Re-evaluate Clinically UBE3A testing
\ No mutation
AC no evidence
AS with AC
FISH/UPD testing May be necessary
UBE3A mutation Test parents
Sporadic imprinting defect
. IC mutation testing
+IC mutation Test parents important reasons: 1) to rule out familial chromosomal abnormalities, associated with increased recurrence risk; 2) to rule out a non-AS chromosomal abnormality that may mimic the AS phenotype. DNA methylation testing is done as an initial evaluation for all patients with suspected AS and will identify up to 80% of the AS cases: the ones with deletion, UPD, and imprinting defect. DNA methylation is a genomic process that mediates epigenetic regulations of gene expression. It involves the cytosines in the CpG islands and is generally associated with down regulation of gene expression. A CpG area at the 5' end of the SNRPN gene in the proximal 15q region is methylated if maternally derived and not methylated if paternally derived. This gene region is used to look for DNA methylation abnormalities in AS or PWS. In AS cases of deletions, paternal UPD-15, and imprinting defects the DNA methylation patterns are abnormal reflecting the deficiency of the maternally specific (methylated) 15q region. Diagnostic DNA methylation testing is traditionally done using a Southern-blotting protocol, based on the use of methylation-sensitive restriction enzymes. More recently, PCR-based methylation tests have been developed based on methylation-specific DNA sequence changes introduced by sodium bisulfite modification. Such tests require minimal amounts of DNA and have been used to retest archived patient cells after negative FISH analyses. FISH analysis using commercially available probes specific for the SNRPN locus is done to look for 15q11q13 deletions after a positive DNA methylation testing, (Fig. 2).
UPD analysis is done in cases of abnormal DNA methylation and normal FISH analysis. This testing protocol uses DNA polymorphisms to trace the inheritance of chromosome 15. DNA specimens from both parents are necessary.
IC mutation screening. In methylation positive, FISH, and UPD-negative cases a search for IC deletion can be done, but is not currently available for routine use.
UBE3A mutation screening. In cases of normal DNA-methylation patterns, the patient phenotype needs reevaluation in order to decide whether UBE3A testing is warranted. If typical AS features are observed UBE3A mutation screening can be considered.1-20,21-1
Fig. 2 Algorithm for the diagnostic evaluations for AS. Abbreviations: MT=DNA methylation testing; + positive; — negative; NC = normal chromosome analysis; AC = abnormal chromosome analysis; UPD = uniparental disomy; IC = imprinting center.
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