Low-cost test could open new avenues for earlier diagnosis and treatment of rare genetic diseases

A newly developed test to simultaneously screen for three rare genetic diseases in newborns was feasible, reliable and scalable, according to a new study.

The research, led by the Murdoch Children’s Research Institute (MCRI), 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 three-chromosome imprinting 15. disorders to be added for the first time to newborn bloodstain screening programs (heel prick test).

The study, published in The Journal of the American Medical Association Network Openwas 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 large-scale disorders.

The one-step test can be used to screen for all three conditions simultaneously, looking at the number of chemical changes or marks called methylation added to affected genes, which are not present at such high or low levels in children without these disorders. .

The Victorian Government has awarded MCRI a $100,000 grant under the Victorian Medical Research Acceleration Fund 2018 to support the development of the new rare disease screening method. Medical Research Minister Jaala Pulford recently visited MCRI to see how the test was working and learn more about its potential.

The study first checked for accuracy, with the test correctly distinguishing most of the 167 samples from people with one of the disorders. It was then tested on 16,579 newborn babies in Victoria, with the test identifying two with Prader Willi, two with Angelman and one with Dup15q.

All 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 are not diagnosed in the first year of life.

MCRI associate professor David Godler said one of the main reasons these disorders are not included in current newborn screening programs is the lack of a low-cost laboratory test that might work. at the population level.

Testing is currently only done on people suspected of having these disorders, and only if the characteristics are recognized by the child’s doctor and then referred for appropriate testing. This is not the case with newborn screening where tests are performed on all newborns before symptoms become apparent.”

David Godler, associate professor at MCRI

Associate Professor Godler said the study found the cost, prevalence of disorders and accuracy of MS-QMA as a first-tier test to be in line with other conditions currently included in newborn screening programs.
The study reported that among the 16,579 newborns screened, the odds that those who tested positive actually had the disease using the MS-QMA were 67%, 33%, and 44% for Angelman. , Prader Willi and the combined detection of chromosome 15. imprinting disorders, respectively.

“Having a high positive predictive value is important for newborn screening as it ensures that there are fewer false positive results that need to be repeated, resulting in lower overall laboratory costs, less work for maternity services to get a repeat blood sample and minimizes the psychological effect on the families,” said Associate Professor Godler.

Professor David Amor of MCRI said that if these findings are replicated in future independent studies, adding these chromosome 15 imprinting disorders to newborn screening programs would allow for earlier diagnosis and the use of interventions. targeted as they emerge, such as gene therapy for Angelman syndrome.

“For Prader Willi, early childhood diagnosis allows for early initiation of growth hormone therapy 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 odyssey diagnosis, reduce medical costs and the significant stress and anxiety that families are currently experiencing while waiting for a diagnosis.”

Melbourne’s son, Chrissy Cimino, Elliott, 4, was diagnosed with Angelman Syndrome at 14 months.

As a baby, Elliott couldn’t sit up straight, never cried or stammered, and had trouble gaining weight. After months of searching for a diagnosis, Chrissy said she was relieved to finally have the answer.

“There were a lot of red flags that were missed, and I knew in my gut that something was wrong,” she said. I continued to persist with medical appointments and did my own research. It was such a relief to have this diagnosis so that we could finally begin the medical interventions.”

But Chrissy said if Elliott had been diagnosed through a newborn screening program, his motor and cognitive skills wouldn’t be as poor.

“We weren’t able to enroll him in the NDIS until he was two and a half, so we missed out on years of intensive physiotherapy, speech therapy and occupational therapy. He’s almost five years old and he’s still not walking. no. If he had been diagnosed earlier, we could have helped him much sooner.”

Doris Hamilton-Brown’s son Lewis, 2, was diagnosed with Prader Willi when he was four weeks old.

Doris said that due to being born small for gestational age, Lewis was taken to the neonatal unit but failed to improve.

“After Lewis failed to get better, doctors started looking at genetic reasons,” she said. “The diagnosis was unexpected and difficult to hear, but getting answers meant we could intervene early.”

Lewis began treatment with growth hormone at seven months, which will help increase muscle mass, reduce fat mass, increase physical activity levels and improve achievement of developmental and cognitive milestones.

“He has just started walking and although he is non-verbal he can understand verbal cues and communicate what he needs to,” Doris said.

She said having a test for Prader Willi and other chromosome 15 imprinting disorders in newborn screening programs would take away a lot of angst, guilt and uncertainty for parents.

“We were lucky that Lewis was able to start treatments and therapies early enough, but for many families, diagnosis can come late and intervention is delayed,” Doris said.


Murdoch Children’s Research Institute

Journal reference:

Godler, DE, et al. (2022) Feasibility of screening for chromosome 15 imprinting disorders in 16,579 neonates using a new genomics workflow. JAMA network open. doi.org/10.1001/jamanetworkopen.2021.41911.

About Antoine L. Cassell

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