Whole genome sequencing finds genetic disorders missed by targeted test in babies

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Whole genome sequencing (WGS) is better than a targeted test at identifying abnormalities responsible for genetic disorders in newborns and infants but also costs more and takes longer, according to a study published in JAMA.

The prospective, multicenter study compared the molecular diagnostic yield and time to results of the two tests in 400 hospitalized infants younger than one year of age with suspected genetic disorders. The participants underwent simultaneous testing with WGS and NewbornDx, a targeted sequencing test of variants in 1,722 genes linked to genetic disorders in newborns and infants.

WGS found a genetic disorder in 49% of the patients, compared to a 27% detection rate for NewbornDx. Athena Diagnostics, which Quest Diagnostics acquired in 2011, sells the targeted gene sequencing test. The targeted panel missed 40% of the WGS diagnoses. Overall, a molecular diagnostic variant was found in 51% of participants; 134 of the 297 identified variants were novel.

Dr. Jonathan Davis, chief of newborn medicine at Tufts Medical Center and co-principal investigator of the study, discussed the implications of the results for the care of babies with suspected genetic diseases in a statement.

“More than half of the babies in our study had a genetic disorder that would have remained undetected at most hospitals across the country if not for genome sequencing technologies,” Davis said. “This study shows that WGS, while still imperfect, remains the gold standard for accurate diagnosis of genetic disorders in newborns and infants.”

NewbornDx has some advantages over WGS, though. The median time to result was 6.1 days for WGS, compared to 4.2 days for the targeted gene sequencing test. While the additional two-day wait for WGS results favors NewbornDx, the study showed that it is possible to accelerate WGS. The turnaround times for WGS and NewbornDx for 107 urgent cases were 3.3 days and 4 days, respectively.

Other considerations may also affect the choice between WGS and targeted gene sequencing tests. WGS costs more and can identify gene variants related to later-life health problems such as Alzheimer’s disease and cancer that the parents of the child may prefer not to know.

The study also identified a need for more standardization of the interpretation of neonatal test results. In 40% of cases, different laboratories identified the same gene abnormality but disagreed on whether it was the cause of the suspected genetic disorder.

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