One-step test to screen newborns for rare genetic disorders

Researchers from the Murdoch Children’s Research Institute (MCRI) have developed a test to screen for three rare genetic disorders simultaneously in newborns. Using the test would enable earlier diagnosis and treatment, paving the way for the three chromosome 15 imprinting disorders — Prader-Willi, Angelman and Dup15q syndromes — to be added to newborn bloodspot screening programs for the first time.

The one-step test can be used to screen for the three conditions 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 validated the use of a low-cost, specialised screening method called Methylation Specific-Quantitative Melt Analysis (MS-QMA) for these disorders at a large scale, with the results published in The Journal of the American Medical Association.

The three rare disorders are characterised by varying degrees of intellectual disability, autism, behavioural problems, seizures and/or severe obesity. About 135 babies are born with one of these disorders each year in Australia, but they are not included in newborn screening programs due to 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 recognised by a child’s doctor, and subsequently referred for appropriate testing,” said MCRI Associate Professor David Godler. “This is not the case with newborn screening, where testing is performed on all newborns before symptoms become apparent.”

Assoc Prof Godler said 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 first checked for accuracy, with the test correctly distinguishing most of the 167 samples from people who had one of the disorders.

The test was then used on 16,579 newborns in Victoria with the test identifying two with Prader-Willi, two with Angelman and one with Dup15q. In the 16,579 newborns screened, the probability of those with a positive test truly having the disease 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 a 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 minimising the psychological effect on families,” Assoc Prof Godler said.

MCRI Professor David Amor said that if these findings were replicated in future studies, adding these 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 said. “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, [and] reduce medical costs and the significant stress and anxiety currently experienced by the families while they await a diagnosis.”

Image credit: ©stock.adobe.com/au/mocker_bat

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