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.

A brief history of human disease genetics

“…For more complex phenotypes-those without a clear match to a specific syndrome, such as neurodevelopmental disorders and multiple congenital anomalies-testing has gravitated towards early deployment of exome and genome-sequencing platforms that offer speedy resolution of what has historically often been a traumatic diagnostic odyssey 15,134 . The power of genomic diagnosis is especially clear for those presenting with monogenic neurodevelopmental disorders and critically ill infants 135,136 . Sequencing of the parent-offspring trio can Review detect de novo variation in dominant disorders and phase biallelic rare variants in recessive disease 13 .…”

Genomic sequencing in acutely ill infants: what will it take to demonstrate clinical value?

“…Friedman and colleagues conclude, “Comparing diagnostic GWS to the current standard of care per case of serious genetic disease diagnosed can provide a practical means of assessing clinical value” and propose, “for a comparative study to provide the robust evidence that is needed, both costs and benefits will have to be collected in a rigorous prospective manner, and the results will need to be analyzed comprehensively.” 2 We concur. Indeed, several cohort studies and randomized trials have either been published or are underway that are tracking health outcomes and costs associated with genomic diagnoses in acutely ill children.…”

“…In this issue, a group of international experts has prepared a white paper that acknowledges the “great promise” of genome-wide sequencing (GWS) for acutely ill infants but emphasizes gaps in evidence. 2 Friedman and colleagues lay out principles for establishing the clinical value of such testing. We agree that it is essential that a robust evidentiary base of benefits be developed to allow health-care providers and payers to make informed decisions on the implementation of NGS technologies in that patient population.…”

“…First, as the authors cogently explain, diagnosis of an untreatable condition based on NGS results may lead to cessation of painful and ultimately futile procedures. 2 For those infants, early genomic diagnoses may lead to earlier death while simultaneously reducing suffering for the child and psychosocial harm to the parents through earlier transition to palliative care. Infants who have treatable conditions can benefit from initiation of appropriate treatment in terms of quality of life, but the extent to which treatment affects survival is not necessarily known.…”

Rapid Phenotype-Driven Gene Sequencing with the NeoSeq Panel: A Diagnostic Tool for Critically Ill Newborns with Suspected Genetic Disease

“…Technological advances in gene sequencing have enabled rapid reading of any part of the genome at an affordable price [8,9]. NICUs are a key target for the implementation of genomic tools [10,11]. Timely and specific diagnosis of newborns can have critical implications for health and wellbeing for the remainder of an infant's life.…”