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BabySeq Project Uncovers Risk of Childhood-Onset Disease in 9 Percent of Newborns

NEW YORK (GenomeWeb) – Genomic sequencing can uncover an increased risk for a childhood-onset disease in about 9 percent of newborns, according to the BabySeq Project team.

The BabySeq Project, one of the National Institutes of Health's Newborn Sequencing in Genomic Medicine and Public Health (NISGHT) studies, is a pilot randomized clinical trial launched to examine the medical, behavioral, and economic effects of newborn sequencing.

In a study in the American Journal of Human Genetics today, the researchers reported that in their cohort of 159 healthy and ill newborns, 15 infants harbored a risk of developing a childhood-onset disease. None of these, they noted, were anticipated based on family or clinical history.

"The BabySeq Project is the first randomized trial of sequencing in newborns and the first study to fully examine the wealth of unanticipated genetic risk information in children," said Robert Green, co-director of the study at Brigham and Women's Hospital and a professor at Harvard Medical School, in a statement. "We were stunned by the number of babies with unanticipated genetic findings that could lead to disease prevention in the future."

The researchers enrolled healthy newborns from the Brigham's well-baby nursery and ill newborns from the neonatal and pediatric intensive care units at the Brigham, Boston Children's Hospital, and Massachusetts General Hospital. Half of each group was randomized to receive standard care and half to obtain standard care plus whole-exome sequencing. One hundred and fifty-nine newborns, 127 healthy and 32 ill, underwent sequencing.

Overall, the researchers identified a risk of childhood-onset disease in 15 of the infants, or 9.4 percent. This included variants in genes linked to cardiomyopathies and biotin deficiency.

Among 85 newborns whose parents consented to receive such results, they also found that 3.5 percent had variants linked to a risk of adult-onset conditions, such as hereditary breast or ovarian cancer or Lynch syndrome.

Additionally, 88 percent of the 159 newborns were carriers for recessive conditions and 5 percent had pharmacogenetic variants that could influence drug-dosing decisions.

Six newborns, the researchers reported, had variants related to heart conditions. This included four newborns with variants in TTN and two with variants in VCL or MYBPC3, all of which are linked to dilated or hypertrophic cardiomyopathies. The researchers noted that these families were referred to specialists to be monitored.

Another infant was found to have bi-allelic variants in a biotinidase deficiency-linked gene. While the newborn was healthy, additional testing uncovered a partial biotinidase deficiency that is now being treated with biotin.

The remaining infants had variants affecting the hearing-loss linked gene KCNQ4 and the KBG syndrome-associated ANKRD11 gene as well as variants in genes associated with atypical hemolytica-uremic syndrome, non-syndromic hearing loss, supravalvular aortic stenosis, congenital adrenal hyperplasia, glucose-6-phosphate dehydrogenase deficiency, glomuvenous malformation, and cystinuria.

For 29 newborns who were ill at enrollment and six initially healthy infants who developed symptoms during the course of the study, the researchers also conducted indication-based analyses. No variants, though, were found that could unequivocally account for their conditions.

Still, the researchers concluded that newborn sequencing could be a powerful tool, though they noted that its application is affected by questions of how to interpret variants associated with conditions with varying ages of onset, penetrance, and inheritance patterns.

They also cautioned that this study was small, especially the NICU group. They suggested that parents with sick infants might have declined taking part since genomic sequencing was not guaranteed.

Additionally, project researchers previously reported that only about 7 percent of families approached to take part in the study ultimately enrolled. Families that declined to take part cited a lack of interest in research, time-consuming study logistics, and being overwhelmed, among other reasons, for opting out.

Going forward, the researchers aim to explore healthcare utilization patterns among their cohort. "Only time will tell how the costs — both financial and in terms of extra medical testing and family stress — balance out against the benefits," senior author and BabySeq co-director Alan Beggs from Boston Children's Hospital said in a statement. "That's what we're really trying to find out."