The Human Genome Project generated the human reference genome over 13 years at a cost of $3 billion.1 That massive undertaking used the low-throughput Sanger method, which sequences one DNA fragment at a time. While this strategy remains useful for interrogating small genomic regions, modern next-generation sequencing (NGS) technologies can simultaneously sequence millions of fragments in a single run, enabling the analysis of hundreds to thousands of genes at once.
Today, rapid whole genome sequencing (rWGS) can deliver results in just a few days—or less—for under $1000.2 Because it captures variation across both protein-coding and non-coding regions of the genome, it could eventually replace most other genomic diagnostic tests. And many clinicians believe rWGS should be considered, not as a last-resort, but as a first line diagnostic tool.
This shift could be transformative for patients with rare genetic disorders that remain unsolved after conventional exome testing. Although approximately 80% of rare diseases have a genetic basis, sequencing approaches based on pre-determined gene panels or even whole exomes still leave many cases unsolved. This makes sense: the exome makes up only 1.5% of the human genome.
The remaining 98.5%, once considered “junk DNA,” contains critical regulatory elements that control how genes are expressed. Variants in these non-coding regions can also cause disease, but are invisible to exome sequencing. As a result, many families endure years of inconclusive testing before receiving a diagnosis. On average the rare disease diagnostic journey lasts five years.
Ending the diagnostic odyssey
Some patients can’t wait years for a diagnosis. In pediatric and neonatal care, diagnostic delays can mean irreversible harm or death. rWGS has emerged as a pivotal advance in genomic medicine for these cases.
One area where accelerated diagnosis is particularly critical is inherited metabolic disease. These disorders affect an estimated 1 in 800 live births and encompass nearly 1,500 distinct conditions. Many manifest in infancy or early childhood, often with rapid progression toward permanent disability or death, if untreated.3
The latest generation of sequencing platforms, such as Illumina’s NovaSeq, Oxford Nanopore Technologies’ PromethION, and PacBio’s HiFi, deliver both accuracy and high throughput. More recently, clinicians are leveraging the complementary strengths of short- and long-read sequencing: short-read platforms remain the workhorse for detecting single-nucleotide variants and small insertions and deletions at scale, while long-read technologies enable more complete resolution of structural variants, repeat expansions, and complex genomic regions that are difficult to map with short reads alone. At the same time, bioinformatics pipelines now rely on artificial intelligence and machine learning to accelerate variant annotation, prioritization, and clinical interpretation.3
While many clinicians agree that rWGS should be one of the earliest steps in the diagnostic pathway, cost, data interpretation challenges, and inequitable access, continue to be formidable barriers. Broader implementation will require investing in infrastructure, training, and policy frameworks. But, on the other side lies improved diagnostic accuracy, more precise clinical decision-making, and better long-term outcomes. In 2024, the Medical Genome Initiative, a consortium of U.S. institutions and labs, called for policies to support equitable access and universal insurance coverage for WGS as a first-tier diagnostic test for rare diseases.4
Expanding access to genomic medicine
A genome-first approach could also reduce dependence on specialist referrals to determine which genetic tests a child should receive. Baylor College of Medicine is currently piloting the MAGNET (Making Genomics Accessible to Newborns in Texas) program to provide WGS and RNA sequencing to neonatal intensive care units (NICUs) in rural Texas, where access to such testing is sparse.
The program uses telehealth to provide genetic counseling and physician consultation. The goal is not only to provide more tailored genomic care to critically ill neonates, but also to understand how to best implement cost-effective, scalable genomic testing models in under-resourced settings.5
In critical care settings such as the NICU and pediatric intensive care units (PICU), WGS is now being integrated into frontline clinical decision-making. Several programs are now testing how genome-first models perform in real-world clinical settings.
One such effort is Seqfirst-neo, a pioneering program that applies an exclusion-based rather than inclusion-based approach to make rWGS available to NICU infants in underserved communities. Developed through a partnership between GeneDX, Seattle Children’s Hospital, and the University of Washington, the program offers testing to infants unless their symptoms can be fully explained by prematurity, infection, or an existing genetic diagnosis.
The group reported its Phase 1 findings, in which nearly half of infants who received rWGS were diagnosed with a genetic condition, compared to roughly 10% in the standard-of-care group. Nearly one-quarter of diagnosed infants had no prior suspicion of a genetic disorder and would not have been offered testing under conventional criteria. The authors estimated that 42% of diagnoses would have been missed under standard care. Notably, significantly more non-white and Black infants received a precise genetic diagnosis in the intervention group, helping to mitigate racial disparities in care.6
Ultra-rapid sequencing moves into the clinic
Although rWGS already delivers results within days, several groups are working to compress turnaround times even further. In 2022, a Stanford University team set a Guinness World Record for the fastest DNA sequencing time at five hours and two minutes. In 2025, a collaboration between Roche Sequencing Solutions, Broad Clinical Labs, and Boston Children’s Hospital broke that record, completing whole genome sequencing in just three hours and 57 minutes using a novel sequencing-by-expansion (SBX) method.7
The team piloted this approach in a NICU setting to assess whether same-shift sequencing—from blood draw to clinical report—could be integrated into critical care workflows. While ultra-rapid sequencing is technically feasible, the authors noted that most existing platforms are not yet suitable for routine clinical use. The primary challenges include limited access to on-demand sequencing capable of running one or a few samples cost-effectively.8
SBX solves many of these limitations. The process involves a biochemical conversion of nucleic acids to a surrogate polymer called Xpandomer, 50 times longer than the parent DNA templates. The high signal-to-noise ratio generates a much cleaner signal. The Xpandomers are threaded through millions of biological pores at the rate of hundreds of millions of reporter codes per second per complementary metal oxide semiconductor (CMOS)-based sensor module. The design supports near-real-time data analysis, adjustable run-times, and small-batch multiplexing.9
Looking ahead: from diagnosis to precision therapies
With the right clinical and policy frameworks, integrating WGS into routine care has enormous benefits. Beyond transforming rare disease diagnosis, it aligns with the broader shift toward personalized medicine.
In some cases, establishing a genetic diagnosis may not directly affect patient management as many inherited disorders still lack targeted therapies. However, in May 2025, researchers used CRISPR-Cas 9 base editing to precisely correct an ultra-rare mutation in an infant, baby K.J., with neonatal-onset carbamoyl-phosphate synthetase 1 (CPS1), a metabolic disorder with an estimated mortality of 50% in early infancy.10
Customizable gene-editing platforms designed for unique “N-of-one” variants could potentially address more than 90% of pathogenic variants in genetic diseases. Although individually rare, these diseases collectively affect hundreds of millions of people worldwide.
In November 2025, the FDA announced a new path to market for products where a randomized clinical trial is not possible. The “plausible mechanism pathway” aims to streamline the approval process (and insurance coverage) for one-of-a-kind treatments for rare diseases, like the one developed for baby K.J.11
Together, rWGS and precision gene-editing technologies are poised to fundamentally reshape pediatric medicine—not only ending the diagnostic odyssey, but offering hope once a diagnosis is finally reached.
References
1. International Human Genome Sequencing Consortium. Finishing the euchromatic sequence of the human genome. Nature. 2004;431(7011):931-945. doi:10.1038/nature03001
2. Natl. Hum. Genome Res. Inst. DNA Sequencing Costs: Data. NHGRI, Bethesda, MD. https://www.genome.gov/about-genomics/fact-sheets/DNA-Sequencing-Costs-Data
3. Zheng J, Yang X. Rapid whole genome sequencing in newborn screening for metabolic diseases. Front Pediatr. 2025;13:1686738. Published 2025 Dec 1. doi:10.3389/fped.2025.1686738
4. Jobanputra V, Schroeder B, Rehm HL, et al. Advancing access to genome sequencing for rare genetic disorders: recent progress and call to action. NPJ Genom Med. 2024;9(1):23. Published 2024 Mar 27. doi:10.1038/s41525-024-00410-2
5.Genetic Study to Determine the Cause of Birth Defects in Newborns in Texas (MAGNET), ClinicalTrials.gov, identifier NCT07102966, accessed Jan. 15, 2026,https://clinicaltrials.gov/study/NCT07102966.
6. Wenger TL, Scott A, Kruidenier L, et al. SeqFirst: Building equity access to a precise genetic diagnosis in critically ill newborns. Am J Hum Genet. 2025;112(3):508-522. doi:10.1016/j.ajhg.2025.02.003
7. Genomics, in a flash: A DNA sequencing world record, accessed Jan. 15, 2026, https://www.roche.com/stories/ngs-sbx-sequencing-world-record
8. Wojcik MH, Larkin K, Cipicchio M, et al. Toward Same-Day Genome Sequencing in the Critical Care Setting. N Engl J Med. 2025;393(20):2063-2065. doi:10.1056/NEJMc2512825
9. Kokoris M, et al. Sequencing by Expansion (SBX) - a novel, high-throughput single-molecule sequencing technology. bioRxiv. 2025;2025.02.19.639056.
10. Musunuru K, Grandinette SA, Wang X, et al. Patient-Specific In Vivo Gene Editing to Treat a Rare Genetic Disease. N Engl J Med. 2025;392(22):2235-2243. doi:10.1056/NEJMoa2504747
11. Prasad V, Makary MA. FDA's New Plausible Mechanism Pathway. N Engl J Med. 2025;393(23):2365-2367. doi:10.1056/NEJMsb2512695
About the author: Lauren Tanabe has a Ph.D. in pharmacology and molecular signaling from Columbia University. She completed her postdoctoral work at the University of Michigan as a Dystonia Medical Research Foundation Fellow and at Wayne State University as an American Cancer Society Fellow.