Williams syndrome

Beth A. Kozel, Boaz Barak, Chong Ae Kim, Carolyn B. Mervis, Lucy R. Osborne, Melanie Porter, Barbara R. Pober*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

159 Scopus citations

Abstract

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.

Original languageEnglish
Article number42
JournalNature Reviews Disease Primers
Volume7
Issue number1
DOIs
StatePublished - Dec 2021

Funding

FundersFunder number
Genetics of Neurodevelopmental Disorders
Williams Syndrome Association0111
Williams Syndrome Australia Limited
Williams Syndrome Charitable Foundation
National Institutes of Health
National Heart, Lung, and Blood InstituteZIAHL006210
Canada Research Chairs
Fundação de Amparo à Pesquisa do Estado de São Paulo2019/21644-0
Fritz Thyssen Stiftung
Conselho Nacional de Desenvolvimento Científico e Tecnológico304897/2020-5
Israel Science Foundation2305/20

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