Phase I of BabySeq study wraps; complete results of DNA sequencing reported for 159 newborns

Whole exome sequencing turns up carriers and various actionable genetic disease risks

Does routine DNA sequencing in newborns yield useful information? The BabySeq study, an NIH-funded project launched in 2015, reports its findings to date, including complete enrollment and interpretation of the sequencing results. The analysis, published January 3rd in the American Journal of Human Genetics, was led by Ozge Ceyhan-Birsoy, PhD of Partners HealthCare andAlan H. Beggs, PhD, director of The Manton Center of Orphan Disease Research at Boston Children’s Hospital.

Current newborn screening tests a baby’s blood for several dozen known, treatable conditions. BabySeq, in contrast, entails whole-exome sequencing and examination of thousands of genes known to be associated with disease. Interpreting the results for families is more complex, since having a genetic variant doesn’t always mean having the disease, and many of the conditions identified may be rare or not currently treatable.

Overall, 316 newborns participated in the BabySeq study: 65 sick infants, from the newborn intensive care units (NICUs) at Boston Children’s, Brigham and Women’s Hospital and Massachusetts General Hospital, and 251 healthy babies from the Brigham and Women’s well-baby nursery. The study is led by Beggs and Robert C. Green, MD, MPH, of Brigham and Women’s, with Amy L. McGuire, JD, PhD and collaborators at the Baylor College of Medicine.

Of the 316 enrolled infants, 157 were randomly assigned to standard newborn screening. The other 159 infants (127 healthy babies and 32 in NICUs) were assigned to whole-exome sequencing in addition to standard newborn screening. Under the study protocol, genetic counselors and study physicians shared results only for genes strongly associated with childhood-onset conditions. A subset of parents also received results about adult-onset conditions, provided they were actionable (diseases with no treatment, such as Alzheimer’s disease, were excluded).

Newborn sequencing results

  • Fifteen babies (9.4 percent) had genetic variants that conferred a high likelihood of a childhood-onset disease or for which early intervention could prevent serious outcomes. Ten were from the well-baby nursery (10/127, or 8 percent) and five from the NICU (5/32; or 16 percent). Conditions included cardiomyopathy, biotinidase deficiency, congenital adrenal hyperplasia, venous malformations, cystinuria, and hearing loss. “None of these findings were predicted based on known clinical or family histories of the newborns,” notes Ceyhan-Birsoy, first author on the paper.
  • 140 of the 159 sequenced newborns — 88 percent — were found to be carriers of one or more genetic variants known to be associated with disease, meaning they had the gene and could pass it on to their own children, but were not at risk for the disease themselves. Most (73 percent) of these variants were rare, identified in only one child.
  • Parents of 85 of the 159 sequenced babies agreed to receive results indicating a risk for actionable adult-onset conditions. Three babies (3.5 percent) had such genetic risk factors, two for breast cancer and one for colon and endometrial cancer. Each was inherited from a parent, who was referred for counseling and potential surveillance for early detection of potential malignancies.
  • Eight babies (5 percent) had a “pharmacogenomic” genetic variant, one that predicts an adverse effect, lack of response or altered dose requirement for particular medications (a cancer chemotherapy drug in four cases, and an immunosuppressive medication in the rest). These eight babies would need to have their prescription or dosage adjusted should they need these medications.
  • Three newborns that passed routine newborn screening were identified to be at risk for conditions included in newborn screening. They had either extremely mild or subclinical disease, or forms not expected to manifest until later in life.
  • Interestingly, only one NICU baby had a likely genetic cause identified for their illness, although up to 16 percent had variants of uncertain significance. Beggs points out, though, that many babies in the NICU have problems that may be unrelated to genetics, such as prematurity or respiratory distress. Also, because infants were chosen for sequencing at random, it’s possible that parents who wanted sequencing to investigate their baby’s symptoms may have opted out of BabySeq, leaving behind a group less likely to have a genetic cause.

Next steps for BabySeq

As previously reported, enrollment in BabySeq was a complex process, with some parents opting not to participate due to the complexities and uncertainties surrounding genetic testing. The babies who were sequenced will be followed over time, and forthcoming papers will report what actions families take based on the genetic findings, what tests they lead to, their cost, and how knowledge of the genetic findings affects family dynamics.

“Sequencing results have potential to raise questions that may be upsetting for parents, but could also lead to helpful or even lifesaving interventions,” says Beggs, the paper’s senior author. “Only time will tell how the costs — both financial and in terms of extra medical testing and family stress — balance out against the benefits. That’s what we’re really trying to find out.”

The study was funded by the National Institute of Child Health and Human Development and the National Human Genome Research Institute of the National Institutes of Health.