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SeqFirst Results Highlight Diagnostic Gains From Rapid Genome Sequencing in Critically Ill Newborns


LOS ANGELES ­– Early results from SeqFirst, a study led by University of Washington researchers in collaboration with Illumina and Sema4, have shown the diagnostic benefits of rapid whole-genome sequencing (rWGS) for newborns in the neonatal intensive care setting.

Reported at this year’s American Society of Human Genetics annual meeting, the results demonstrated “clear opportunities” for improving equitable access to genetic diagnostics for critically ill infants, according to the researchers.

“The motivation behind SeqFirst is that it is unacceptable that a precise genetic diagnosis for rare conditions is not more widespread and is not being delivered equitably to families across the nation,” said Tara Wenger, a physician scientist at the University of Washington and SeqFirst’s co-investigator, who presented data from the project’s first phase at the conference.

According to Wenger, the conventional diagnostic workflow in the neonatal intensive care unit (NICU) normally starts with a neonatologist suspecting an infant may have a genetic disorder. From there, depending on the clinician's level of suspicion, the type of the presumed condition, and the accessibility of a hospital’s genetic testing offerings, a neonatologist may order certain genetic tests or transfer the patient to another hospital with greater resources.

“The SeqFirst workflow disrupts this process,” Wenger said, adding that rather than adopting inclusion-based criteria, where a neonatologist must suspect a genetic disorder, SeqFirst embraces a broader exclusion-based enrollment standard. This means the study offers rWGS as a first-tier test to all qualifying infants as long as their clinical presentations are not fully explained.

Wenger showcased data from phase one of SeqFirst’s neonatal arm, which entailed a head-to-head comparison between the conventional inclusion-based genetic diagnostic workflow with SeqFirst’s exclusion-based rWGS approach.

Specifically, from January 2021 to January 2022, in parallel to the conventional genetic testing workflow for all patients, SeqFirst researchers reviewed electronic medical records daily to identify NICU patients whose clinical presentations could not be fully explained by prematurity, infection, trauma, or an existing genetic diagnosis. These infants were offered enrollment in the study for trio-based rWGS through GeneDx, a genetic testing company acquired by Sema4 earlier this year.

During the study period, 411 infants were admitted to the NICU at Seattle Children's, of whom 234 were eligible for the SeqFirst study. Parents of 209 of these patients were approached by the study while their child was in the NICU, Wenger said, but more than 80 declined participation, with the most common reasons being “feeling overwhelmed” or not responding by the enrollment deadline.

The parent-reported race and ethnicity of the infants enrolled in SeqFirst, Wenger said, were “very similar” to the overall patient demographic at Seattle Children's NICU. While English was the language of consent for the majority of enrolled families, a small number of them provided consent in Spanish, Marshallese, or Arabic.

Overall, of the125 infants enrolled in this study, 79 had abnormal results reported by GeneDx, triggering further clinical assessment by the study’s genetics team. In the end, SeqFirst helped fully or partially explain the clinical findings of just over half of the participants.

In particular, of the 62 infants who received a genetic diagnosis in the study, 44 obtained the diagnosis first through rWGS, and 39 out of these 44 patients had a change of their medical management because of the results.

In addition, Wenger said, 16 of the 62 patients would not have received a diagnosis through the conventional workflow, and an additional 10 would not have received a diagnosis due to the conventional diagnostic protocol for their type of malformation and the hospital's laboratory stewardship policies. In summary, the conventional clinical approach would have missed 42 percent of the infants diagnosed through SeqFirst, she added.

Beyond that, Wenger noted that the study’s “most striking finding” was revealed when the team compared the race and ethnicity data of the infants who obtained a genetic diagnosis through SeqFirst. Specifically, among the participants who had not been identified by the neonatology team as being at risk of having a genetic disorder before the study, the majority were from non-white racial and ethnic groups, with “very few” white non-Hispanic infants, she pointed out.

Wenger said one of the major focus areas for SeqFirst moving forward is to explore factors contributing to the disparity of genetic consultations.