
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.
Topics: Animals; Auditory Cortex; Disease Models, Animal; Humans; Induced Pluripotent Stem Cells; Interneurons; Mice; Phenotype; Trans-Activators; Williams Syndrome
PubMed: 36152627
DOI: 10.1016/j.cell.2022.08.022 -
Current Opinion in Endocrinology,... Feb 2021Williams syndrome is a multisystem disorder caused by a microdeletion on chromosome 7q. Throughout infancy, childhood, and adulthood, abnormalities in body composition... (Review)
Review
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.
Topics: Body Composition; Humans; Williams Syndrome
PubMed: 33165016
DOI: 10.1097/MED.0000000000000588 -
Current Biology : CB Dec 2007
Topics: Animals; Elastin; Face; Facies; Form Perception; Humans; Language; Lim Kinases; Mice; Space Perception; Williams Syndrome
PubMed: 18088580
DOI: 10.1016/j.cub.2007.09.037 -
The Turkish Journal of Pediatrics 2017Yuan SM. Congenital heart defects in Williams syndrome. Turk J Pediatr 2017; 59: 225-232. Williams syndrome (WS), also known as Williams-Beuren syndrome, is a rare... (Review)
Review
Yuan SM. Congenital heart defects in Williams syndrome. Turk J Pediatr 2017; 59: 225-232. Williams syndrome (WS), also known as Williams-Beuren syndrome, is a rare genetic disorder involving multiple systems including the circulatory system. However, the etiologies of the associated congenital heart defects in WS patients have not been sufficiently elucidated and represent therapeutic challenges. The typical congenital heart defects in WS were supravalvar aortic stenosis, pulmonary stenosis (both valvular and peripheral), aortic coarctation and mitral valvar prolapse. The atypical cardiovascular anomalies include tetralogy of Fallot, atrial septal defects, aortic and mitral valvular insufficiencies, bicuspid aortic valves, ventricular septal defects, total anomalous pulmonary venous return, double chambered right ventricle, Ebstein anomaly and arterial anomalies. Deletion of the elastin gene on chromosome 7q11.23 leads to deficiency or abnormal deposition of elastin during cardiovascular development, thereby leading to widespread cardiovascular abnormalities in WS. In this article, the distribution, treatment and surgical outcomes of typical and atypical cardiac defects in WS are discussed.
Topics: Child; Child, Preschool; Heart Defects, Congenital; Humans; Williams Syndrome
PubMed: 29376566
DOI: 10.24953/turkjped.2017.03.001 -
American Journal of Medical Genetics.... May 2010In the nearly 50 years since the description of Williams syndrome by [Williams et al. (1961); Circulation 24:1311-1318], the focus of scientific inquiry has shifted from...
In the nearly 50 years since the description of Williams syndrome by [Williams et al. (1961); Circulation 24:1311-1318], the focus of scientific inquiry has shifted from identification, definition, and description of the syndrome in small series to genotype-phenotype correlation, pathophysiologic investigation in both humans and in animal models, and therapeutic outcomes in large cohorts. Study of this rare syndrome has provided insight into the structure and function of the extracellular matrix, has contributed to understanding of genomic structure and rearrangement, and is beginning to elucidate genetic underpinnings of learning, language, and behavior. The results of current research not only recommend interventions that can be implemented now, but also identify areas requiring additional investigation, and suggest future therapeutic approaches.
Topics: Animals; Genetic Association Studies; Humans; Williams Syndrome
PubMed: 20425781
DOI: 10.1002/ajmg.c.30266