The evolving role of exomes and genomes in clinical practice

At the 2025 American College of Medical Genetics and Genomics (ACMG) annual meeting in Los Angeles, we hosted a focused session on the role of exome and whole genome sequencing (WGS) in clinical and research settings. The goal was to spark conversation about available technologies, implementation challenges, and future strategies. Four expert speakers shared insights on clinical utility, followed by a lively audience Q&A.

This blog captures key takeaways from the event, including when and why broader testing is preferred over targeted panels, how to optimize virtual panels, and reimbursement realities. Whether you're a lab director, clinician, or genetic counselor, these insights offer timely guidance.

Table of contents

Exome vs. genome sequencing vs. targeted panels: Why broader testing improves diagnostics

Historically, targeted panels have been the cornerstone of many diagnostic workflows. However, as our understanding of gene-disease associations evolves, so too must our approach to testing.

Exome sequencing can adapt to the dynamic nature of clinical genetics. Take carrier screening, for example. As Mahmoud Aarabi, Medical Director of UPMC Cytogenetics Laboratories, explained, the list of genes recommended for autosomal recessive and X-linked carrier screening by ACMG¹ is continuously updated based on new phenotypic and population data. Rather than continually revising panel content, exome sequencing provides a flexible, future-ready alternative. Phenotyping also plays a critical role. In prenatal testing, complete phenotyping can boost exome diagnostic yield by 7-10%.²

Jeanette McCarthy, Principal Consultant at Zifo, emphasized how labs can maximize efficiency using virtual panels (slice panels) to analyze exome data. With this approach, labs validate the wet lab component once and can then revise gene content as needed without extensive revalidation.

But designing virtual panels well requires careful forethought. She recommended selecting only genes with robust disease-gene validity, accounting for technically challenging targets (e.g., SMN1, PMS2), and avoiding copy number variation (CNV) analysis for genes that lack sufficient evidence of a loss-of-function mechanism. Additionally, genes should be excluded when the only relevant variant types cannot be reliably detected by exome sequencing - for example, including ATXN7 is unhelpful due to exomes' inability to detect repeat expansions.

Joe Jacher, Genomenon and trained genetic counselor, highlighted the clinical and economic case. "You can save $20,000 by skipping from microarray straight to exome," he noted, citing peer-reviewed research.³ Indeed, the literature supports exomes/genomes as first- or second-tier tests for congenital anomalies or intellectual disability.⁴ For neurodevelopmental disorders (NDDs), exome sequencing outperforms chromosomal microarray analysis in both diagnostic yield and cost-effectiveness when used early.^4,5

Reimbursement challenges: How insurance impacts exome and genome testing in clinical practice

One of the largest challenges to broader adoption of exome and genome sequencing in clinical settings is insurance coverage. Despite proven utility, reimbursement remains inconsistent and often favors exome over genome sequencing, which is often restricted to research use.

In pediatric oncology, for example, current guidelines may still prioritize legacy tests like karyotyping and FISH over broader sequencing approaches, even when those legacy tests fall short of delivering a diagnosis.

To navigate this, some labs are adopting hybrid models. At Stanford Medicine, clinical panels are run on a genome backbone, enabling targeted reporting first, with the option for expanded analysis later if required. It also positions the lab for a future where broader genome analysis becomes more widely accepted and reimbursed.

If insurers continue to favor exomes, exome-on-genome workflows may be a practical interim solution to futureproof workflows and streamline reanalysis as new insights emerge.

Genome sequencing advantages: What exomes miss in clinical diagnostics

WGS offers some clear technical advantages. It covers both coding and non-coding regions, provides more uniform coverage than exomes, and captures structural variants and repeat expansions with greater accuracy.

Jennefer Carter, Senior Genetic Counselor and part of the Stanford Undiagnosed Diseases Network (UDN), described how WGS delivered diagnoses in cases where exome sequencing would have failed. Among 283 Stanford UDN patients, WGS revealed diagnoses in cases involving CNVs/structural variants, repeat expansions, and non-coding variants - challenging variant types often missed by exomes.

Audience members agreed. One noted that "genome + RNASeq is the way forward," pointing to savings from eliminating multiple legacy tests. But RNASeq has its own limitations, such as with conditions affecting tissues where genes are not expressed in the blood.

Moreover, there were warnings of variability in commercial genome testing. Some labs restrict genome interpretation to just 10 bp into introns unless another variant prompts deeper review. Transparency and education are essential to ensure providers understand what their patients are receiving.

Despite historical limitations, some institutions are already shifting toward genome-first approaches. A genetic counselor from Children's Hospital Los Angeles noted that their team now defaults to WGS for most send-outs. Encouragingly, insurer coverage is improving, and third-party labs have been able to cover costs to build evidence for future reimbursement.

Moving forward: Practical advice and a call to action

So, what can clinical labs and providers do today to prepare for an exome- and genome-enabled future?

1. Design flexibly - Use virtual panels on exome/genome backbones to accommodate evolving gene lists.
2. Account for technical feasibility - Focus on genes and variant types detectable with current tools.
3. Educate and advocate - Ensure providers understand the scope, benefits, and limitations of testing options. Push for greater transparency from commercial labs.
4. Prepare for broader data interpretation - Consider testing on genome backbones where feasible, for deeper reanalysis.
5. Support policy change through data - Collaborate to collect and publish evidence supporting reimbursement of WGS.

While WGS promises broader insights, exome sequencing remains the most practical and reimbursable tool today. It balances diagnostic yield, cost, and flexibility, making it a strategic choice for many clinical settings.

As infrastructure, interpretation tools, and reimbursement models continue to evolve, WGS will play a growing role in routine care. But for now, optimizing the use of exomes while laying the groundwork for a genome-based future, offers the best of both worlds.

The discussion at ACMG 2025 made clear: the path to better patient outcomes lies in making high-quality genomic testing more accessible, informed, and actionable.

Visit our to learn more about SOPHiA DDM™ exome and genome solutions.

References

1. Gregg AR, Aarabi M, Klugman S, et al. Genet Med Off J Am Coll Med Genet. 2021;23(10):1793-1806.
2. Aarabi M, Sniezek O, Jiang H, et al. Hum Genet. 2018;137(2):175-181.
3. Stark Z, Tan TY, Chong B, et al. Genet Med Off J Am Coll Med Genet. 2016;18(11):1090-1096.
4. Manickam K, McClain MR, Demmer LA, et al. Genet Med Off J Am Coll Med Genet. 2021;23(11):2029-2037.
5. Srivastava S, Love-Nichols JA, Dies KA, et al. Genet Med Off J Am Coll Med Genet. 2019;21(11):2413-2421.