Prospective, phenotype-driven selection of critically ill neonates for rapid exome sequencing is associated with high diagnostic yield



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.

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Corresponding authors

Correspondence to Pankaj B. Agrawal MD, MMSc or Timothy W. Yu MD, PhD.

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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.

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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).

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  • exome sequencing
  • neonates
  • intensive care unit

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