New One-Step Test Screens for Three Rare Genetic Disorders Simultaneously In Newborns

The research, led by the Murdoch Children’s Research Institute (MCRI; Victoria, Australia), reported that screening for Prader Willi, Angelman and Dup15q syndromes using the new type of test would open new avenues for earlier diagnosis and treatment, paving the way for the three chromosome 15 imprinting disorders to be added to newborn bloodspot screening programs (heel prick test) for the first time.

The study was the first to validate the use of a low-cost, specialized screening method called Methylation Specific-Quantitative Melt Analysis (MS-QMA), developed by MCRI researchers, for these disorders at a large scale. The one-step test can be used to screen for the three conditions simultaneously, by looking at the number of chemical modifications or marks called methylation added to affected genes, which are not present at such high or low levels in children without these disorders.

The study first checked for accuracy, with the test correctly distinguishing most of the 167 samples from people who had one of the disorders. It was then tested on 16,579 newborns in Victoria with the test identifying two with Prader Willi, two with Angelman and one with Dup15q. The three rare disorders are characterized by varying degrees of intellectual disability, autism, behavioral problems, seizures and/or severe obesity. These disorders are not included in newborn screening programs, and many go undiagnosed in the first year of life. A key reason why these disorders were not included in current newborn screening programs was the lack of a test with low laboratory costs that could work at a population scale.

The study found the cost, disorder prevalence and accuracy of MS-QMA as a first-tier test were in line with other conditions currently included in newborn screening programs. The study reported that in the 16,579 newborns screened, the probability of those with a positive screening test, truly having the disease using MS-QMA, was 67%, 33% and 44% for Angelman, Prader Willi and combined detection of chromosome 15 imprinting disorders, respectively. If these findings were replicated in future independent studies, adding these chromosome 15 imprinting disorders to newborn screening programs would allow for earlier diagnosis and using targeted interventions as they emerge, such as gene therapy for Angelman syndrome.

“For Prader Willi, diagnosis in infancy allows for early initiation of growth hormone treatment to improve long term health outcomes,” said MCRI Professor David Amor. “For Angelman and Dup15q, most infants do not receive an early diagnosis that would allow intervention in the first year of life. But such early diagnosis, if available through newborn screening, could prevent the diagnostic odyssey, reduce medical costs and the significant stress and anxiety currently experienced by the families while they await a diagnosis.”

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Murdoch Children’s Research Institute