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Newborn Sequencing Study Highlights Potential for Diagnosis of Unknown Disease

NEW YORK (GenomeWeb) – Researchers at the Children's Hospital of Eastern Ontario have tested the feasibility of implementing a sequencing-based diagnostic test for newborns with suspected genetic disorders who are admitted to the neonatal intensive care unit and found that they were able to identify a molecular cause in 40 percent of the patients.

The results of the 20-patient pilot study, which were reported this week in the Canadian Medical Association Journal, "highlighted the potential of next-generation sequencing to deliver molecular diagnoses rapidly with a high success rate," the authors wrote.

The team recruited 20 patients who were admitted to NICUs of two regional hospitals — the Children's Hospital of Eastern Ontario and the Ottawa Hospital. Twelve were analyzed retrospectively, while eight were analyzed prospectively. The researchers required specific clinical findings of the newborns — one or more congenital malformations, dysmorphic features, growth abnormalities, neurologic impairment, or features indicating a metabolic condition.

They used Illumina's TruSightOne panel, which analyzes 4,813 genes that are associated with known clinical phenotypes, and sequenced DNA from the affected newborns as well as from both parents on the MiSeq instrument.

The researchers diagnosed eight out of the 20 newborns with this approach. At the same time, clinicians pursued traditional testing for all 20 newborns, finding diagnoses for only two patients, who were also diagnosed via the NGS test.

In an editorial accompanying the study in CMAJ, Sarah Bowdin, a geneticist at the Hospital for Sick Children in Toronto, wrote that the finding "bolsters the argument for employing a very broad, yet clinically relevant, gene panel when the patient's phenotype suggests a disease process that is clinically and genetically heterogeneous."

Of the eight patients who were diagnosed, clinical management was changed for two. For one patient, who was diagnosed with renal tubular dysgenesis, the physician was able to prescribe medication that improved his kidney function. For the second patient, the molecular diagnosis ultimately led to the decision to surgically remove both kidneys during a kidney transplant. In the other six patients who were diagnosed, the result enabled the health provider to give a more accurate prognosis to the family, as well as better counseling.

Turnaround time was not a focus of the study, and thus ranged from two to 58 weeks. The variability reflected the availability of sequencing capacity, the authors noted.

"Integration of next­generation sequencing will enable molecular diagnosis during the hospital stay soon after birth, instead of families having to wait months to years for a diagnosis, which is the current norm," the authors wrote.

Researchers at other hospitals have turned to sequencing to help diagnose newborns with suspected genetic disease. For instance, a team at Children's Mercy Hospital has implemented a whole-genome sequencing pipeline, called STAT-seq, which can return provisional results as quickly as 26 hours.

Also, GeneDx has developed a rapid exome sequencing test that provides a preliminary report within five to seven days and Baylor College of Medicine's diagnostic laboratory offers a "lightning exome" test.

The team at Children's Hospital of Eastern Ontario noted that while such genome-or exome-wide approaches are more comprehensive, one benefit of the targeted approach that they used is that "testing can be performed in a hospital­based molecular laboratory, using smaller and more affordable next­ generation sequencing platforms, rather than the larger infrastructure that is often found only in dedicated genomics centers."

In addition, genetic testing in Canada is currently outsourced to other countries, which can add time and expense to the process, whereas this approach can be "performed in a hospital-based laboratory without the need to send samples away," David Dyment, a clinical investigator at the CHEO Research Institute and senior author of the study, said in a statement.

The authors wrote that they next plan to evaluate the test to determine diagnostic rates for specific clinical presentations, to assess timing of return of results, and to determine the best time to pursue NGS in order to "decide whether this method should be used as a first tier test in the NICU or as a final investigation in an outpatient clinic."