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April 11, 2024

Rare Perspectives Insights: Addressing VUS and Diversity in Rare Diseases through Newborn Sequencing

The potential of Newborn sequencing promises to eliminate variants of unknown significance by generating diverse genetic data from birth, enabling early disease detection, intervention, and comprehensive understanding of genetic variations across populations.

In the February installment of our Rare Perspectives Roundtable Series, I had the honor of discussing “The End of VUS? Impact and Treatment of Rare Diseases” with Dr. Heather McLaughlin, PhD- Senior Director, Molecular Diagnostics at Pharming; and Nicole Miller, PhD, Vice President- Molecular Diagnostics at Ultragenyx. Our panel addressed a range of issues centered around the potential elimination of VUS by 2030. One of the main themes of our discussion was the importance of aggregating genetic data, the gaps in our current data, and a potential solution for both.

We need more genetic data

In labs around the world, new genomic variant data is generated daily, adding to our current store of genetic knowledge. The challenge has always been to organize, annotate, and interpret this variant data to help clinicians in correlating genetic test results with clinical outcomes. While it is true there’s plenty of genetic data already available, there’s still a pressing need for more. The knowledge gap is largely the result of what are known as variants of unknown significance (VUS) and they pose a significant challenge. Although recent years have seen strides in curating the human genome, this has captured only a fraction of all possible disease-causing variants and even among variants that have been seen, the evidence for pathogenicity is not yet sufficient to say with clinical certainty that they are disease-causing.

We need more diverse genetic data

In addition to benefiting from more genetic data, we must strive for a greater diversity of genetic data. The sequencing efforts of the past had centered primarily around a few ethnic groups. To promote improvements in patient outcomes for all patients, there is a clear and urgent need for more diverse genetic data. To date, most data come from studies on a western European population. As our panelist Dr. Miller commented, “if you are of European descent, you’re on the side of a better chance of getting a rare disease diagnosis than you are if you are not of European descent because our reference genomes are not fully representing all of the different backgrounds of people.” This imbalance is echoed in Giogio Sirugo’s work, “The Missing Diversity in Human Genetic Studies” (Cell, 2019), which underscores the risk of incomplete or erroneous application of these data – “The lack of ethnic diversity in human genomic studies means that our ability to translate genetic research into clinical practice or public health policy may be dangerously incomplete, or worse, mistaken.” Just as we are beginning to realize the promise of Precision Therapeutics, where we use information about a patient’s genes or proteins to prevent, diagnose, or treat disease, we need the most diverse genetic dataset to be the most effective and precise.

Newborn Sequencing: A Potential Solution

Newborn sequencing offers a promising potential solution to address both the data problem and the diversity problem. This approach promises not only early disease identification and treatment but also a transformative understanding of genetic diversity. By implementing universal newborn sequencing, we can harness a vast pool of genetic information that encompasses a diverse range of ethnicities, providing a more comprehensive understanding of genetic variations and their clinical implications.
One of the key advantages of newborn sequencing is its ability to capture genetic data from a population at birth. Unlike traditional genetic studies that often rely on adult participants, newborn sequencing allows for the collection of genetic information from individuals across diverse ethnic backgrounds right from birth. This early intervention not only ensures timely diagnosis and treatment but also facilitates the aggregation of longitudinal data, enabling researchers to track disease progression and to better understand the trajectory of various conditions over time.
Dr. McLaughlin emphasized,

“The potential of a genotype-first healthcare strategy made possible by newborn sequencing. Early detection of genetic variations can lead to preemptive monitoring for disease markers and interventions before the onset of symptoms. Such an approach could significantly enhance patient outcomes and contribute to a deeper understanding of the genotype-phenotype interplay.”

Implementing newborn sequencing at a national level may also mitigate healthcare access disparities, ensuring every child, irrespective of socioeconomic or geographic factors, is sequenced. Nonetheless, the broad application of newborn sequencing must be navigated with consideration for ethical issues, informed consent, privacy safeguards, and the establishment of data management infrastructures.


From the sequencing of the first human genome to today’s advanced routine variant interpretations that influence patient care, we have made significant progress. Yet, the complete resolution of VUSs remains on the horizon. I am confident that with a more comprehensive and diverse dataset, we can propel healthcare and scientific inquiry forward into a future free of the VUS challenge that plaques clinicians and patients alike.

If you haven’t already done so, I highly recommend you watch Rare Perspectives Roundtable: The End of VUS? Impact on Diagnosis and Treatment of Rare Diseases, and gain insights into the likelihood of eliminating VUS – and what it would mean if we did.

Mark J. Kiel, MD, PhD
Chief Scientific Officer & Co-Founder
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