A novel approach for diagnosis and newborn screening for 22q11 deletion syndrome

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DESCRIPTION (provided by applicant): Digeorge syndrome/Velocardiofacial syndrome/22q11.2 deletion syndrome is a complex disorder due to a microdeletion of 1.5 or 3 Mb on the long arm of chromosome 22. This is one of the most common deletion syndromes affecting approximately 1:3000 live births. Affected individuals may be diagnosed shortly after birth due to the presence of a congenital heart defect. However, those individuals without a heart defect usually have a significant lag in time before diagnosis, despite multiple medical problems. Some of the associated conditions such as hypoparathyroidism or thymic aplasia require immediate therapy soon after birth. Other conditions such as the speech delay, school difficulties or the development of schizophrenia have their onset in childhood and adolescence, but would benefit from early recognition and treatment. Currently this microdeletion is detected through the use of fluorescent in situ hybridization demonstrating a hemizygous deletion on chromosome 22. While this assay is commercially available, it is expensive and time consuming to perform and requires a sample of whole blood. This makes the assay unsuitable for use in population screening. The specific aims of this proposal are to develop an assay using a DNA probe labeled with an infrared dye to detect a 2 fold copy difference in normal controls versus patients with the deletion using DNA extracted from dried blood spots. This assay could be used for diagnosis and as a population based screening test for this disorder. The sensitivity and specificity and reliability of the assay will be measured using a small cohort of known controls and affected patients (confirmed by FISH) with repeated measures, then assessed for reliability in a larger cohort of cases and controls and ultimately in an unknown population sample using newborn dried blood spots. The goal of this project is to develop an assay that is quick, sensitive, specific and can be run in a semiautomated fashion allowing for high throughput population screening. PUBLIC HEALTH RELEVANCE: Given the frequency of the 22q11 disorder, the relative complexity and the need for early intervention routine newborn screening for 22q11 Deletion syndrome is indicated. The high incidence of this disorder, along with the need for early intervention, makes 22q11.2 deletion syndrome a good candidate for newborn screening.