Newborn Sequencing in Genomic Medicine and Public Health

Abstract

The rapid development of genomic sequencing technologies has decreased the cost of genetic analysis to the extent that it seems plausible that genome-scale sequencing could have widespread availability in pediatric care. Genomic sequencing provides a powerful diagnostic modality for patients who manifest symptoms of monogenic disease and an opportunity to detect health conditions before their development. However, many technical, clinical, ethical, and societal challenges should be addressed before such technology is widely deployed in pediatric practice. This article provides an overview of the Newborn Sequencing in Genomic Medicine and Public Health Consortium, which is investigating the application of genome-scale sequencing in newborns for both diagnosis and screening.

FIGURE 1

A, Diagram of the protocol in progress at BWH and BCH, Boston, Massachusetts. Infants are recruited from the well baby nursery at BWH and from the ICUs at BCH and BWH. After a pre-enrollment session with a study genetic counselor and completion of baseline outcomes, enrolled infants are randomly assigned to receive NBS and family history or NBS, family history, and exome sequencing. Results are disclosed to the family by a study genetic counselor and physician, and postdisclosure outcomes are collected. Follow-up is performed at 3 and 10 months after disclosure. Medical, behavioral, and economic outcomes are collected throughout the study from surveys, medical record reviews, and consultation with the families. B, Diagram of the protocol in progress at NICUs at Children’s Mercy Hospital, Kansas City (CMH) and Rady Children’s Hospital, San Diego (RCHSD). Eligible patients are infants <4 months old in whom a clinical genetic test or genetic consult was ordered, or those with 1 major anomaly or 3 minor structural anomalies, or an abnormal laboratory test suggestive of a genetic disease, or an abnormal response to standard therapy for a major underlying condition. Enrolled infants are randomly assigned to receive standard diagnostic testing or standard tests and rapid WGS of parent–infant trios. Diagnostic results are returned. Primary outcome measures are rate of molecular diagnosis in 28 days, time to diagnosis, and whether the diagnosis provided a change in clinical management. C, Diagram of the NBSeq protocol in progress at UCSF. NBSeq uses archived residual DBS from a very large and diverse population to examine the diagnostic utility of exome sequencing in 2 parallel projects. For metabolic disorders (left), DBS samples from deidentified true positives (TP), false positives (FP), and false negatives (FN) are subjected to exome sequencing, variant calling, and interpretation under blinded models for evaluation of first-tier screening and in conjunction with MS/MS and clinical data for evaluation of second-tier screening. A predetermined list of 93 genes relevant to the metabolic disorders is the basis for the exome assessment. Consented, identified patients with immune disorders with no gene identified (right) also undergo NBS DBS retrieval and exome sequencing and analysis, in this case with a pipeline restricted to immune system genes. Analysis protocols for both applications undergo refinement based on integration of observed sensitivity and specificity with genome analysis tools. Enrollees with immune disorders can obtain confirmational clinical gene testing, and their assessment of risks, benefits, and uncertainties of exome sequencing for NBS are solicited. D, Diagram of the North Carolina Newborn Exome Sequencing for Universal Screening protocol in progress at the University of North Carolina at Chapel Hill. This study is enrolling healthy newborns, identified prenatally, and children affected with known conditions identified through standard NBS (metabolic disorders, hearing loss, pulmonary disorders). Parents use an electronic decision aid in addition to an in-person consultation with a genetic counselor to determine whether to have their child undergo sequencing. Exome sequencing is performed, with analysis of a panel of genes associated with childhood-onset medically actionable conditions (NGS-NBS) for all participants and indication-based analysis for patients from the diagnosed cohort. Participants are randomly assigned at the time of return of results. Parents in the control arm receive only the primary diagnostic findings and NGS-NBS results, whereas parents in the decision arm will use the electronic decision aid to choose between 3 additional categories of optional genomic information (adult-onset medically actionable conditions, childhood-onset non–medically actionable conditions, and carrier status for recessive conditions). Parents will also participate in longitudinal surveys to assess their responses to the genomic information.