When should incidental findings in genetic testing be reported? In a recent clinical case, this became an urgent, real-world decision. What began as an investigation into a suspected fetal heart condition led to the unexpected discovery of a separate, potentially deadly disorder. One that was treatable, but only if caught in time.

In a letter to the editor¹ published in The New England Journal of Medicine (2025), Fennell et al. describe how prenatal sequencing uncovered compound heterozygous variants in ADAMTS13, which produces an enzyme essential in regulating clot formation and is associated with congenital thrombotic thrombocytopenic purpura (TTP). The incidental finding allowed the clinical team to plan and deliver treatment at birth, significantly improving the newborn’s chances of survival.

An Unexpected Finding

Prenatal trio exome sequencing was carried out at 31 weeks and 4 days, after ultrasound imaging revealed left ventricular dilation, hypertrabeculation, and skeletal anomalies. The analysis confirmed a pathogenic splice-site variant in FLNC, consistent with cardiomyopathy.

But the sequencing also uncovered compound heterozygous missense variants in ADAMTS13: p.L183Q, classified as likely pathogenic, and p.C527S, initially considered a variant of uncertain significance (VUS). Both were located in prespacer domains, regions critical for the enzyme’s function. Further structural analysis showed that cysteine-527 forms a disulfide bond with cysteine-508, a site previously associated with congenital TTP. 

This insight, supported by past clinical reports, justified the reclassification of p.C527S as likely pathogenic and indicated a high risk of neonatal onset disease. Although the discovery was incidental, the availability of treatment and the predicted severity supported formal reporting. The clinical team now had a window to act.

Racing Against Time

What made this case remarkable wasn't just the incidental discovery, but how quickly and effectively the clinical team mobilised in response. With just more than a month to prepare, they developed a detailed perinatal management plan that included delivery at a tertiary care center, immediate cord blood testing, and precautions in case of severe thrombocytopenia. Fresh frozen plasma was arranged for administration upon delivery, and approval was sought for recombinant ADAMTS13, a newly available therapy not yet stocked locally.

Recombinant ADAMTS13 was approved by the FDA only days before delivery. Although it could not be secured in time for birth, the team moved ahead with their contingency plan. When the infant was delivered at 38 weeks, the predictions proved accurate. Cord blood analysis showed normal hemoglobin but a critically low platelet count of 8x10⁹ per litre. ADAMTS13 activity was under 1%, confirming the TTP diagnosis.

A Coordinated Response

The clinical team acted immediately. Fresh frozen plasma was administered within the first hour of birth and continued every four to six hours, and intensive phototherapy was initiated to manage severe hyperbilirubinemia. Despite these interventions, the infant remained in a precarious condition; thrombocytopenia persisted, and gastrointestinal bleeding required platelet transfusions.

Thrombotic complications were not limited to laboratory findings. Imaging revealed blood clots in the pulmonary valve, internal jugular vein, brain, and liver, indicating the disease process had begun before birth.

By day 15, compassionate access to recombinant ADAMTS13 was secured, and weekly prophylactic infusions began. The response was clear. No further TTP exacerbations occurred, and by 17 months of age, the child showed normal growth, development, and organ function.

The Power of Preparation

In precision medicine, the impact of genetic information depends entirely on whether it can inform clinical decisions. This case illustrates that principle. The discovery of likely pathogenic variants was significant, but it was the coordinated response that changed the outcome. Without prenatal warning, the newborn would likely have presented with unexplained severe thrombocytopenia and multi-organ involvement, making timely diagnosis and intervention far less likely.

The multidisciplinary team took a methodical approach. They reassessed the genetic variants in light of structural modelling and published cases, developed a detailed delivery plan, and arranged for specialist support and interventions. Critically, the team made clinical decisions based on uncertain information. Although the variants were classified as likely pathogenic and VUS, the potential consequences of inaction outweighed the risks of proceeding.

Ethical Complexities

Few areas of prenatal genomics raise more ethical questions than incidental findings. Should variants unrelated to the initial clinical concern be reported? What if their clinical significance is uncertain? How do we weigh the anxiety of incomplete information against the chance to prevent serious harm?

In this case, the availability of effective treatment shifted the balance. Although the variants were incidental and included one of uncertain significance, the potential for early intervention justified disclosure. Six months later, the parents reported no negative effects from the experience. Instead, they felt informed and prepared, with a clear understanding of the need for urgent care after birth.

These views are not isolated. Studies suggest that most parents want access to secondary findings from prenatal genomic sequencing, particularly for childhood-onset conditions that are clinically actionable. One study found that 86% of expectant parents opted to receive secondary findings when given the choice. Others have shown strong interest in receiving information even about non-treatable or adult-onset conditions, though willingness decreases slightly in these scenarios, particularly when results include VUS. However, the overall trend points to a strong preference for access to information, provided that adequate support and counseling are available². 

As genomic testing expands, ethical decision-making will need to account for not only clinical risk but also parental values and the practical realities of communication and consent.

Looking Forward

As prenatal genomic testing becomes more routine, the chance of identifying incidental but clinically relevant findings will increase. This case shows how early genetic insights, when matched by clinical preparedness, can change the course of care.

Advances in noninvasive techniques are making it easier to analyse fetal genomes without the risks of invasive sampling. At the same time, questions remain about how to handle genes like ADAMTS13, where some variants have clear consequences but others are harder to interpret. Including such genes in carrier screening panels may help, but only if supported by robust interpretation frameworks.

This case also underscores the need for clear communication, pretest counseling, and clinical pathways that allow families to make informed decisions. As our technical capabilities grow, so too does the responsibility to act with care, clarity, and purpose.

Conclusion

This case illustrates how incidental findings from prenatal genomic sequencing can inform clinical decisions with immediate impact. A diagnosis that might not have been made in time was instead anticipated, planned for, and treated from birth.

The outcome depended not only on sequencing technology but on thoughtful interpretation, timely planning, and coordinated care. Re-evaluating uncertain findings in light of structural data and clinical context enabled a response that likely changed the infant’s trajectory.

Importantly, this case highlights the need for frameworks that support interpreting variants in their genomic context. That includes considering not just the variant itself, but where it occurs and how it relates to function. It also underscores the value of pretest counseling, multidisciplinary collaboration, and infrastructure that allows early signals to be recognised and acted upon.

Not all clinical teams will want to act on or even see secondary findings, especially in time-limited prenatal settings. This raises questions about how to balance opportunity with feasibility. Standardising how secondary findings are handled and working with clinical teams to define scalable and context-aware processes will be essential if these insights are to support care rather than complicate it.

Not every incidental finding will lead to treatment. But when they do, being prepared to interpret and respond can make all the difference.

References

1. Fennell AP, Roscioli T, Buckley M, et al. Lifesaving Diagnosis through Prenatal Genomic Sequencing. N Engl J Med. 2025;393(1):93-95. doi:10.1056/NEJMc2506080
2. Vears D, Amor DJ. A framework for reporting secondary and incidental findings in prenatal sequencing: When and for whom? Prenat Diagn. 2022;42(6):697-704. doi:10.1002/pd.6097