Enhancing Diagnostic Precision with Exome Sequencing for Copy Number Variants

Using Exome Sequencing to Improve Detection of Copy Number Variants in Pediatric Patients

Recent advancements in genetic diagnostics have highlighted the potential of exome sequencing (ES) beyond detecting single-gene mutations. Traditionally employed to diagnose Mendelian disorders—conditions caused by inherited or de novo pathogenic variants—ES is now being recognized for its broader utility, particularly in identifying copy number variants (CNVs). CNVs, which involve duplications or deletions of DNA segments, are responsible for a significant proportion of genetic disorders but are often underdetected with conventional methods.

Typically, chromosomal microarray (CMA) is employed to detect CNVs; however, CMA has limitations, especially in identifying smaller CNVs (less than 50kb), which can lead to false-negative results. In contrast, recent research by Dr. Jianling Jenny Ji and colleagues, published in npj Genomic Medicine, has demonstrated that analyzing CNVs using data from exome sequencing can substantially increase diagnostic yield.

In their study, the team evaluated exome data from 1,538 pediatric patients, most of whom were of diverse American ancestries. They identified diagnostic CNVs in 4.6% of cases, ranging from small deletions to extensive chromosomal abnormalities. Notably, this approach was particularly beneficial in patients referred from hematology and neonatology departments. Importantly, the diagnostic gains were consistent across different ancestries, underscoring the method's broad applicability.

This integration of CNV analysis into ES workflows offers several clinical benefits. It enhances the diagnostic process by uncovering CNVs that traditional methods might miss, thereby enabling more accurate diagnoses. This, in turn, supports better genetic counseling, informs treatment strategies, and guides family planning. Furthermore, because exome sequencing is already part of some diagnostic protocols, adding CNV analysis leverages existing data without the need for separate tests.

Dr. Ji emphasizes that this strategy could reduce the number of inconclusive cases and increase the likelihood of diagnosis in complex pediatric genetic disorders. As genetic testing continues to evolve, incorporating CNV detection into ES is poised to become a standard practice, offering a more comprehensive understanding of the genetic underpinnings of disease.

For more detailed insights, see the original study: npj Genomic Medicine - DOI: 10.1038/s41525-025-00478-4.

Source: https://medicalxpress.com/news/2025-05-exome-sequencing-variants-diagnostic-yield.html