Williams Syndrome (WS) and Supravalvar Aortic Stenosis (SVAS) DNA and Tissue Bank

NCT02706639 | Completed

• 2 other identifiers: 16007416-H-0074
• Study Type: observational
• Target: 305
• Locations: 1 country
• Sites: 3

Brief Summary

Williams syndrome is a rare genetic disorder occurring in 1:8000-12,000 individuals. It is caused by the deletion of 25-27 coding genes, including elastin (ELN) on the 7th human chromosome. Haploinsufficiency for these genes leads to the features of the condition, including:

• Distinctive facial features;
• Characteristic vascular problems including hypertension, focal vascular stenosis, (when present in the aorta this is referred to as SVAS), vascular stiffness and differences in heart rate variability;
• Endocrine abnormalities including hypercalcemia, hypothyroidism, and early puberty;
• Metabolic concerns with colic and failure to gain weight in infancy and obesity and early glucose intolerance in adulthood;
• Characteristic neurocognitive profile comprised of cognitive impairment, high sociality with concurrent social awkwardness, difficulty with visual-spatial tasks, relative strengths in speech, and lack of social fear;
• Anxiety and chronic pain in adulthood Most individuals with WS carry the same basic deletion on Chromosome 7q11.23. However, each feature may present as mild or more severe in any given individual. Variation in the presence and severity of these vascular phenotypes remains unexplained. The supravalvar aortic stenosis (SVAS) phenotype is caused by haploinsufficiency for elastin. This can come about due to the WS deletion (as above) or due to heterozygous variation in elastin (ELN) gene itself in this region. When this protein is reduced, connective tissues lose its strength, flexibility, and overall support. When this happens in the aorta, it may cause vascular narrowing that presents as shortness of breath, chest pain, and even heart failure if left untreated. Narrowing also occurs in other vessels especially the pulmonary and renal arteries. Changes in non-vascular elastic tissues such as the skin and lungs also occur. As in WBS, phenotypic variation also occurs in people with ELN gene changes--This variability remains unexplained despite all the on-going research. Most individuals with features of SVAS have either WS or an elastin variant. There are, however, a smaller number of individuals with the phenotypic features of the condition whose genetic underpinnings are yet to be defined (they are referred to as SVAS-like). Additionally, there are 26 other coding genes within the WS critical region that contribute to various other features of the condition Objective:
• To collect historical information and to bank DNA, cells, and tissue from individuals with genetic alterations in the WS/ELN gene region, those with an SVAS -like phenotype and unaffected family members/controls to facilitate future research into the many phenotypes seen in these individuals.
• Currently, we plan to use the collected samples to identify genetic and environmental factors that contribute to the variability in different phenotypes (vascular and non-vascular) in individuals with WS, SVAS and SVAS-like conditions, individuals with variation in WS genes other than elastin and unaffected family members and controls. For the non-vascular features of WS and SVAS-like conditions for which a specific gene has not been implicated in the disease, we would also like to identify causative genes as well as modifiers. Likewise, by evaluating people with variation in other WS region genes, we can determine what contribution those genes make to the studied phenotypes. Controls will be both used to assess the frequency of genetic features in people without the phenotype in question and to evaluate heritability, penetrance, and expressivity of relevant variants.

Conditions

Cardiovascular Disease; Supravalvular Aortic Stenosis; Williams Syndrome

Keywords

Biospecimen Procurement; Laboratory Research Specimens; Sample Collection; Rare Diseases; Natural History

Outcome Measures

Primary Outcomes (1)

• To collect historical information and bank specimens form individuals with Williams Syndrome and SVAS for future research

  The overall objective of this study is to collect historical information and to bank DNA, cells and tissue from individuals with WS and SVAS to facilitate future research into the many phenotypes seen in these individuals.

  ongoing

Secondary Outcomes (1)

• To identify genetic and environmental factors that contribute to the variability in different phenotypes in individuals with WS, SVAS, and SVAS-like conditions

  ongoing

Study Arms (5)

SVAS/SVAS-like group

Children or adults must: be between the ages of 0-85; have clinical features of SVAS; SVAS-like condition; have genetic testing results that imply affected status (SVAS has decreased penetrance)

Unaffected related (family member) controls

Children or adults: family members be between the ages of one month old and 85 years old, not carry a diagnosis of WS, SVAS, an SVAS-like condition or a known (at the time of enrollment) WS gene region variant.

Unaffected unrelated controls

Adults, 18-85: unrelated controls be between the ages 18 and 85 years old, not carry a diagnosis of WS, SVAS, an SVAS-like condition or a known (at the time of enrollment) WS gene region variant.

WS group

Children or adults must: be between the ages of 0 and 85; have a presumed or confirmed diagnosis of WS; have a parent/guardian available to provide consent and assist in answering medical questions

WS region gene changes

Children or adults must: be between the ages of 0-85; have clinical or research genetic testing that reports gene variation in one or more genes in the WS region (ELN variants alone will be considered in the SVAS category but other changes to the region that include ELN plus other genes may be grouped in this category).

Eligibility Criteria

• Age: 1 Day - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Affected: 1) people with WS (adults and children), 2) people with ELN-related SVAS (adults and children), 3) people with SVAS-like conditions (those with an SVAS phenotype but no known pathologic variant in ELN, (adults and children)) 4) individuals with single or oligogenic variation in WS genes other than ELN (adults and children) Unaffected: 5) unaffected family members of participating subjects (children or adults), enrolled as controls 6) unrelated unaffected adult controls.

You may qualify if:

• We will recruit individuals with WS, SVAS or SVAS-like conditions, individuals with variation in WS genes other than ELN and unaffected family members or unrelated controls
• Children or adults participating in this study as part of the WS group must:
• be between the ages of 0 and 85
• have a presumed or confirmed diagnosis of WS (typical or atypical deletions overlapping the WS region are acceptable, as are clinical diagnoses made by a physician familiar with WS) have a parent/guardian available to provide consent and assist in answering medical questions
• Children or adults participating in the study as part of the SVAS/SVAS-like group must:
• be between the ages of 0 and 85
• have clinical features suggestive of SVAS or an SVAS-like condition OR have no clinical features of SVAS or of an SVAS-like condition but have genetic testing results that imply affected status (SVAS has decreased penetrance).
• Have a parent/guardian available to provide consent and assist in answering medical questions if they are a minor (not applicable to adults)
• Children or adults with WS region gene changes (variation affecting one or more WS region genes):
• be between the ages of 0 and 85
• have clinical or research genetic testing that reports gene variation in one or more genes in the WS region (ELN variants alone will be considered in the SVAS category but other changes to the region that include ELN plus other genes may be grouped in this category).
• Have a parent/guardian available to provide consent and assist in answering medical questions if they are a minor or if they have cognitive impairment that would impede their ability to consent on their own behalf.
• Children or adults serving as unaffected family members or adult unrelated controls must:
• family members be between the ages of one month old and 85 years old
• unrelated controls be between the ages 18 and 85 years old

Sponsors & Collaborators

• National Heart, Lung, and Blood Institute (NHLBI): lead

Study Sites (3)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110-1010, United States

Location

Nationwide Children's Hospital

Columbus, Ohio, 43205, United States

Location

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Williams Syndrome; Aortic Stenosis, Supravalvular; Cardiovascular Diseases; Rare Diseases

Condition Hierarchy (Ancestors)

Intellectual Disability; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Aortic Valve Stenosis; Aortic Valve Disease; Heart Valve Diseases; Heart Diseases; Chromosome Disorders; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn; Ventricular Outflow Obstruction; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Manfred Boehm, M.D.

  National Heart, Lung, and Blood Institute (NHLBI)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 8, 2016
• First Posted: March 11, 2016
• Study Start: May 11, 2016
• Primary Completion: March 7, 2025
• Study Completion: March 7, 2025
• Last Updated: May 1, 2026

Record last verified: 2026-04-29

Locations

US (3)