Seq—shorthand for “sequence”— has become a more recognizable term thanks to a novel and provocative genomics initiative called the BabySeq Project. The project, officially launched in May 2015, was designed to explore the impact of whole-exome sequencing (WES) on newborn infants and their families. A randomized, controlled trial to sequence healthy and sick infants and then provide sequencing information, it is the first of its kind. Those infants randomized to receive WES undergo genetic sequencing of all protein-coding genes and analysis of about 1,700 genes implicated in childhood health, along with 18 years of follow up genetic counseling.
The project is directed by Robert C. Green, geneticist and physician at Brigham and Women’s Hospital, Harvard Medical School and the Broad Institute, and Alan H. Beggs of Boston Children’s Hospital and Harvard Medical School. Funding, totaling $25 million, comes from the National Institute of Child Health and Development and the National Human Genome Research Institute.
Two weeks ago at the American Society of Human Genetics (ASHG) 2016 Annual Meeting in Vancouver, project leaders presented their findings thus far. There they offered some unexpected insights revealed by the challenges they’ve faced during the recruitment process.
To date, BabySeq has recruited more than 160 families. The goal is to enroll a total of 480 babies, half from well-baby nurseries and half from neonatal intensive care units at two Boston-area hospitals. Half of the newborns enrolled will undergo WES and screening for 1,700 variants of genes associated with childhood-onset diseases, and the results will be compared to the other cohort undergoing conventional newborn disease screening using biochemical analysis of blood spots (the neonatal heel prick, or Guthrie test). So far 51 families have received WES results of their infants, and researchers have identified potentially harmful genetic variants in four of the healthy babies. All four variants were dominant, requiring only one copy of the gene to cause disease; three have an inherited mutation implicated in heart disease, and the fourth is linked to an enzyme defect. None of the four babies have yet to show symptoms of their conditions. These variants would not have been detected if not for WES, suggesting the value of the initiative.
Perhaps more interesting at this early stage are the insights the study has offered regarding the attitude of parents toward the procedure itself and the implications of such results. A press release issued by the ASHG included this statement by BabySeq Project Manager and genetics counselor Shawn Fayer:
“…we are now collecting data from medical record reviews and parental surveys, in order to measure medical benefits, harms, and costs, as well as parents’ understanding of genetic sequencing, their attitudes and anxieties about it, and any actions they may have taken based on the results.”
The “attitudes and anxieties” of parents clearly are impacting the study because enrollment has proven to be a challenge. When Green and his colleagues first began to explore their BabySeq Project idea nearly four years ago, they surveyed more than 500 parents of healthy newborns and found that nearly half of those surveyed expressed being “very” or “extremely” interested in participating. In reality, of the more than 2400 couples approached since the project launched, only about seven percent have signed up. The data collected have revealed that those who declined to participate expressed a range of valid concerns including the fear of receiving unfavorable or uncertain results, the potential for insurance discrimination, and concerns about confidentiality and privacy.
Prospective parents are no doubt considering the variety of ethical dilemmas and uncertainty they might face if told that their newborn does indeed harbor a gene variant that is considered pathogenic or harmful. For some diseases such as childhood-onset colon cancer, this knowledge could make a difference, as there are actions that parents and physicians can take to keep a child healthy. Regular screening during childhood could lead to early detection which is the key to successful treatment. Yet in the case of diseases that manifest themselves later in life but have no effective treatment or cure, parents are left to grapple with the ethical ramifications that his information raises. Perhaps it’s not surprising that the vast majority of families offered the chance to sequence their newborn child’s genome choose not to do it.
Another compelling result the study may reveal is the effect that genomic information may have on parent-child relationships. For example, if a parent knew that their child is predisposed to a developmental disability, would the parent tend to underestimate that child’s abilities? Would it negatively impact the parent’s ability to bond with the child? And, as for the physicians who hold that genomic information, would it influence their decision making about ordering more tests and interventions? If so, would those interventions prove to make those babies healthier or simply waste money?
While ASHG recently provided the BabySeq project leaders a platform to share their results at its recent annual meeting, the organization itself has taken the position that only newborns with undiagnosed illnesses should undergo whole genome sequencing. And, in those cases, only those genes likely to be implicated in the suspected illness should be analyzed. The outcome of BabySeq should help to clarify the usefulness of WES information over time and how it is used in medical decision making. It will take many years of follow-up to determine the ultimate benefits, as well as possible harms, from a novel initiative of this kind. The concerns cited by parents choosing to decline the opportunity to participate may be borne out, yet at the risk of not knowing what medical conditions are written into their newborn’s genetic code.
If you’re interested in reading about a family who benefited from this novel medical approach years before the BabySeq Project was developed, check out the recently published book One in a Billion. This story profiles Nic Volker and his family, as well as his team of physicians, as they race to save Nic from a life threatening illness and the role that genomic sequencing plays in their struggle. Written by two newspaper journalists who covered the story from its dramatic beginning, authors Mark Johnson and Kathleen Gallagher were part of the journalism team that won the Pulitzer Prize in 2011 for explanatory reporting.
Might other children be saved from potentially fatal diseases through whole-exome sequencing? We must wait to find out.
Nicole Sandler
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