Genetic Diagnostic Testing
Laboratory diagnostic testing for AS can be complex. One approach to laboratory evaluation of an individual in whom the diagnosis of AS is suspected (above) starts with a DNA methylation analysis of the AS/PWS imprinting center region. The DNA methylation test is positive in AS when one of three mechanisms is present: the large common deletion, uniparental disomy, and defects in the imprinting center. If the methylation test is positive, additional studies are needed to define the specific genetic mechanism. In such situations, the next step typically is to perform a FISH (fluorescent in situ hybridization) chromosome test in order to see if the common 15q11.2-13 deletion is present (other methods can detect this deletion, such as array-based comparative genomic hybridization [CGH]). If the FISH test is normal, the next step is to rule out paternal uniparental disomy (UPD) by additional molecular testing involving parental bloods. Individuals with a positive AS DNA methylation study who have normal FISH and normal uniparental disomy studies are then presumed to have an imprinting defect. The imprinting defect can be further studied to determine if there is a DNA deletion involving the imprinting center. If the methylation test is negative, mutation analysis of the UBE3A gene may detect an abnormality. Molecular testing for IC region deletions is available clinically from a small number of laboratories.