Back to ListThe Risk of Relying on a Single Genetic Assay : Lessons from Newborn Screening for SMA
With the remarkable advances in gene therapy in recent years, spinal muscular atrophy (SMA)—once considered an untreatable disease—has undergone a major shift in its clinical paradigm. When detected early, SMA is now a treatable condition. As a result, SMA has been incorporated into newborn screening (NBS) programs in many countries, helping save the lives of countless children.
However, the world of life science and genetics is often more complex than we expect. In this article, based on a recent study published in The American Journal of Human Genetics, we explore how false-positive results can occur in genetic testing and why correcting them can create significant value for both patients and healthcare systems.
Two “Healthy” Babies Who Challenged the Textbooks
The standard newborn screening test used to identify SMA patients typically relies on PCR (polymerase chain reaction) to detect the deletion of a specific region of the SMN1 gene—exon 7.
Recently, two newborns—one from Germany and one from Australia—were reported to have zero copies of the SMN1 gene, according to this screening test. Even more strikingly, the infant from Germany was also reported to have no copies of SMN2, the backup gene that can partially compensate for SMN1 loss.
Yet something did not add up. Clinically, both infants appeared completely healthy and showed no signs of disease. What was going on?
The Cause of the Diagnostic Error: A Blind Spot in the Assay
Further genetic analyses, including detailed sequencing, eventually revealed the answer. Both infants actually carried one copy of the SMN1 gene, but a small four–base pair deletion was present in exon 7.
The key issue was the location of this deletion. It occurred exactly within the primer binding site used by the newborn screening assay. Because the PCR primers could not bind properly, the assay failed to detect the gene and incorrectly interpreted the result as “SMN1 deletion.”
In other words, the screening test produced a false-positive result because the detection system itself could not recognize the altered DNA sequence.
A Powerful Insight: “Less Can Still Be Enough”
The mutation caused a frameshift during protein synthesis, theoretically producing an abnormal protein. But why were the infants healthy?
To answer this question, the researchers conducted advanced cellular experiments and zebrafish model studies. They discovered that although the mutant gene produced only very small amounts of protein, the resulting protein was structurally stable and highly heat-resistant.
Remarkably, when this mutant gene was introduced into zebrafish models suffering from SMA-like symptoms, their motor function and survival improved significantly.
This finding provides an important biological insight. It challenges the long-standing assumption that the complete absence of full-length SMN protein is incompatible with survival. Instead, it suggests that even a very small amount of a structurally stable protein may be sufficient to maintain motor function.
The Enormous Economic and Social Value Created by Precise Diagnosis
Through this rigorous verification process, the two infants were able to avoid receiving extremely expensive gene therapy. The children are now 24 months old and continue to show completely normal development without any treatment.
What would have happened if clinicians had relied only on the false-positive screening result and proceeded with treatment?
Not only would healthy infants have been exposed to unnecessary medical stress, but more than 4 million USD per patient (over 5 billion KRW) in unnecessary medical costs could have been spent. This case demonstrates how precise genetic analysis can help protect health insurance resources and limited healthcare budgets, ensuring that medical resources are directed to patients who truly need treatment.
For clinicians working in real-world practice, this case offers an important lesson and practical guidance.
The Importance of a Multi-Step Diagnostic Approach
This case provides an important lesson for clinicians working in real-world practice.
To improve the accuracy of newborn screening and minimize misdiagnosis, a stepwise diagnostic approach is recommended:
- Confirm the NBS result
Even when SMN1 deletion is reported by newborn screening, additional testing should be performed. - Cross-validate copy number
Reconfirm the SMN1 copy number using an alternative method. - Perform full sequencing if results disagree
If the first and second results are inconsistent, full sequencing of the SMN1 gene should be conducted to identify hidden variants, particularly in primer binding regions.
NGS-Based SMA Newborn Screening
In NGS-based SMA newborn screening, SMN1 exon 7 homozygous deletion can be evaluated using the nucleotide that distinguishes SMN1 from SMN2 (c.840C>T) together with read coverage across exon 7. This approach can provide additional evidence and help increase the specificity of screening results.
However, NGS also has limitations. Because SMN1 and SMN2 share approximately 99% sequence homology, conventional short-read NGS cannot always clearly distinguish between the two genes.
As a result, certain variants—including SMN1 heterozygous deletions, some intragenic variants, and gene conversion events—may be difficult to detect accurately using NGS alone.
Therefore, when interpreting NGS-based SMA screening results, it is often advisable to consider orthogonal validation using copy-number–based methods such as MLPA or qPCR when necessary.
Ultimately, the key point is not to rely on a single test but to interpret multiple layers of data together.
Accurate diagnosis forms the basis for deciding whether treatment is needed—and this decision carries profound implications not only for patients and their families, but also for the healthcare system as a whole.
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