Defining the Brain Phenotype of Children With Williams Syndrome

  • participants needed
  • sponsor
    National Institute of Mental Health (NIMH)
Updated on 1 July 2022
genetic disorder
social interaction
Accepts healthy volunteers


  • Little is known about how the brain changes during childhood and adolescence, how genes affect this process, or how the brains of people with Williams syndrome change during this period. Genetic features of Williams syndrome affect the brain s development, but the details of this process have not been studied over time. Researchers are interested in using magnetic resonance imaging to study how the brain changes in healthy children and children with Williams syndrome and related genetic disorders.
  • To study developmental changes in the brains of healthy children and children who have been diagnosed with Williams syndrome or a related genetic disorder.
  • Healthy children and adolescents between 5 and 17 years of age.
  • Children and adolescents between 5 and 17 years of age who have been diagnosed with Williams syndrome or genetic characteristics that overlap with Williams syndrome.
  • Participants will have a brief physical examination and tests of memory, attention, concentration, and thinking. Parents will be asked about their child s personality, behavior characteristics, and social interaction and communication skills.
  • Both participants and their parents may be asked to complete additional questionnaires or take various tests as required for the study.
  • Participants will have approximately 10 hours of magnetic resonance imaging (MRI) scanning, usually over 4 to 5 days, within a one month period. Some of these tests will require the participants to do specific tasks while inside the MRI scanner.
  • Participants will be asked to return to the National Institutes of Health clinical center to repeat these procedures every 2 years thereafter until age 18.


Williams syndrome (WS) is a rare disorder caused by hemizygous microdeletion of approximately 1.6 megabases on chromosomal band 7q11.23, typically by spontaneous mutation. The disorder is characterized by a collection of unique neuropsychiatric manifestations, including marked visuospatial construction deficits and hypersociability. Because the genes involved in WS are known, the study of neural mechanisms in WS affords a privileged setting for investigating genetic influences on complex brain functions in a bottom-up way.

Previous neuroimaging studies of adults with WS resulted in a clear delineation of the WS brain phenotype. Underlying the syndrome s cognitive hallmark, visuospatial construction impairment, is a neurostructural anomaly (decreased gray matter volume) and adjacent abnormal neural function in the parietal sulcus region of the dorsal visual processing stream. Subtle structural hippocampal alterations, along with abnormalities in regional cerebral blood flow, neurofunctional activation, and N-acetyl aspartate concentration also contribute to the visuospatial phenotype. Underlying the syndrome s social cognition features are structural and functional abnormalities in the orbitofrontal cortex, an important affect and social regulatory region that participates in a fronto-amygdala regulatory network found to be dysfunctional in WS.

The findings in adult WS patients have created a paradigm for identifying brain phenotypes linked to specific genes and for guiding research aimed at understanding the mechanism by which gene effects are translated in the brain to clinical phenomena. However, it is clear that the cognitive and behavioral disturbances in WS emerge over the course of childhood and adolescence from a complex interplay of altered neural systems, which must be studied from a developmental and translational perspective. To meet this imperative, we propose a cross-sectional and longitudinal neuroimaging study of children with WS to track the emergence and modification of the altered neural circuitry observed in the adult population. With non-invasive multimodal magnetic resonance imaging including structural MRI, functional MRI (fMRI), and diffusion tensor MRI-we propose to target those neural systems associated with key clinical features (e.g. visuospatial construction impairment and abnormal social cognition). We will employ experimental methods previously successful in assessing cognitive and emotional processing in the adult population. For neurofunctional studies, each task paradigm is optimized to provide adequate statistical power for single subject mapping, and to be amenable for young children. Additionally, structural MRI studies allowing for in depth tracking of structural changes, including changes in gray-white matter ratios and the integrity of white matter tracts throughout the brain. Blood samples for genetic analysis will be collected. One hundred children with classic WS deletions, those with smaller deletions, and those with duplications, along with 50 of their unaffected siblings, will be studied at the NIH Clinical Center at two-year intervals for repeat neuroimaging studies. Additionally, approximately 115 unrelated, healthy children will also be studied. fMRI tasks will be piloted on fifteen of the latter. We will continue to study the children enrolled in this protocol after they turn 18 in order to determine the developmental trajectory of brain structure and function from childhood through adulthood. Additionally, fifty adults with classic WS deletions, those with smaller deletions, and those with duplications will be studied at the NIH Clinical Center at two-year intervals for repeat neuroimaging studies in order to establish good adult end-points for our imaging protocol. Studying adults with WS and abnormalities of the WS genetic region with the same tasks and scanner as used for children will allow us to establish an adult WS comparison group against which children can be directly compared and also allow us to better determine the maturation of neural structure and function in WS through adulthood. Typically developing children whom we will continue to study after they turn 18 will serve as the control comparison group for adults with WS.

Primary outcome measures include size and integrity of grey and white matter; afunctional MRI BOLD responses during rest, cognitive and emotion information processing; DTI anisotropy measures of white matter tracts; tissue perfusion (blood flow) measured with arterial spin labeling (ASL); and mcDespot myelin water fraction.

Secondary outcome measures include relationship of neuropsychological assessments and genotyping to the imaging results.

Our prior success in delineating the brain phenotype in adult WS patients will provide the crucial context within which to view the emergence and modification of these neural circuit abnormalities from a developmental perspective in children with WS and from which to launch translational studies of specific gene effects on brain and behavioral phenotypes.

Condition Williams Syndrome
Clinical Study IdentifierNCT01132885
SponsorNational Institute of Mental Health (NIMH)
Last Modified on1 July 2022


Yes No Not Sure

Inclusion Criteria

For all participants, the following inclusion criteria will apply
Greater than 5 years old
Able to provide assent if below the age of 18, or consent if 18 years of age or older. Parents will provide consent for participants below the age of 18. For patients who do not have the capacity to provide informed consent, consent may be obtained from a guardian or the holder of the DPA
Additionally, 7q11.23 CNV participants must have a typical 7q11.23 CNV or other genetic
abnormality in the WS critical region of chromosome 7q11.23, and control participants must
have normal intelligence

Exclusion Criteria

For all participants who will participate in MRI scanning, the following exclusion criteria
will apply
Any chronic or acute medical condition severe enough to interfere with task
performance or interpretation of MRI data
Any medication that might interfere with task performance or interpretation of MRI
Any medical condition that increases risk for MRI (e.g. pacemaker, metallic foreign
body in eye or other body part, dental braces)
Pregnancy (a urine pregnancy test will be performed prior to all MRI procedures for
that would make collecting blood unsafe
all females of child-bearing potential
NIMH employees and staff and their immediate family members will be excluded from the
study per NIMH policy
For parents who will undergo blood draws only, they will not be able to participate if they
have a condition
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