The Role of Genome Sequencing in Neonatal Intensive Care Units

Abstract

Genetic diseases disrupt the functionality of an infant's genome during fetal-neonatal adaptation and represent a leading cause of neonatal and infant mortality in the United States. Due to disease acuity, gene locus and allelic heterogeneity, and overlapping and diverse clinical phenotypes, diagnostic genome sequencing in neonatal intensive care units has required the development of methods to shorten turnaround times and improve genomic interpretation. From 2012 to 2021, 31 clinical studies documented the diagnostic and clinical utility of first-tier rapid or ultrarapid whole-genome sequencing through cost-effective identification of pathogenic genomic variants that change medical management, suggest new therapeutic strategies, and refine prognoses. Genomic diagnosis also permits prediction of reproductive recurrence risk for parents and surviving probands. Using implementation science and quality improvement, deployment of a genomic learning healthcare system will contribute to a reduction of neonatal and infant mortality through the integration of genome sequencing into best-practice neonatal intensive care.

Keywords: NICU; genomics; neonatal intensive care unit; newborn infants; precision medicine.

Figure 1.

The current inflection point in precision neonatology for single locus genetic diseases. The cost of research-grade genome sequencing (black line) and time to result of diagnostic rWGS (blue line) have been decreasing for ten years. The number of known genetic diseases (yellow line) has increased dramatically since the advent of next generation sequencing. The number of approved genetic therapies for childhood-onset genetic diseases (teal line) is rapidly increasing.

Figure 2.

Steps and minimum times of rapid genetic disease diagnosis by whole genome sequencing and implementation of precision neonatology. EHR, electronic health record.

Figure 3.

Comparison of the traditional approach to etiologic diagnosis of genetic diseases in NICU infants with rWGS-informed precision medicine. Values are from the NSIGHT2 RCT (11, 23, 43)

Figure 4.

Genome-informed neonatology is a learning healthcare delivery system with four components: 1. Education, engagement, and equipping (yellow line); 2. Rapid, diagnostic whole genome sequencing (green line); 3. Translation into precision neonatology (blue line); 4. Therapeutic innovation (blue line). Learning feedback loops are shown.

Figure 5:

Cost effectiveness of precision neonatology is dependent on time to result. a. Cost savings during the initial hospitalization from first-tier use of rWGS for NICU infants with suspected genetic diseases in Project Baby Bear. b. Total cost savings.