Prader-Willi (PWS) and Angelman (AS) syndromes are different genetic disorders caused by opposite effects of DNA methylation at the same genomic location. Both have a reported frequency of approximately 1 in 15,000 births and are associated with intellectual disability. PWS is the most common genetic cause of life-threatening obesity; importantly, it can be effectively treated with hormone therapy and restricted diet if detected early. There is a strong case for including PWS and AS into newborn screening programs as there are clear benefits for affected infants and their families through early diagnosis and intervention. A key requirement for any new condition to be included in newborn screening is a test with high sensitivity and low cost ($1 to $3 per individual). The test must be ethical and ideally based on one or two 3 mm punches of dried blood spot material. Although DNA methylation testing of the SNRPN gene regulatory region detects most PWS (99%) and AS (78%) cases, use of one 3 mm punch of newborn blood spot material has not been validated. Dr Godler’s team has developed a novel, low-cost methylation test named Methylation Specific Quantitative Melt Analysis (MS-QMA) and shown that methylation testing of FMR1 can be used to effectively diagnose Fragile X syndrome (FXS), another relatively common genetic disorder (1 in 4000 in the general population). This test has been applied in more than 3000 cases using DNA from blood, cheek cells, saliva and newborn blood spots. Two important questions will be asked in this study: (1) Is MS-QMA a feasible approach for combined FMR1/SNRPN newborn screening? (2) Does SNRPN methylation change over time, and if so, in what proportion of patients? The first question will be addressed using 5000 newborn blood spots from control babies from the general population, 50 PWS, 50 AS and 50 FXS babies. A combined FMR1/SNRPN methylation test performed on the same 3 mm blood spot punch would have reagent costs of only $2 per test per condition. This would be far more cost-effective than testing for each condition separately. The next step would be inclusion of the SNRPN methylation test into a large scale FXS (50,000 babies) prospective newborn screening pilot being planned for late 2016 to early 2017. The second question will be addressed by examining the correlations between MS-QMA methylation data in dried blood spots of affected children of age 1 to 10 years and that in their newborn blood spots retrieved from Victorian Clinical Genetic Services repositories. The significance of question 2 is related to improved understanding of the epigenetic changes as children with AS and PWS grow up. Methylation at some genomic locations is stable from birth over time, while methylation at others changes with the child’s development. This has not been studied for the PWS and AS and is relevant for determining prognosis for AS and PWS babies.