AJHG: Newborn Genomic Sequencing Pilot in the U.S. Reveals Actionable Genetic Risks Undetected by Standard Screening

Editor’s Note: This article is reprinted from BioExplorer, authored by Chen Moyi. VCBeat has republished it with authorization.

Most newborns undergo heel prick blood screening and other tests at birth to diagnose certain conditions, such as phenylketonuria and congenital hypothyroidism. However, the range of diseases detectable through these biochemical tests is not comprehensive.

How to Overcome This Limitation? Newborn Sequencing May Be the Answer.

Image source: AJHG

Recently, a team of scientists reported in the American Journal of Human Genetics (AJHG) that they performed exome sequencing on 127 healthy newborns and 32 affected newborns, identifying 15 infants carrying genetic variants. These variants predispose the newborns to disease risks that are undetectable by conventional screening methods.

Image source: The Genomes2People

This study is part of a project called the “BabySeq Project.” Five years ago, the National Institutes of Health (NIH) funded four projects, including BabySeq, aimed at exploring the application of genomic sequencing in newborn screening.

BabySeq is the first randomized trial to sequence newborns, jointly initiated by researchers from Brigham and Women's Hospital and Boston Children's Hospital, with participation from researchers at Baylor College of Medicine.

All 268 families participating in the trial met with a genetic counselor to discuss their general family history. Subsequently, more than half of the families underwent whole-exome sequencing for their newborns, and all variants were validated using Sanger sequencing.

Ozge Cehan-Birsoy, the clinical molecular geneticist leading the study, and her team review these sequencing data to prepare a clinical report, which is then provided to the newborn’s family, included in their medical records, and made available for use by pediatricians.

In the report, Cehan-Birsoy et al. provided information indicating any risk of pediatric diseases in children, as well as gene mutations associated with adverse drug reactions in pediatric medication. Furthermore, the researchers allowed the parents of newborns participating in the trial to choose whether they wished to be informed about genetic variants associated with the risk of developing adult-onset diseases, such as BRCA1 and BRCA2.

Specifically, the study showed that among 159 infants who underwent sequencing, 15 carried genetic variants associated with an increased risk of pediatric diseases. These variants are linked to a variety of conditions, including several types of heart disease (such as dilated or hypertrophic cardiomyopathy and supravalvular aortic stenosis), biotinidase deficiency, and hearing loss.

Among them, newborns carrying mutations associated with biotin metabolism enzyme deficiency were further tested and confirmed to have partial biotinidase deficiency (Biotinidase Deficiency, a rare disease), which can lead to skin rashes, hair loss, and seizures. Currently, biotin is being added to the infant’s diet, which is expected to prevent the clinical manifestations of this condition.

In addition, two infants had BRCA2 mutations associated with cancer in their genomes, one of whom had a mother with a family history of breast cancer. Eight infants carried gene mutations associated with adverse drug reactions.

Dr. Alan Beggs (Image source: Boston Children's Hospital)

Alan Beggs, a geneticist at Boston Children’s Hospital and one of the initiators of the BabySeq project, stated that they are currently facing a challenge: most of the genetic variants they identify are not associated with any diseases the newborns currently have. So, how exactly will these genetic variants affect the children? Although such genetic information may have certain predictive value, it is not definitive. It is also possible that the children will not develop any related diseases in the future.

Furthermore, he noted that while newborn genomic sequencing may yield beneficial, even life-saving, effects, it can also cause anxiety for parents. What is the precise balance between the financial burden and familial psychological stress imposed by sequencing-based screening and the benefits it confers? This is the very question the BabySeq Project seeks to answer. Time will provide the response.

Cynthia Powell, a pediatrician and geneticist at the University of North Carolina at Chapel Hill, concurred with this view. She expressed hope that researchers would conduct long-term follow-up of newborns who underwent sequencing to ascertain their subsequent disease incidence. Nevertheless, Powell maintained that the study provided compelling evidence demonstrating the utility of genomic sequencing.

However, despite the fact that sequencing can provide more information about newborns, there are still many obstacles to its widespread adoption. On one hand, it is estimated that clinical exome sequencing may cost several thousand dollars per person; in contrast, newborn heel prick screening and blood tests cost at most a few hundred dollars. On the other hand, whether exome sequencing will lead to better outcomes for infants remains to be seen. Furthermore, the accurate and comprehensive interpretation of genetic data remains a significant unresolved challenge.

In recent years, as sequencing technology has become increasingly prevalent in clinical applications, we appear to be moving toward the “era of genomic medicine.” In the future, not only will sequencing costs continue to decline, but the interpretation of genetic data will also undoubtedly become more sophisticated. Each individual’s genetic information will grow increasingly important.

Despite this clear trend, the U.S. newborn sequencing program has not progressed smoothly. In 2016, Science reported that fewer than 10% of invited families agreed to participate in the project. So, would you be willing to have your newborn sequenced?