Will Sequencing Penetrate Newborn Screening, Infant Care?

What is believed to be the first healthy, U.S. baby to have his DNA sequenced prenatally was born this summer, according to MIT Technology Review. (A handful of fetuses have been sequenced as part of investigation of abnormalities.) The child’s father, a graduate student and professional genetics blogger who did the sequencing for the sake of coolness and not medicine, believes sequencing of fetuses will become routine practice. Will prenatal sequencing become the norm? Not likely any time soon, according to experts DTET spoke to. However, sequencing is being discussed as an alternate technology for newborn screening (NBS) tests. Yet employment of the technology for NBS is fraught with ethical considerations, and some believe the notion of sequencing newborns challenges the very intention of NBS—to identify potentially lethal or life-changing conditions that have effective treatments if detected early. The best interest of the child has been the driver of NBS decisions and has been the focus of early attention on the use of genetic testing in children. Generally, professional societies do not support the systematic genotyping of newborns or young children. The problem, of course, is too much information including identification of conditions that don’t manifest until adulthood or genetic variants for which the clinical significance is not fully known. “The discussion of the possible role for sequencing in NBS must ultimately be about whether or not it improves infant and child health,” says Michelle Lewis, M.D., from Johns Hopkins’ Genetics and Public Policy Center (Baltimore). “Technology must have a clear benefit for the public’s health. NBS is designed as part of state public health programs which serve the population as a whole, which is different from a clinician with an obligation to an individual patient.” The pivotal considerations for use of whole-genome sequencing (WGS) in next-generation sequencing (NGS) include the ethical consideration of what information to report, as well as resource and logistical issues surrounding counseling, follow-up reportingy, and the potential need for additional diagnostic testing and care. “My personal viewpoint is that it is a pretty bad idea to do WGS in NBS, but targeted NGS panels is a spectacular idea,” says Jonathan Berg, M.D., Ph.D., a clinical geneticist at University of North Carolina, Chapel Hill (UNC). Targeted or staged approaches to WGS are being considered as a possibility to prioritize and filter the number of findings. Agreement remains elusive as to the criteria needed to generate a list of reportable conditions as well as timing of reporting. Some have suggested withholding some results until parents have had more time deliberate the implications, until the child reaches maturity, or until mutations gain evidence of validity and clinical utility. “A more elegant approach would be a system of screening enabling screening of relevant conditions at a relevant point in time,” says Berg, who concedes such a scenario would pose challenges with follow-up and a lack of interoperable medical records. If results were reported outside of the framework of NBS, when there is a “captive audience,” there are also considerations for an expanded role of the health department and the pediatrician or family physician. Others have proposed a two-tiered approach with a “classical” NBS and a WGS screening with additional parental consent, which some fear could create “justice” and access issues. “There is an urgent need for discussion and some level of international professional and public consensus,” particularly surrounding the appropriateness of returning incidental findings, wrote Bartha M. Knoppers from McGill University in Canada, in a commentary piece published in Science Translational Medicine in March. “Were NBS programs to incrementally expand their screening panels to introduce WGS, the reception may be discordant, disorganized, and disruptive. The policies of NBS should be discussed prospectively and carefully.” Parent’s Perspective The National Institutes of Health last year funded four pilot programs ($25 million over five years) under the Genomic Sequencing and Newborn Screening Disorders research program to evaluate if sequencing of newborns’ genomes provides useful medical information beyond current NBS programs. All of the funded programs (Brigham and Women’s Hospital in Boston, Children’s Mercy Hospital in Kansas City, Mo., University of California, San Francisco, and UNC) will incorporate assessments of the ethical, legal, or social implications of using genomic information in the newborn period into the projects. Early research is showing that even parents who have experienced a positive NBS result with their infant have reservations about the types of information they would want from WGS as part of NBS, according to an abstract presented at the National Society of Genetic Counselors Annual Educational Conference (New Orleans; Sept. 17-20). Researchers from Stanford University, led by Shannon Rego, conducted interviews with seven parents who had a child screen positive on NBS since August 2005 to assess their attitudes toward WGS as part of NBS. Parents expressed strong interest in learning about medical conditions in their infant that were treatable or preventable. While several parents also wanted to know about untreatable and nonpreventable conditions, usually citing a desire to be better prepared for the future, the parents who only wanted actionable information believed knowledge of these other conditions “would be a burden.” These reservations, the authors say, are more pronounced than those expressed in previous studies. Takeaway: Routine sequencing as part of NBS or healthy infant care is unlikely to gain traction in the near future due to ethical considerations of which conditions to report, as well as resource limitations, particularly in the public health system. However, as sequencing prices continue to drop, experts do see a role emerging for targeted sequencing panels in NBS. Side Box: NBS Then and Now Sept. 30 marked the 50th anniversary of newborn screening, which began as a recommendation to routinely screen all newborns for phenylketonuria. The recommended uniform screening panel, devised by the U.S. Department of Health and Human Services’ Discretionary Advisory Committee on Heritable Disorders in Newborns and Children, consists of 31 core conditions and reporting of 26 secondary conditions. The number and type of conditions varies by state. Side Box: SCID: A Case Study of a New NBS Condition A newborn screening test for severe combined immunodeficiency (SCID) reliably identifies infants with this life-threatening inherited condition, leading to prompt treatment and high survival rates, according to an article published Aug. 20 in the Journal of the American Medical Association (JAMA). The researchers also determined that SCID affects approximately one in 58,000 newborns, making it less rare than previously thought. SCID is the first set of heritable immune disorders included in NBS and is characterized by defective T cell production, which can result in life-threatening infections. Early detection is imperative for optimal treatment and survival. Isolated DNA from infant dried blood spots can be assayed using polymerase chain reaction to detect T cell receptor excision circles (TRECs), a biomarker for naive T cell lymphopoiesis and identifier of SCID. NBS for SCID began in 2008 in Wisconsin and, while added to the national recommended uniform panel for NBS in 2010, is only tested for in 23 states, the District of Columbia, and the Navajo Nation. Researchers led by Antonia Kwan, Ph.D., from the University of California, San Francisco, examined 3 million tests (January 2008 to July 2013) from 11 NBS programs to evaluate SCID screening algorithms and test performance data. Screening detected 52 cases. Screening caught all infants with SCID.  Cutoffs for referral testing varied (less than 40 TREC/μL in seven programs and  less than 252 TREC/μL in three programs). Variations in follow-up practices were also seen across states. “The TREC assay has proven excellent for detecting disorders with poor T-cell production . . . , but finding additional immune defects prior to onset of recurrent or life-threatening infections will require further methods,” write the authors. “Genomic sequencing may be required to detect deleterious mutations in primary immune defects, of which nearly 200 are known.” But some caution that standardization of NBS, including test performance, is needed before the more complicated issues accompanying sequencing can be addressed. “Before [SCID] screening becomes universal in the United States, agreement is needed on what constitutes a positive TREC screening test, on ensuring referrals to physicians competent to make a diagnosis, and on providing definitive therapy to every infant detected with SCID in every state,” writes Neil A. Holtzman, M.D., from Johns Hopkins Medical Institutions (Baltimore), in an accompanying JAMA editorial. “The technological advances in newborn screening since [phenylketonuria] screening was first recommended in the United States 50 years ago have been remarkable. However, organizational advances that ensure safe and effective NBS nationwide have not matched them.”