Elsevier

Seminars in Perinatology

Volume 39, Issue 8, December 2015, Pages 623-631
Seminars in Perinatology

Rapid whole genome sequencing and precision neonatology

https://doi.org/10.1053/j.semperi.2015.09.009Get rights and content

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.

Introduction

The completion of the first composite human genome sequence in April, 2003 marked the dawn of the promise of precision medicine—a new approach to medicine wherein diagnosis, treatment, and risk factor modification would be informed by an individual’s unique genetic make-up. While mature models of precision medicine remain to be defined, changes in the speed and cost of whole genome sequencing (WGS) are bringing the details of initial applications into focus. NIH Director, Francis Collins, foresees a society in which every baby will have access to their sequenced genome in order to modify their strategies for disease prevention, detection and treatment.1 In the 2015 State of the Union Address, President Barack Obama announced the creation of a precision medicine initiative, ultimately to provide each individual with personalized information to drive expedient diagnoses and individualized, more effective treatments. The transformation of healthcare through the use of personal WGS information has already begun in Neonatal Intensive Care Units (NICUs). Since 2011, neonatologists at our institution have, through research protocols, used research-based rapid WGS in acutely ill infants and their parents to diagnose the underlying genetic cause of the neonates’ conditions.2, 3, 4 Furthermore, in a research setting, it is now possible to sequence human genomes at a cost of less than $1000 per individual. At this early stage in its evolution, we review the premise, practicality, and potential of rapid WGS for neonatal precision medicine.

Section snippets

Monogenic diseases: neonatal impact and incidence

Monogenic diseases are conditions causally related to genomic change(s), or variant(s), in a single gene. This collection of diseases is currently most amenable to diagnosis through WGS because the causative variants frequently involve one or a few contiguous DNA nucleotides in one or a handful of genes. These variants interfere with the efficient functioning of a gene product through disruption of transcription, translation, protein modification, complex assembly, or function. They may be

Rapid whole genome sequencing methods

While the specifics of rapid WGS will differ from institution to institution, we have reported on our 3 year experience of sequencing selected neonates and infants for diagnosis of likely genetic diseases2, 3, 4 described briefly as follows. Enrollment of parental and proband trios is preferred, and every effort is made to sequence both parents. After informed consent is obtained, the presenting clinical features are ascertained by review of electronic health records and translated into

Experience with whole genome sequencing in neonates

Our early experience with rapid WGS involved 35 acutely ill infants whose genomes were sequenced with their families as parent–child trios.4 All infants were less than 4 months of age at time of enrollment, had a suspected genetic cause of their symptoms, and lacked a molecular or genetic diagnosis. The infants enrolled for sequencing had diverse presentations, with symptoms typically apparent at birth (Table 1) and received multiple standard genetic tests in addition to WGS. In this highly

Clinical outcomes and impact of genomic diagnoses

The clinical impact of WGS testing was positive in 65% of diagnoses according to clinician report. Specific services enabled by these rapid genetic diagnoses included institution of palliative care, initiation of new subspecialist consultant, or change in medication, diet, imaging study, surgical procedure, or specific genetic counseling. Of the 13 diagnoses made prior to discharge or death, 11 (85%) were considered to have acute clinical utility. Palliative care was instituted more often in

Two illustrative cases of clinical impact

Of the previously published cases, two are presented as illustrations of potential clinical impact.4 The first, CMH487, was admitted to the NICU at birth with multiple congenital anomalies. He developed acute hepatic failure on day of life (DOL) 56. Intravenous corticosteroids and immunoglobulin were started empirically on DOL 67 and 69, respectively. The infant–parent trio was enrolled on DOL 71. Rapid WGS gave a provisional molecular diagnosis of hemophagocytic lymphohistiocytosis. Since this

Ongoing research

Using our baseline three year experience with rapid WGS of selected neonates and infants for diagnosis of likely genetic diseases, we developed a prospective study of the diagnostic, clinical, and psychosocial utility of rapid WGS in the NICU (ClinicalTrials.gov Identifier: NCT02225522). This study is part of a multicenter investigation funded by the NIH under the Newborn Sequencing In Genomic medicine and public HealTh (NSIGHT) collaborative, which seeks to explore the implications,

Current limitations

Rapid WGS is a quickly evolving technology that still has multiple limitations. Causative larger, structural variants that affect single loci are sought using computational tools, but these methods currently lack sufficient sensitivity and specificity for clinical use. The short sequences generated in rapid WGS preclude their use for diagnosis of triplet repeat expansion disorders and in some disease genes with nonfunctional but highly homologous intronic regions called pseudogenes. Sequencing

Ethics of widespread genome sequencing

The prospect of WGS of infants is forcing society to grapple with ethical issues such as the child’s right to an open future, a family’s right to know about health predispositions, the nature of informed consent, and returning of results related to adult onset diseases or risk factors of conditions not manifesting during infancy and/or childhood. Much literature exists related to the issue of return of secondary (or incidental) genetic variant findings, but without coalescence to a consensus.

Future implications for precision medicine

The evidence to date, while retrospective, strongly suggests that rapid WGS does have utility for timely genetic disease diagnosis for ill NICU infants, even before a fully developed symptom complex evolves. However, prospective evidence has not yet been published. A goal of the Children’s Mercy NSIGHT study is to prospectively assess the diagnostic yield of rapid WGS with that of standard genetic testing in a randomized, controlled study. We seek to also address important questions of which

Acknowledgements

This work was funded by grant U19HD077693 from NHGRI and NICHD.

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