Novel Blood Test Diagnoses Newborns with Rare Genetic Disorders

A team of Australian researchers has developed a test to screen newborns for three rare genetic disorders simultaneously.

These conditions, which are called chromosome 15 imprinting disorders, comprise Angelman syndrome (AS), Prader-Willi syndrome (PWS), and chromosome 15 duplication syndrome (Dup15q). They are caused by deletions, duplications, or epimutations at the same imprinted region located at chromosome 15q11-q13. The three disorders are characterised by varying degrees of intellectual disability, autism, behavioral problems, seizures, and/or severe obesity. In general, these disorders are not included in newborn screening programs and usually are not diagnosed in the first year of life.


To rectify this situation, investigators at the Murdoch Children’s Research Institute (Melbourne, Australia) employed a technique called methylation-specific quantitative melt analysis (MS-QMA) based on methylation analysis of the SNRPN (Small nuclear ribonucleoprotein-associated protein N) gene.

MS-QMA combines the qualitative strengths of high resolution melt technology and the high-throughput, quantitative real-time PCR standard curve to provide accurate quantification of DNA methylation in a single assay. MS-QMA has been shown to correlate with the more cumbersome reference methods of Southern blot and MALDI-TOF MS, and even to perform better with low quality DNA, e.g. DNA extracted from newborn blood spots. Analysis of MS-QMA raw data is performed by a custom designed computer algorithm, which simultaneously performs all analysis steps.

For the current study, the investigators validated the methylation test on 1356 samples. Results demonstrated high sensitivity and specificity and positive and negative predictive values that differentiated newborn blood spots and blood, saliva, and buccal DNA of 109 Prader-Willi, 48 Angelman, and nine Dup15q patient samples from neurotypical control samples. Newborn blood spots from 16,579 infants from the general population were then tested, identifying two with Prader-Willi syndrome, two with Angelman syndrome, and one with Dup15q syndrome. 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.

“For Prader Willi, diagnosis in infancy allows for early initiation of growth hormone treatment to improve long term health outcomes,” said senior author Dr. David Amor, professor of human genetics at the Murdoch Children’s Research Institute. “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.”

The chromosome 15 imprinting disorders study was published in the January 4, 2022, online edition of The Journal of the American Medical Association Network Open.

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Murdoch Children’s Research Institute