Prader-Willi syndrome (PWS) is caused by absence of a paternal contribution of 
the chromosome region 15q11-q13, resulting from paternal deletions, maternal 
uniparental disomy, or rare imprinting mutations. Laboratory diagnosis is 
currently performed using fluorescence in situ hybridization (FISH), DNA 
polymorphism (microsatellite) analysis, or DNA methylation analysis at locus 
PW71 (D15S63). We examined another parent-of-origin-specific DNA methylation 
assay at exon alpha of the small nuclear ribonucleoprotein-associated 
polypeptide N gene (SNRPN) in patients referred with clinical suspicion of PWS 
or Angelman syndrome (AS). These included 30 PWS and 17 AS patients with known 
deletion or uniparental disomy status, and a larger cohort of patients (n = 512) 
suspected of PWS who had been analyzed previously for their methylation status 
at the PW71 locus. Results of SNRPN methylation were consistent with known 
deletion or uniparental disomy (UPD) status as determined by other molecular 
methods in all 47 cases of PWS and AS. In the larger cohort of possible PWS 
patients, SNRPN results were consistent with clinical diagnosis by examination 
and with PW71 methylation results in all cases. These data provide support for 
the use of SNRPN methylation as a diagnostic method. Because methylation 
analysis can detect all three major classes of genetic defects associated with 
PWS (deletion, UPD, or imprinting mutations), methylation analysis with either 
PW71 or SNRPN is an efficient primary screening test to rule out a diagnosis of 
PWS. Only patients with an abnormal methylation result require further 
diagnostic investigation by FISH or DNA polymorphism analysis to distinguish 
among the three classes for accurate genetic counseling and recurrence-risk 
assessment.