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Williams syndrome

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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.

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Fig. 1: Salient features of Williams syndrome.
Fig. 2: Genomic organization of the Williams syndrome critical region.
Fig. 3: Phenotypic consequences of deleting key genes in the Williams syndrome critical region.
Fig. 4: Facial features of children and adults with Williams syndrome of different ethnic backgrounds.
Fig. 5: Developmental milestones for very young children with Williams syndrome.
Fig. 6: Prevalence of psychiatric diagnoses in individuals with Williams syndrome throughout the lifespan.

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Acknowledgements

The authors thank the anonymous individual with WS and her parents who provided the family experience interview as well as those who provided facial photographs for Fig. 4 and Supplementary Table 1. The authors thank the persons with WS and their families belonging to the Associação Brasileira de Síndrome de Williams, Canadian Association for Williams Syndrome, WIlliams Syndrome Australia Limited, and Williams Syndrome Association (USA) for continued participation in studies and the support of research that allows the knowledge of WS to grow. The authors thank Z. Urban for discussion of elastin biology and management strategies for vascular disease in WS. B.A.K. was supported by the Department of Intramural Research at the National Heart, Lung and Blood Institute of the National Institutes of Health. C.B.M. was supported by the Williams Syndrome Association (grant number 0111). B.R.P. was supported by the Williams Syndrome Association and the Williams Syndrome Charitable Foundation, USA. M.P. was funded by Williams Syndrome Australia Limited. B.B. was funded by the Fritz Thyssen Stiftung and the Israel Science Foundation (Grant No.2305/20). L.R.O. was supported by a Canada Research Chair in the Genetics of Neurodevelopmental Disorders. C.A.K. was supported by FAPESP 2019/21644-0 and CNPq 304897/2020-5.

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Authors and Affiliations

  1. Translational Vascular Medicine Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA

    Beth A. Kozel

  2. The Sagol School of Neuroscience and The School of Psychological Sciences, Tel Aviv University, Tel Aviv, Israel

    Boaz Barak

  3. Department of Paediatrics, Universidade de São Paulo, São Paulo, Brazil

    Chong Ae Kim

  4. Department of Psychological and Brain Sciences, University of Louisville, Louisville, KY, USA

    Carolyn B. Mervis

  5. Department of Medicine, University of Toronto, Toronto, Ontario, Canada

    Lucy R. Osborne

  6. Department of Psychology, Macquarie University, Sydney, Australia

    Melanie Porter

  7. Department of Paediatrics, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Barbara R. Pober

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Contributions

B.A.K. and B.R.P. developed the outline for the manuscript, engaged the contributors and synthesized the final manuscript. All authors participated in the research, writing, and editing of the document and all approved the final version of the manuscript. C.A.K. provided clinical photos and M.P. conducted the family experience interview.

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Correspondence to Barbara R. Pober.

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The authors affirm that human research participants provided informed consent for: publication of the photographs in Fig. 4 and Supplementary Table 1 and taking part in the family experience interview.

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Nature Reviews Disease Primers thanks A. Selicorni, D. Gothelf, J. Van Herwegen, P. Ortiz-Romero, who co-reviewed with V. Campuzano, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Kozel, B.A., Barak, B., Kim, C.A. et al. Williams syndrome. Nat Rev Dis Primers 7, 42 (2021). https://doi.org/10.1038/s41572-021-00276-z

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