JAMA Asks: Why Does Diagnosis Still Take Five Years?

JAMA asks a pointed question in its April 2026 issue: with genomic technology this advanced, why do patients with rare genetic diseases still wait an average of four to six years for a diagnosis? The answer lies not in the technology, but in how care is structured. WES/WGS achieves diagnostic yields of approximately 50% in children with congenital anomalies and neurodevelopmental disorders — and early diagnosis directly determines access to treatment.

---

Is “Rare” Really Rare?

The word “rare” can imply low clinical priority. The numbers tell a different story.

Of the approximately 7,000 recognized rare diseases, 80% have a genetic etiology, affecting an estimated 30 million people in the United States alone. Genetic conditions account for roughly one-third of pediatric hospital admissions and nearly half of inpatient charges.¹ Individually uncommon, collectively these diseases represent one of the heaviest burdens on pediatric health systems.

Why Does Diagnosis Still Take Four to Six Years?

A Viewpoint published in JAMA by Ostrer (2026) addresses this directly.² The diagnostic odyssey is not a technology problem. The authors identify four structural drivers:

• Insufficient clinical recognition of early phenotypic clues
• Delayed referral to specialist care
• Fragmented diagnostic pathways
• Inequitable access to expertise and advanced therapies

The consequences extend beyond inconvenience. Many genetic conditions have a therapeutic window — a period during which intervention can meaningfully alter the disease course. Miss that window, and the opportunity for disease modification may be lost entirely.

WES/WGS: A Case for First-Line Testing

Genomic sequencing is no longer a last resort. When guided by standardized phenotyping frameworks such as the Human Phenotype Ontology, WES/WGS achieves diagnostic yields of approximately 50% in children with congenital anomalies, neurodevelopmental disorders, and sensory deficits.² On this basis, the American College of Medical Genetics and Genomics (ACMG) endorses genomic sequencing as a first- or second-tier diagnostic test.³

The case is equally compelling in critical care settings. An estimated 10–25% of NICU admissions in the US involve an undiagnosed genetic condition.² Pediatric centers that have adopted rapid genome sequencing report diagnostic yields of 40–50%, with frequent and clinically meaningful changes in patient management.

What Early Diagnosis Changes

The clinical value of earlier diagnosis is well-documented. It leads to:

• Fewer unnecessary tests and procedures
• Reduced psychosocial burden on families
• Genotype-informed treatment selection — including enzyme replacement therapy, pharmacologic chaperones, small-molecule agents, and gene-based interventions
• Access to disease-modifying treatment within a narrowing therapeutic window

When treatment response depends on the specific variant identified, diagnostic precision and timing are inseparable from clinical outcome.

---

What Needs to Change — and for Whom

For clinicians

The diagnostic odyssey most often begins — and stalls — in the primary care setting. The paper calls for a clear shift away from watchful waiting toward proactive, phenotype-driven evaluation. In practice, this means three things:

• Recognize early phenotypic signals — unexplained developmental delay, congenital anomalies, or complex multisystem presentations should prompt early consideration of a genetic etiology
• Refer early — suspicion alone, without confirmed diagnosis, is sufficient grounds for specialist referral
• Treat genomic testing as a first-line tool, not a last resort

For diagnostic laboratories

Returning a result is not enough. The paper calls on laboratories to:

• Provide rapid reporting — in NICU and PICU settings, hours matter
• Deliver variant-specific interpretation — functional effects differ even within the same gene, and these differences directly inform treatment decisions
• Participate in global data sharing — rare disease interpretation improves with scale, and no single institution has sufficient data to work alone

---

If you are considering WES/WGS for a patient with suspected rare genetic disease, we would be glad to support you. 3billion provides genomic diagnostic services to over 1,000 clinicians across 70 countries.

---

Q. Why does it still take four to six years to diagnose a rare genetic disease? The delay is not a technology problem — it is a structural one. Key drivers include insufficient clinical recognition of early phenotypic clues, delayed specialist referral, fragmented diagnostic pathways, and inequitable access to advanced care. (Ostrer, JAMA 2026)

Q. In which patients should WES/WGS be considered first? Children presenting with congenital anomalies, neurodevelopmental disorders, or sensory deficits are strong candidates for early genomic testing. When guided by standardized phenotyping frameworks, WES/WGS achieves diagnostic yields of approximately 50%. ACMG endorses genomic sequencing as a first- or second-tier test in these populations.

Q. How does earlier WES/WGS affect treatment decisions? Many genetic conditions have a therapeutic window during which intervention can alter the disease course. Early diagnosis enables genotype-informed treatment selection — including enzyme replacement therapy, small-molecule agents, and gene-based interventions — before that window closes.

Q. How useful is genomic sequencing in the NICU? An estimated 10–25% of NICU admissions in the US involve an undiagnosed genetic condition. Centers that have adopted rapid genome sequencing report diagnostic yields of 40–50%, with frequent and clinically meaningful changes in patient management.

Q. How can I submit a case to 3billion? Cases can be submitted and inquiries made through portal.3billion.io. 3billion currently serves over 1,000 clinicians across 70 countries.

References

1. Gjorgioski S, et al. Genetics and pediatric hospital admissions, 1985 to 2017. Genet Med. 2020;22(11):1777-1785. doi:10.1038/s41436-020-0871-9
2. Ostrer H. When Rare Is Common—Rethinking Pediatric Genetic Care. JAMA. 2026;335(15):1293-1294. doi:10.1001/jama.2026.2072
3. Manickam K, et al. Exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability. Genet Med. 2021;23(11):2029-2037. doi:10.1038/s41436-021-01242-6