Genome-wide sequencing in acutely ill infants: genomic medicine's critical application?

Abstract

Diagnostic genome-wide sequencing (exome or genome sequencing and data analysis for high-penetrance disease-causing variants) in acutely ill infants appears to be clinically useful, but the value of this diagnostic test should be rigorously demonstrated before it is accepted as a standard of care. This white paper was developed by the Paediatric Task Team of the Global Alliance for Genomics and Health's Regulatory and Ethics Work Stream to address the question of how we can determine the clinical value of genome-wide sequencing in infants in an intensive care setting. After reviewing available clinical and ethics literature on this question, we conclude that evaluating diagnostic genome-wide sequencing as a comprehensive scan for major genetic disease (rather than as a large panel of single-gene tests) provides a practical approach to assessing its clinical value in acutely ill infants. Comparing the clinical value of diagnostic genome-wide sequencing to chromosomal microarray analysis, the current evidence-based standard of care, per case of serious genetic disease diagnosed provides a practical means of assessing clinical value. Scientifically rigorous studies of this kind are needed to determine if clinical genome-wide sequencing should be established as a standard of care supported by healthcare systems and insurers for diagnosis of genetic disease in seriously ill newborn infants.

Keywords: Exome sequencing; Health policy; Neonatal intensive care unit; genome sequencing.

Fig. 1. Hypothetical 180-day mortality of severely ill infants with suspected genetic disease without diagnostic genome-wide sequencing (GWS) (green curve) or with the benefit of diagnostic GWS (red and purple curves).

Note that diagnostic GWS is postulated to have two opposing effects on mortality: In infants diagnosed as having a condition that is lethal early in infancy, diagnostic GWS permits substitution of comfort care for intensive support, which results in earlier death (red portion of the curve). Some other infants with potentially lethal conditions are diagnosed as having a treatable condition, and the institution of precision therapy provides a reduction in mortality (purple portion of the curve). Figure redrawn after Petrikin et al., 2015 (ref. )