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

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:

1. 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.

2. 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.

Eligibility:

People ages 0-85 with either WS, SVAS, and/or an SVAS-like condition, unaffected family members or adult unrelated controls.

Design:

This study is not a treatment protocol.

This study will consist of:

Collection of personal history (questionnaires) and medical record data (relevant physician notes, lab and diagnostic tests and studies) to study the natural history of these conditions, allow stratification of disease severity, and identification of environmental risk factors;

Collection of blood, saliva, urine and surgical tissue waste to allow DNA and RNA preparation as well as study of tissues both in situ and through the generation of IPSCs;

Expression studies on available tissues (lymphocytes, IPSCs, vascular, skin, other collected tissues) to look for differential regulation of target genes;

Direct imaging of tissues (lymphocytes, IPSCs, vascular, skin, other collected tissues);

Storage of collected data and specimens for future research;

A questionnaire may be sent to participants or parent/guardian or LAR to respond on behalf of participant....