Photo of sleeping newborn baby holding adult thumb to represent newborn genome sequencing to test for treatable genetic disorders.
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An analysis from the BabySeq Project, which trialed newborn sequencing in apparently healthy and unwell babies, found 17 infants with potentially pathogenic monogenic genetic findings that were all moderately or highly actionable.

Of these infants, two-thirds were referred to specialist consultation, treatment or surveillance and all their at-risk first-degree relatives were also tested and referred to care if found to be carriers.

Although it is not yet widespread, using newborn genetic sequencing to assess disease risk or diagnose unknown genetic conditions is gaining in popularity and is becoming more accessible due to the increased availability and more affordable price of the technology in recent years.

A concern about using this technology to screen apparently healthy babies is whether anything can be done about the findings. The BabySeq Project, which began in 2015, was one of the first studies around the world to trial newborn sequencing in both apparently healthy babies and those in intensive care. Almost 1000 genes linked to disease were selected and genotyped in the participants.

In the current study, published in the American Journal of Human Genetics, the authors presented data they collected on the actionability of the genetic findings discovered in 17 infants (11 apparently well, and 6 unwell) from a group of 127 apparently healthy babies and 32 infants in intensive care who were enrolled in the BabySeq Project.

The team, led by Robert C. Green, a professor at Harvard Medical School and medical geneticist at Brigham and Women’s Hospital, assessed how actionable a genetic finding was based on a modified ClinGen actionability semi quantitative metric, with all 17 findings classified as moderately or highly actionable.

Thirteen medical conditions were linked to the 17 genetic findings and interventions were available for all of them ranging from increased medical surveillance for cancer to supplementation with biotin in a child with partial biotinidase deficiency. To assess if these interventions were implemented, the investigators followed up all of the infants tested for three to five years.

In three of the infants, the genetic findings prompted the discovery of a subclinical phenotype that hadn’t previously been picked up. In the rest of the group, the genetic findings were pathogenic or likely pathogenic mutations in the genes: TTN, BRCA2, G6PD, SLC7A9, KCNQ4, CD46, VCL, MYBPC3, MSH2, and CYP21A2, increasing the future risk of diseases such as cancer or cardiovascular conditions, among others.

In 13 cases, family members were also assessed after the child’s results were disclosed and some adult cases of the conditions or carriage of risk alleles were also discovered.

“For example, the maternal grandfather of an infant with a maternally inherited likely pathogenic variant in TTN had previously been clinically diagnosed with dilated cardiomyopathy and, as a result of the finding in his grandchild (the BabySeq infant-participant), was subsequently confirmed to carry the same variant. Consequently, the infant’s mother is now routinely followed by echocardiography,” write the authors. The mothers of three infants who were identified with elevated risk for adult-onset cancer also chose to undertake risk-reducing surgeries.

In 16 of the infants, the disclosure of the genetic findings led to recommendations for specialist consultations and follow-up testing for the child and, in cases such as the examples above, family member testing. Overall, 10 infants and their families attended an initial consultation with a specialist and eight continued to receive care.

“By screening apparently healthy newborns, entire families were alerted for the first time that dangerous but treatable genetic variants were present,” said Green in a press statement. “We were stunned to see that with no specific guidance from the study, newborn sequencing prompted life-saving actions among several mothers.”

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