A newly developed test to screen for three rare genetic disorders simultaneously in newborns was feasible, reliable, and scalable, recent research shows. 

The research reported that screening for Prader Willi, Angelman, and Dup15q syndromes using the new type of test—called Methylation Specific-Quantitative Melt Analysis (MS-QMA)—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—led by the Murdoch Children’s Research Institute (MCRI) and published in The Journal of the American Medical Association Network Open—was the first to validate the use of the specialized screening method 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 disorders are characterized by varying degrees of intellectual disability, autism, behavioral problems, seizures, and/or severe obesity. About 135 babies are born with one of these disorders each year in Australia, but the disorders are not included in newborn screening programs, and many go undiagnosed in the first year of life. 

MCRI associate professor David Godler, PhD, says 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.

“Tests are currently only performed on those suspected of having these disorders, and only if features are recognized by a child’s doctor, and subsequently referred for appropriate testing,” says Godler. “This is not the case with newborn screening where testing is performed on all newborns before symptoms become apparent.” 

Godler says 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.  

“Having a high positive predictive value is important for newborn screening as it ensures that there is lower number of false positive results that need to be repeated, leading to lower overall laboratory costs, less work for maternity services in obtaining a repeated blood sample and minimizes the psychological effect on families,” he added.

MCRI professor David Amor, PhD, says that 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,” he says. “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.”

Researchers from The Royal Children’s Hospital, the University of Melbourne, E.D.G. Innovations and Consulting, Hunter Genetics, University of Kansas Medical Centre, University of Padua, Città della Speranza, Greenwood Genetic Center, University of Chile and the Victorian Clinical Genetics Services also contributed to the study.   

Featured image: A newly developed test to screen for three rare genetic disorders simultaneously in newborns was feasible, reliable and scalable, according to a new study. Photo: Picsea