Rapid whole genome sequencing and precision neonatology

Abstract

Traditionally, genetic testing has been too slow or perceived to be impractical to initial management of the critically ill neonate. Technological advances have led to the ability to sequence and interpret the entire genome of a neonate in as little as 26 h. As the cost and speed of testing decreases, the utility of whole genome sequencing (WGS) of neonates for acute and latent genetic illness increases. Analyzing the entire genome allows for concomitant evaluation of the currently identified 5588 single gene diseases. When applied to a select population of ill infants in a level IV neonatal intensive care unit, WGS yielded a diagnosis of a causative genetic disease in 57% of patients. These diagnoses may lead to clinical management changes ranging from transition to palliative care for uniformly lethal conditions for alteration or initiation of medical or surgical therapy to improve outcomes in others. Thus, institution of 2-day WGS at time of acute presentation opens the possibility of early implementation of precision medicine. This implementation may create opportunities for early interventional, frequently novel or off-label therapies that may alter disease trajectory in infants with what would otherwise be fatal disease. Widespread deployment of rapid WGS and precision medicine will raise ethical issues pertaining to interpretation of variants of unknown significance, discovery of incidental findings related to adult onset conditions and carrier status, and implementation of medical therapies for which little is known in terms of risks and benefits. Despite these challenges, precision neonatology has significant potential both to decrease infant mortality related to genetic diseases with onset in newborns and to facilitate parental decision making regarding transition to palliative care.

Keywords: Genetic diagnosis; Genetic testing; Genomics; Neonatology; Precision Medicine.

Figure 1

Actual and desired 120-day mortality of NICU infants receiving rapid genetic disease diagnoses. In suffering neonates with hopeless diagnoses, rapid diagnosis will allow planned withdrawal of support in a more timely manner. Precision medicine interventions in remaining infants are anticipated to reduce infant mortality.

Figure 2

Actual and desired time to genetic disease diagnosis by rapid WGS (STATseq). Ideally, blood samples would be obtained at birth and diagnoses would be returned by DOL 2 to optimize provision of precision medicine.