Copy Number Variant Analysis Improves Diagnostic Yield in a Diverse Pediatric Exome Sequencing Cohort

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Exome sequencing (ES) is commonly used to diagnose Mendelian disorders, which occur when pathogenic variant(s) in a gene are either inherited from one or both parents or are de novo. Examples of such disorders include cystic fibrosis and sickle cell anemia. However, ES is not the first choice for detecting copy number variants (CNVs), which are typically deletions or duplications of DNA segments. CNVs cause a significant proportion of genetic disorders. Chromosomal microarray (CMA) is traditionally used to detect CNVs, but it may not always be clinically ordered. Additionally, it is limited to detecting larger CNVs (typically larger than 50kb), which can result in false negatives if the CNV is smaller in size.

Jianling Jenny Ji, MD, MS, FACMG, and colleagues conducted a study, recently published in Nature Partner Journal of Genomic Medicine, with the goal to assess the additional diagnostic value of CNV analysis using ES data, particularly in a diverse pediatric cohort with varying clinical backgrounds. In this study, CNV analysis was performed on exome data from 1,538 pediatric patients, most of whom were admixed Americans. Dr. Ji and team identified diagnostic CNVs in 4.6% of patients, ranging from small deletions to large chromosomal rearrangements. The study found that CNV analysis using ES can increase diagnostic yield, especially in cases referred from hematology and neonatology. Importantly, there were no significant differences in diagnostic yield across different ancestries, highlighting the method's applicability to diverse populations. The findings show that incorporating CNV analysis into exome sequencing workflows provides significant diagnostic benefits.

“Our study demonstrates that incorporating copy number variant analysis into exome sequencing workflows increases diagnostic yield in diverse pediatric cohorts,” Dr. Ji explains. This approach increases the likelihood of identifying CNVs missed by traditional methods and can help diagnose conditions in patients where CNV analysis was not clinically ordered but exome data is available. Additionally, this strategy could lead to more comprehensive genetic counseling and better family planning for affected individuals. By improving the overall diagnostic yield, this approach could reduce the number of unsolved cases and offer long-term benefits in clinical settings, particularly in pediatric genetic testing.

CHLA Research Theme: Personalized Prevention and Care
Title: Copy number variant analysis improves diagnostic yield in a diverse pediatric exome sequencing cohort
CHLA Authors: Avinash Dharmadhikari, PhD, DABMGG, NYCQ; Alexander Markowitz; Dolores Estrine; Catherine Quindipan; Simran Maggo; Ankit Sharma; Dennis Maglinte; Matthew Deardorff, MD, PhD, FACMG; Jaclyn Biegel, PhD, FACMG; Xiaowu Gai, PhD; Miao Sun, PhD, D(ABMGG), F(ACMG); Ryan Schmidt, MD, PhD; Gordana Raca, MD, PhD, FACMG; Jianling Jenny Ji, MD, MS, FACMG
Journal: Nature Partner Journal of Genomic Medicine