New test to screen newborns for rare genetic disorders paves the way for earlier diagnosis and treatment

Date:
January 24, 2022
Source:
Murdoch Childrens Research Institute
Summary:
A newly developed test to screen for three rare genetic disorders
simultaneously in newborns was feasible, reliable and scalable,
according to a new study.



FULL STORY ==========================================================================
A newly developed test to screen for three rare genetic disorders simultaneously 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 the three chromosome 15 imprinting
disorders to be added to newborn bloodspot screening programs (heel
prick test) for the first time.

The study, published in The Journal of the American Medical Association
Network Open, was the first to validate the use of a low-cost, specialised 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 Victorian State Government provided a $100,000 grant to MCRI as part
of the 2018 Victorian Medical Research Acceleration Fund to support the development of the new screening method for the rare disorders. Medical Research Minister Jaala Pulford visited MCRI recently to see how the
test worked and to learn more about its potential.

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.



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The three 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 the disorders are not included in newborn screening
programs, and many go undiagnosed in the first year of life.

MCRI Associate Professor David Godler said 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 recognised by a child's doctor, and subsequently referred for appropriate testing," he said. "This is not the
case with newborn screening where testing is performed on all newborns
before symptoms become apparent." Associate Professor 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 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 per cent, 33 per cent
and 44 per cent 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 minimises the psychological effect on families," Associate
Professor Godler said.



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MCRI Professor David Amor said 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
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, reduce medical costs and the significant
stress and anxiety currently experienced by the families while they
await a diagnosis." Melbourne's Chrissy Cimino's son Elliott, 4, was
diagnosed with Angelman syndrome at 14 months.

As a baby Elliott couldn't sit upright, never cried or babbled and
struggled to put on weight. After searching for a diagnosis for months,
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 wasn't right," she said. I kept persisting with medical appointments and I did my own research. It was such a relief to have that diagnosis so we could finally start 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 couldn't get him on the NDIS until he was two and half so we missed
out on years of intensive physio and speech and occupational therapies. He
is almost five and he still isn't walking. If he was diagnosed earlier we
could have helped him a lot sooner." Doris Hamilton-Brown's son Lewis,
2, was diagnosed with Prader Willi at four weeks of age.

Doris said 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 the doctors started to look at genetic reasons," she said. "The diagnosis was unexpected and tough to hear but
getting answers meant we could intervene early." Lewis started growth
hormone treatment at seven months, which will help with muscle bulk,
reduce fat mass, increase physical activity levels and improve attainment
of developmental and cognitive milestones.

"He has just started walking and while he is non-verbal he can understand verbal cues and communicate what he needs," Doris said.

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

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

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, Citta` della Speranza,
Greenwood Genetic Center, University of Chile and the Victorian Clinical Genetics Services also contributed to the study.

========================================================================== Story Source: Materials provided by
Murdoch_Childrens_Research_Institute. Note: Content may be edited for
style and length.


========================================================================== Journal Reference:
1. David E. Godler, Ling Ling, Dinusha Gamage, Emma K. Baker, Minh Bui,
Michael J. Field, Carolyn Rogers, Merlin G. Butler, Alessandra
Murgia, Emanuela Leonardi, Roberta Polli, Charles E. Schwartz, Cindy
D. Skinner, Angelica M. Alliende, Lorena Santa Maria, James Pitt,
Ronda Greaves, David Francis, Ralph Oertel, Min Wang, Cas Simons,
David J. Amor.

Feasibility of Screening for Chromosome 15 Imprinting
Disorders in 16 579 Newborns by Using a Novel Genomic
Workflow. JAMA Network Open, 2022; 5 (1): e2141911 DOI:
10.1001/jamanetworkopen.2021.41911 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/01/220124103901.htm

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