3billion Re-analysis Part 3: Clinical Updates Expand Diagnosis – Case Sharing

Genomic testing is not a one-and-done procedure.

Today, I would like to share two cases to explain why the addition and verification of clinical information are crucial in genomic analysis.

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🧬 Clinical Data Changes, Interpretation Evolves — The Power of Reanalysis

When clinical information is updated, the same genomic data can take on a completely different meaning.

The two cases below clearly demonstrate how ‘clinical information updates’ influence interpretation.

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📝 Case 1: From NF1 Alone to NF1 + FANCA (Dual Diagnosis)

Initial Analysis (2023) 📌

The patient underwent genomic testing with the following symptoms:

• Epilepsy
• Hydrocephalus
• Strabismus
• Café-au-lait macules
• Axillary freckling
• Optic glioma

These represent the typical clinical presentation of Neurofibromatosis Type 1 (NF1). A pathogenic variant was indeed confirmed in the NF1 gene, leading to a sole diagnosis of NF1.

Two FANCA variants were also found in the same analysis. However, they were not included in the report at the time because there were no clinical features suggestive of the autosomal recessive disorder Fanconi Anemia. Furthermore, it was considered possible that the two variants were located on the same chromosome (in cis), which would not cause the disease.

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📌 Clinical Update (January 2024)

A year later, the primary physician sent new information: “Fanconi Anemia is suspected.”

This single sentence provided sufficient evidence to re-examine the FANCA variants.

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🔎 Reinterpretation Results

The two FANCA variants initially detected were now considered highly likely to be compound heterozygous, meaning they were inherited from different parents. Crucially, the patient’s updated clinical changes now precisely aligned with the features of a FANCA-related disorder.

Consequently, the patient’s diagnosis was expanded from NF1 alone → NF1 + FANCA (Dual Diagnosis).

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📝 Case 2: From ARHGEF9 Alone to Re-evaluation of MOCS1 Variants

Initial Analysis (October 2022) 📌

The patient’s main symptoms were:

• Stroke-like episode
• Seizure
• Microcephaly

The analysis confirmed and reported a pathogenic variant in the ARHGEF9 gene.

At the time, two variants were also detected in the MOCS1 gene. However, this was not deemed a significant combination and was not reported because there were no typical findings of Molybdenum Cofactor Deficiency (MoCD).

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Clinical Update (October 2024) 📌

The primary physician sent the results of biochemical tests: “Very low uric acid and elevated sulfocystine.”

This combination represents the highly typical biochemical signature of MoCD.

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Reinterpretation Results 🔎

The Likely Pathogenic (LP) + Variant of Uncertain Significance (VUS) combination in MOCS1, which was initially considered insignificant, now precisely aligned with the new clinical and biochemical information.

The report was updated from ARHGEF9 alone → ARHGEF9 + Suspected MOCS1 (Further evaluation needed).

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🔍 What These Two Cases Illustrate

In both patients, a pathogenic variant was already confirmed in the initial analysis, resulting in a ‘diagnosed’ status. However, as clinical information was added over time, variants that were initially considered insignificant were newly highlighted.

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Reanalysis due to Symptom Updates Occurs in Various Forms

Reanalysis triggered by updated symptoms can result in several outcomes:

• POS → POS (Dual diagnosis or expanded diagnosis)
• Initial NEG → Upgrade to VUS
• NEG → POS (Often considered the most dramatic outcome)

In practice, the change from NEG → POS is actually very rare in 3billion’s internal data, and the reason is clear: 3billion’s initial analysis is robust.

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When We Choose Not to Report Pathogenic/Likely Pathogenic (P/LP) Variants

What is critical in genomic analysis is not simply “a P/LP variant exists,” but rather, “Is this variant causing the disease in this patient right now?”

Therefore, a P/LP variant is not reported in cases such as:

• When the core symptoms predicted by the variant are not confirmed in the provided clinical information.
• When a variant associated with an adult-onset disorder is found incidentally in a child.

The principle is: If a variant is clinically insignificant at present, even if it exists, it is not reported.

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The Critical Question: Absent or Unrecorded?

A significant issue arises here: Is the “absence of symptoms” truly absent, or is it simply unrecorded?

This distinction is crucial for the following reasons:

✔️ Why Must Core Symptoms Be Confirmed?

• To confirm the possibility of a Sample–Patient Mismatch.
• To prevent inaccurate variant interpretation.
• Ultimately, because it is directly related to patient safety.

✔️ Why Does This Issue Occur?

• The clinical information on the request form may be limited.
• The department ordering the test may not be familiar with the core symptoms of the genetic disorder.
• Possibility of a specimen labeling error.

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3billion’s Initial Analysis: More Than Just Listing Variants

Therefore, 3billion’s initial analysis is not merely a list of variants. It involves a comprehensive review of all factors:

• Does the variant explain the patient’s symptoms?
• Is any crucial clinical information missing?
• Is there a possibility of a sample error?

Because all these elements are reviewed comprehensively, the necessary interpretation is already largely completed during the initial analysis phase in many cases, meaning the results do not change significantly even if symptoms are added later.

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Moving Forward: Strategic Management Utilizing Systems

The two patient cases clearly demonstrate that an update in clinical information leads to a critical expansion, often resulting in a ‘Dual diagnosis.’

In other words, the physician’s attentive observation of the patient’s changing condition is the decisive factor that maximizes the diagnostic yield of reanalysis.

However, as discussed in Part 2, requesting reanalysis at frequent intervals without a change in symptoms can be inefficient. Ultimately, the solution to maximizing the genomic diagnostic yield is not ‘frequent requests,’ but rather ‘Strategic Management Utilizing Systems.’

Just as critical as clinical updates is the unceasing evolution of genomic knowledge. Changes in the field of genetics—such as the publication of new genetic information and the reclassification of variant pathogenicity—never stop. 3billion has built a system to preemptively address these knowledge shifts technologically, so clinicians do not have to track and worry about every change individually.

In the next article, we will detail how the core solution—the Automated Reanalysis System—alleviates concerns about the reanalysis request cycle and automatically updates the diagnosis based on genetic evolution, providing a true long-term benefit to patients.