Study: Low-cost MS-QMA Feasible for Newborn Screening of PWS

Marisa Wexler MS avatar

by Marisa Wexler MS |

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A low-cost screening test called methylation-specific quantitative melt analysis (MS-QMA) could feasibly be used to conduct newborn screening for Prader-Willi syndrome (PWS) and related conditions, according to a new study.

The study, “Feasibility of Screening for Chromosome 15 Imprinting Disorders in 16579 Newborns by Using a Novel Genomic Workflow,” was published in JAMA Network Open.

Early diagnosis of PWS can lead to better health outcomes and lower costs of raising a child with the condition. As such, in recent years there has been a push to implement newborn screening — that is, testing babies when they are born for PWS and other conditions caused by abnormalities in chromosome 15, such as Angelman syndrome and chromosome 15 duplication syndrome (Dup15q).

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MS-QMA is a test of DNA methylation — a type of DNA modification — that has been explored for diagnosing PWS. However, the feasibility of using MS-QMA at the scale needed for newborn screening was unclear.

Now, an international team led by researchers in Australia tested the feasibility of large-scale MS-QMA testing. The team first developed a MS-QMA workflow, which they used to assess 1,356 samples, including 77 from people with PWS (median age 3 years), 46 from people with Angelman syndrome, and nine from those with Dup15q.

Statistical analyses revealed that the sensitivity (true-positive) rate for PWS was 99%, while the specificity (true-negative) rate was 100%. High rates were also seen for the other conditions.

The team then applied their MS-QMA workflow to analyze 16,579 samples of blood from newborns. In 92 of these samples, values were outside normal ranges.

The abnormal samples were sent for further testing using another method called competitive priming initiated nested quantification by droplet digital polymerase chain reaction (CINQ ddPCR). This testing confirmed a diagnosis of PWS in two patients. Angelman syndrome was confirmed in two patients, and Dup15q in one.

The team then calculated the positive predictive value, or PPV, for MS-QMA as a diagnostic test for these conditions. PPV is the chance that someone who tests positive for a condition actually has it.

“Having high PPVs is important for newborn screening, because it ensures that (1) there is a lower number of false-positive results that need to be repeated, leading to lower overall laboratory costs; (2) there is less work for maternity services in obtaining a repeat blood sample for the majority of cases flagged as potential positives; and (3) there is minimized psychological effect from false-positive calls for the families contacted as part of the follow-up,” the researchers wrote.

The PPV for PWS was 2.7%. PPVs for Angelman and Dup15q were 10% and 1.1%, respectively. These values are “compatible with screening for other conditions in the state sponsored programs,” the scientists added.

In addition to accuracy, another critical feature of large-scale tests is that they not be too expensive. According to the researchers, the reagent cost in their study allows for testing at a cost of less than $1.30 per condition per infant.

“If these findings and the preliminary prevalence estimates are confirmed in larger future prospective studies, this workflow could ensure that early interventions for these disorders are uniformly available to most infants from birth as part of state-sponsored newborn screening programs,” the investigators concluded.