Williams syndrome

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.

Figure 1.. Salient features of Williams syndrome.

The age of peak prevalence and frequency of prominent signs or symptoms in organ systems affected in Williams syndrome are indicated. Features in bold are the common presenting features listed in the Clinical Diagnosis sectionin the main text. Further reading for features in plain text is included in Supplementary box 1. ^aEstimates of co-occurring autism spectrum disorder (ASD) vary (12–20%). Most individuals with Williams syndrome who have ASD fit in Wing and Gould’s active-but-odd subtype of ASD rather than the aloof subtype of ASD^,. As such, the diagnosis of, and interventions for, ASD in Williams syndrome are complex and ideally benefit from engagement of practitioners who are knowledgeable about both disorders. ^bSound sensitivities include one or more of the following: hyperacusis, odynacusis, auditory allodynia and auditory fascinations. ADHD, attention deficit hyperactivity disorder; CV, cardiovascular; DM, diabetes mellitus; GERD, gastro-oesophageal reflux disease; ID, intellectual disability. Note: Figure 1 was re-drawn by the Nature Reviews Disease Primers art editor and permission for reproduction of the final figure was not granted by the publisher. Please see the published version of the paper for the final Fig. 1 at DOI: 10.1038/s41572-021-00276-z

Figure 4.. Phenotypic consequences of deleting key genes in the Williams syndrome critical region.

Putative or elucidated genotype–phenotype relationships for six genes in the Williams syndrome critical region (WSCR) are depicted, including elastin (ELN), general transcription factor II-I (GTF2I), BAZ1B, LIM domain kinase 1 (LIMK1), syntaxin 1A (STX1A) and carbohydrate-responsive element-binding protein (ChREBP). Phenotypes in mouse models and in individuals with Williams syndrome are indicated for ELN and the GTF2I genes because, presently, their mechanisms of action are best delineated and they offer the best targets for therapy. Note: Figure 4 was redrawn by the Nature Reviews Disease Primers art editor and permission for reproduction of the final figure was not granted by the publisher. This version was designed using BioRender. This material is labeled as Fig. 3 in the published version of the paper DOI: 10.1038/s41572-021-00276-z

Figure 5.. Facial features of children and adults with Williams syndrome of different ethnic backgrounds.

Facial photos of individuals with molecularly-confirmed Williams syndrome of different racial and/or ethnic backgrounds aged 2 months to 52 years. Distinctive features in infants and children include broad forehead, peri-orbital fullness, flat bridge of the nose, full cheeks, long philtrum, and a small delicate chin. Many adolescents and adults continue to have micrognathia, and the face often elongates over time while the nasal bridge is no longer flat, and there is fullness of the lips with a wide mouth (especially appreciated when smiling). Parents or caregivers for all pictured individuals signed consent for publication of their family member’s image. The presence of more male than female photos in adolescents and adults solely reflects availability of subjects. Note: This material is labeled as Fig. 4 in the published version of the paper DOI: 10.1038/s41572-021-00276-z.

Figure 6.. Developmental milestones for very young children with Williams syndrome.

Median ages (in months) and 90^th and 10^th percentiles for attainment of various gross motor, fine motor, cognitive and language milestones by very young children with Williams syndrome (yellow bars) relative to typically developing children (aqua bars)^,–. Numbers in red typeface indicate median age; numbers in black typeface indicate 90^th percentile (to the left of the median) and 10^th percentile (to the right of the median). TD, typically developing. Note: Figure 6 was redrawn by the Nature Reviews Disease Primers art editor and permission for reproduction of the final figure was not granted by the publisher. This material is labeled as Fig. 5 in the published version of the paper DOI: 10.1038/s41572-021-00276-z