The 21st century has ushered in significant advances in genetics and genome editing. From the completion of the Human Genome Project to the development of CRISPR-based therapies, science has made leaps in understanding and treating chronic diseases at the molecular level. These innovations have transformed how clinicians approach complex conditions, moving from broad treatment protocols to precision medicine tailored to individual genetic profiles.
Next-generation sequencing (NGS) represents part of this transformation. In 2026, NGS testing is no longer confined to academic centers or rare disease clinics. It’s increasingly becoming part of routine diagnostic workups in oncology, prenatal care and infectious disease management. Despite its growing presence, many physicians still grapple with when to order it, how to interpret results and how to navigate the logistical and financial barriers that come with it.
This article explores how NGS is redefining clinical decision-making, the benefits and challenges it presents and what the future holds for this diagnostic tool.
What is NGS testing & why order it?
Next-generation sequencing (NGS) is a high-throughput technology that allows for the rapid sequencing of large stretches of DNA or RNA. Unlike traditional Sanger sequencing, which analyzes one gene at a time, NGS can sequence multiple genes—or even entire genomes—simultaneously. This capability makes it particularly valuable in identifying mutations, copy number variations and other genetic alterations that drive disease.
NGS testing has the potential to change management, inform prognosis or guide treatment decisions. This is especially true in oncology, where the availability of targeted therapies like larotrectinib (for NTRK fusion-positive solid tumors) and sotorasib (for KRAS p.G12C mutations) has made genomic profiling a cornerstone of precision oncology.
According to Sermo polling, various factors influence physicians’ decisions to order NGS testing. Most commonly, members cited clear impact on treatment decisions (27%) and guideline or protocol recommendations (19%). 30% of respondents reported not being involved in ordering NGS tests at all, highlighting the uneven adoption of this technology across specialties and practice settings.
Best applications of NGS testing in practice
NGS has found its place across multiple clinical contexts, each with unique considerations and benefits. In response to a poll, Sermo members ranked where they believe it’s making the biggest impact:
Oncology (tumor profiling, targeted therapy selection)
Tumor profiling using next-generation sequencing allows clinicians to identify actionable mutations that can be targeted with specific therapies. This approach has reshaped treatment strategies for cancers like non-small cell lung cancer, prostate and colorectal cancer, where genetic alterations dictate therapeutic strategy.
In the Sermo poll, 35% of physicians reported that oncology was the clinical context where they most commonly encountered or considered NGS testing. One general practitioner considers it one of the most straightforward applications. “There isn’t much information about NGS usage in practice and when clearly needed,” they write. “More helpful in malignancies I think for more predictable patterns of disease.”
The shift toward molecular diagnostics in oncology is supported by evolving treatment guidelines. Organizations like the National Comprehensive Cancer Network (NCCN) now recommend comprehensive genomic profiling for advanced non-small cell lung, prostate, ovarian, and bile duct cancers, making NGS an essential component of the diagnostic workup.
Rare or undiagnosed genetic conditions
For patients with rare or undiagnosed genetic conditions, NGS can provide answers that were previously out of reach. Whole exome sequencing (WES) and whole genome sequencing (WGS) allow clinicians to identify pathogenic variants across thousands of genes, often leading to a definitive diagnosis after years of uncertainty.
20% of physicians in the Sermo poll identified rare or undiagnosed genetic conditions as their most common application for considering NGS. A pediatrician and Sermo member emphasized its importance: “The greatest opportunities for NGS testing in clinical practice are the ability to identify a patient’s illness, often a child’s. As a pediatrician, I recognize its importance when it allows for diagnoses that, with appropriate supportive therapies, can change the patient’s quality of life.”
Prenatal or reproductive medicine
NGS has also impacted prenatal and reproductive medicine, offering noninvasive prenatal testing (NIPT) and carrier screening with high sensitivity. These tests can detect chromosomal abnormalities, single-gene disorders and microdeletions that might otherwise go unnoticed until after birth.
One general practitioner raised ethical concerns. “It’s more and more used, notably in oncology or prenatal diagnoses, which is useful for treatment and prevention,” they note. “But uses like commercial testing for abnormalities without any health problems, just to know if one can develop a disease, seems worrying for ethical and psychological reasons.”
Pharmacogenomics
Pharmacogenomics uses genetic information to predict how patients will respond to medications. DNA-based genotyping panels can identify variants in drug-metabolizing enzymes, helping clinicians avoid adverse drug reactions and optimize therapeutic efficacy.
Pharmacogenomics accounted for only 4% of votes in the Sermo poll. Adoption has been slow, partly due to limited insurance coverage and a lack of clinical decision support tools. “Testing can be unaffordable vs well accessible depending on scenario, location and insurance,” notes an OBGYN on Sermo. However, as electronic health records (EHRs) begin to integrate pharmacogenomic data, this application could grow.
Infectious disease or pathogen sequencing
NGS is increasingly used to identify pathogens in cases of unexplained infection or outbreaks. Metagenomic sequencing can detect bacteria, viruses, fungi and parasites in a single test, offering a comprehensive diagnostic solution when traditional cultures fail. Just 4% of poll respondents highlighted this as a common use for NGS, but point-of-care sequencing could eventually become more feasible.
4 key advantages of NGS testing
The benefits of next-generation sequencing extend beyond its ability to detect genetic variants. Here’s how NGS is improving patient care:
More comprehensive detection
NGS-based liquid biopsy platforms are being used in the development of multi-cancer early detection (MCED) tests, though clinical utility and guideline integration are still evolving. These tests analyze circulating tumor DNA (ctDNA) in blood samples to identify cancer signals across dozens of tumor types. This comprehensive approach increases the likelihood of early detection, when treatment is most effective.
Early detection capabilities
One of the most promising applications of NGS is its ability to capture cancer signals in the early stages, often before symptoms appear. Liquid biopsy tests using next-generation sequencing can detect low levels of ctDNA, with the potential to enable earlier intervention.
Precise localization
Beyond detecting cancer, some NGS-based assays can help predict tissue of origin—a critical feature for guiding treatment when the primary tumor site is unknown. This precision could help oncologists tailor therapy to the specific cancer type, improving outcomes and reducing unnecessary treatments. However, the NCCN guidelines for Cancer of Unknown Primary currently do not universally recommend NGS for localization.
Operational advantages
NGS results are often available within two to three weeks. There’s no radiation exposure, minimal discomfort and minimal risk to the patient. “Next-generation sequencing (NGS) has revolutionized clinical diagnostics, particularly in oncology and inherited disease management, by allowing rapid, comprehensive, and increasingly affordable sequencing of the genome,” observes one pathologist on Sermo.
In a Sermo poll, 13% of physicians reported that NGS frequently changes patient management in a meaningful way, while 37% said it does so occasionally.
Overcoming the logistical barriers of NGS testing
Despite its benefits, NGS testing faces significant logistical hurdles that limit its widespread use. A pediatrician on Sermo highlights “cost, response times, and the interpretation of uncertain variants.”
Sermo poll respondents ranked the most common challenges and strategies to address them. Here’s an overview of each:
Variants of uncertain significance
A frustrating aspect of NGS testing is the identification of variants of uncertain significance (VUS)—genetic changes that cannot be confidently classified as pathogenic or benign. VUS can complicate clinical decision-making, leaving physicians and patients in a state of uncertainty.
To address this, clinicians can rely on curated databases like ClinVar and consult with genetic counselors or molecular tumor boards. Over time, as more data accumulates, many VUS are reclassified, so periodic review of results is useful.
Limited clinical actionability of results
Not all genetic variants have therapeutic implications. In some cases, NGS results provide diagnostic clarity but offer no actionable treatment options. This is particularly common in rare disease contexts, where effective therapies may not yet exist.
17% of poll respondents cited limited clinical actionability as a major challenge. The solution lies in setting clear expectations with patients before testing and focusing NGS use on cases where actionable findings are likely.
Insurance denials or reimbursement issues
Cost remains a significant barrier to NGS adoption. While the price of sequencing has dropped dramatically, insurance coverage is inconsistent, and some types of tests are denied by certain plans or require extensive prior authorization.
16% of physicians in the Sermo poll identified insurance issues as a top challenge. “Using NGS results are part of the new Updated WHO for Haematological malignancies, however targeted therapy are hardly available in Private practice due to Medical aid restrictions, and not nearly feasible in Government practice,” writes one pathologist from South Africa.
To avoid reimbursement challenges, clinicians can familiarize themselves with payer policies, use CPT codes correctly and provide thorough documentation of medical necessity.
Long turnaround times
9% of physicians cited turnaround time as a barrier. NGS testing can take weeks to complete, which may delay treatment decisions. To mitigate this, clinicians can order NGS early in the diagnostic process and use rapid turnaround panels when available.
Lack of education or training
Many physicians feel underprepared to interpret NGS results. 14% of poll respondents cited lack of education or training as a significant challenge. “There is a shortage of knowledge and specialists in NGS—and the road ahead is wide open,” writes an intensive care physician.
The solution: invest in continuing medical education (CME) programs, leverage decision support tools embedded in EHRs and collaborate with geneticists or molecular pathologists when interpreting complex results.
How confident are physicians in interpreting NGS test results?
Sermo polling data reveals that interpreting NGS results remains a learning curve for many clinicians. Only 9% of respondents feel very confident interpreting NGS results independently, while 26% rely on reports and support tools. Another 20% feel moderately confident with specialist or genetics support, and 10% report low confidence. A substantial 34% do not interpret NGS results at all.
NGS will only reach its full potential if physicians know how to use it, a neurologist on Sermo believes. “NGS is a major step toward personalized medicine, but its real impact depends on how effectively we translate genomic data into practical clinical decisions,” they write.
A general practitioner shared a practical approach: “In my experience, because of the high costs associated with it, I refer to protocols for when to order it. I interpret the results using guides and a second opinion from colleagues who work in oncology or genetics. It requires training and experience to deliver the results to the patients in a simple, user-friendly manner.” The takeaway: support tools can help translate complex genomic data into actionable insights.
The future outlook: NGS testing in the 21st century
Polled physicians on Sermo foresee the role of NGS expanding in various areas of medicine. 21% of voters believe NGS will become standard of care in many specialties, while27% expect it to expand mainly in oncology and rare disease. “In oncology, it will become a standard and will represent an advance in treatments,” predicts one radiation oncologist.
Another 26% think NGS will remain limited to select indications and 11% think that growth may outpace clinicians’ ability to interpret results.
2026 may usher in a move toward point-of-care sequencing for infectious diseases and rapid diagnostics. Portable sequencers are being deployed in research and outbreak settings, allowing real-time pathogen identification and antimicrobial resistance profiling. This shift has the potential to improve outbreak response and outcomes in critically ill patients.
At the same time, artificial intelligence is playing an increasingly important role in NGS interpretation. AI algorithms can flag actionable variants, predict drug responses and identify novel therapeutic targets.
Transforming clinical care, one sequence at a time
In 2026, NGS could transform precision medicine. The benefits of NGS include comprehensive detection, early diagnosis, precise localization and noninvasive testing. However, challenges remain, from interpreting variants of uncertain significance to navigating insurance denials.
Join the conversation on Sermo to share your diagnostic wins, discuss the ethical boundaries of expanding NGS into newborn screening and routine wellness and connect with physicians who are shaping the future of precision medicine. In a field as rapidly evolving as genomics, the best insights come from the frontlines of clinical care.
