To investigate the impact of rapid-turnaround exome sequencing in critically ill neonates using phenotype-based subject selection criteria.
Intensive care unit babies aged <6 months with hypotonia, seizures, a complex metabolic phenotype, and/or multiple congenital malformations were prospectively enrolled for rapid (<7 day) trio-based exome sequencing. Genomic variants relevant to the presenting phenotype were returned to the medical team.
A genetic diagnosis was attained in 29 of 50 (58%) sequenced cases. Twenty-seven (54%) patients received a molecular diagnosis involving known disease genes; two additional cases (4%) were solved with pathogenic variants found in novel disease genes. In 24 of the solved cases, diagnosis had impact on patient management and/or family members. Management changes included shift to palliative care, medication changes, involvement of additional specialties, and the consideration of new experimental therapies.
Phenotype-based patient selection is effective at identifying critically ill neonates with a high likelihood of receiving a molecular diagnosis via rapid-turnaround exome sequencing, leading to faster and more accurate diagnoses, reducing unnecessary testing and procedures, and informing medical care.
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The research team thanks all clinical teams involved for their help, as well as the patients and their families. This work was supported in part by a sponsored research agreement between GeneDx and Boston Children’s Hospital; the National Institutes of Health under award numbers U19HD077671, U54HD090255, R01AR068429, and R01HD075802; the William F. Milton Fund; and the resources of The Manton Center for Orphan Disease Research Gene Discovery Core. C.S.G. was partly supported by a William Randolph Hearst Fellowship. M.H.W. was supported by T32 GM 7748-40.
Rapid exome sequencing for this study was performed by GeneDx, a commercial genetic diagnostic company. Authors D.C., S.Y., and J.J. are employed by GeneDx. The other authors declare no conflicts of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Gubbels, C.S., VanNoy, G.E., Madden, J.A. et al. Prospective, phenotype-driven selection of critically ill neonates for rapid exome sequencing is associated with high diagnostic yield. Genet Med 22, 736–744 (2020). https://doi.org/10.1038/s41436-019-0708-6
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