Newborn Sequencing Delivers Some Unanticipated Findings

Newborn genomic sequencing (NGS) can identify risk for a wide range of disorders that otherwise may not be detected, even in seemingly healthy babies, according to a study published Jan. 3 in the American Journal of Human Genetics. Additionally, this early knowledge can lead to surveillance, interventions, or avoidance of some medications that can improve health outcomes for newborns and their families.

“We were stunned by the number of babies with unanticipated genetic findings that could lead to disease prevention in the future,” said Robert Green, M.D., co-director of the BabySeq Project study, in a statement.

BabySeq Project is a pilot randomized clinical trial that explores the medical, behavioral, and economic impacts of NGS. NGS has the potential to expand screening and clinical management, reduce the diagnostic odyssey for ill newborns, and provide information to guide future reproductive planning. Long-term, NGS can provide pharmacogenomic information that could be beneficial throughout the patient’s lifespan and can provide a genetic dataset available for reanalysis, as indications arise. However, variant interpretation and appropriate reporting of findings remain challenges.

The researchers report on findings from NGS in 159 newborns (127 healthy newborns in well nurseries and 32 ill newborns in an intensive care unit [NICU]). Babies in the NICU were not preselected on the basis of having a suspected genetic disorder. Half of the newborns in each cohort were randomized to receive standard care, including state-mandated newborn screening and genetic counseling based on their family histories. The others received NGS in addition to standard care.

Only pathogenic and likely pathogenic variants were returned. Results fell into four groups: monogenic disease risk that is highly penetrant and present or manageable during childhood; carrier status for any gene meeting the monogenic disease risk reporting criteria; pharmacogenomic genes associated with drugs that might be used in the pediatric population; and actionable, adult-onset disease-associated gene. These included five of 59 American College of Medical Genetics and Genomics (ACMG) actionable genes (BRCA1, BRCA2, MLH1, MSH2, and MSH6. The other 53 ACMG genes were already being returned on the basis of being childhood-onset or childhood-actionable conditions.

Some patients underwent indication-based analysis (IBA). For these analyses, all variants with evidence of a possible contribution to the infant’s indication, including variants of uncertain significance were returned. Sanger sequencing was used to confirm all reported variants.

The researchers report that NGS identified a risk of childhood-onset disease in 9.4 percent newborns (n = 15), but none of the disease risks were anticipated based on the infants’ clinical or family history. Of these identified newborns, 10 were healthy.

Eleven newborns had variants expected to have moderate penetrance or variable expressivity based on the literature, but the variants were considered as medically actionable during childhood (e.g., cardiomyopathies for which surveillance with regular echocardiograms and electrocardiograph could significantly reduce the risk for sudden cardiac death). NGS identified risk for newborn screening-targeted conditions (e.g., hearing loss, biotinidase deficiency) in three newborns that passed newborn screening.

NGS also identified actionable adult-onset disease risk in three of 85 newborns whose parents consented to receive this information (e.g., pathogenic variants conferring risk for hereditary breast and ovarian cancer and Lynch syndrome). Further, these variants were also identified in the mothers of the three children.

“Our findings suggest that thoroughly sequencing newborns reveals potentially life-saving information in both infants and their parents far more commonly than was previously thought and should encourage our entire field to re-evaluate the value of comprehensively analyzing and disclosing genomic information at any age,” said Green in a statement.

Carrier status for recessive childhood-onset disorder was reported in 88 percent of infants and pharmacogenomics variants were in 5 percent. While variants for carrier status were frequently identified, nearly three-quarters of variants were identified only once in throughout the cohort.

IBA were performed in 29 of 32 NICU newborns and six of 127 healthy newborns who later had presentations prompting analysis. However, analysis did not reveal any variants that sufficiently explained the indication, although however, suspicious but uncertain results were reported in five newborns.

Testing parental samples contributed to the interpretation and reporting of results in eight percent of newborns overall, including both variants of disease risk and carrier status variants for which adult carriers could present symptoms.

Takeaway: NGS can identify risk for many conditions that would otherwise not be detected through family history or usual care. However, many reporting issues still need to be further researched, including age of onset and penetrance, as well as downstream costs for the system and psychosocial impacts for families.