Unlike the research study in which a dedicated research team was readily available to identify and screen infants based on specific inclusion criteria, enroll and consent families, and collect and send samples, routine clinical care involves constantly rotating clinical team members with differing perspectives as well as competing clinical demands 21, 22. Subsequently, rapid ES was integrated into routine clinical care in our institution’s NICU. The diagnoses informed management in 24/29 infants (83%).

A genetic diagnosis was identified in 29/50 infants (58%), including two infants with variants identified in novel disease genes, and the highest yield was seen in infants with neurological phenotypes, specifically hypotonia and/or seizures. Between March 2017 and November 2018 (hereafter referred to as Phase I), 50 infants had rapid ES performed, mainly from the Level IV NICU at Boston Children’s Hospital (BCH). We previously performed a prospective pilot study of rapid ES in critically ill infants using phenotype-based selection criteria, enrolling infants <6 months corrected gestational age (GA) with an ICU indication and new onset (<7 days) of hypotonia, seizures, a complex metabolic phenotype, and/or multiple congenital anomalies, as well as one infant with a disorder of sex development 11. Multiple studies of ES/GS in critically ill infants have demonstrated diagnostic yields of 20–60% (with the highest yields reported with phenotype-driven selection), decreased time to genetic diagnosis (especially when rapid testing is performed), an impact on clinical care, and perception of high utility by clinicians and parents 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20.

Recently, there has been increasing use of massively-parallel sequencing tests, namely exome sequencing (ES) and genome sequencing (GS), for infants in intensive care settings. Traditionally, the genetic diagnostic odyssey has been long, costly, potentially invasive, and difficult for these infants and their families. Many infants admitted to Neonatal Intensive Care Units (NICUs) have a known or suspected genetic disorder, and these conditions contribute significantly to morbidity and mortality 1, 2. Based on our experience, we have identified strategies to optimize the clinical implementation of rapid ES in the NICU. Overall, rapid ES was utilized in the NICU after the pilot research study, often as the first-tier sequencing test, and could identify the majority of disease-causing variants, shorten the diagnostic odyssey, and impact clinical care.

Compared to other genetic tests, rapid ES had similar or higher diagnostic yield and similar or decreased time to result. Compared to the previous research study, clinically integrated rapid ES had a significantly lower diagnostic yield and increased time from NICU admission and genetics consult to ES report, but identified four genetic diagnoses that may have been missed by the research study selection criteria. The majority of diagnoses acutely impacted clinical management (14/22 (64%)). Clinical rapid ES was performed in 80/230 infants (35%) with a suspected genetic disorder and identified a genetic diagnosis in 22/80 infants (28%). We performed a retrospective cohort analysis of infants admitted with suspected genetic disorders to the NICU from Decemto Maand compared results to those obtained from a previous research study cohort (Mato November 30, 2018). We investigated the integration of rapid ES into routine clinical care after a pilot research study in a Level IV Neonatal Intensive Care Unit (NICU). Genomic sequencing is a powerful diagnostic tool in critically ill infants, but performing exome or genome sequencing (ES/GS) in the context of a research study is different from implementing these tests clinically.

Next meeting of anomaly committee