Improved genomic characterization of a clinically heterogeneous pediatric cohort with WGS vs. WES.

Whole genome sequencing (WGS) comprehensively detects DNA sequence variation, enabling assessment of genetic disorders. The primary aim of this study was to investigate the diagnostic utility of WGS for pediatric musculoskeletal disorders by comparing it with whole exome sequencing (WES), which is more widely used but not as comprehensive in its coverage of the genome. This multi-center cohort study consists of WGS and WES analysis for 36 pediatric patients with musculoskeletal disorders of unknown etiology and, where available, their parents and siblings. WGS and WES were performed on DNA extracted from saliva samples. Secondary analysis of sequence data and tertiary analysis with interpretation of sequence variants were performed using the Illumina DRAGEN and Emedgene platforms, respectively. We evaluated 36 patients, and the median age was 11 years. The most common phenotypes included thoracolumbar scoliosis and gait disturbance. The median number of candidate variants per patient identified by WES and WGS were 57.5 and 90.5, respectively. 38 pathogenic or likely pathogenic variants were identified by WGS, providing a potentially diagnostic (tier-1) candidate for 22 of 36 (61.1%) patients. 12 of the 38 tier-1 variants (31.6%) were identified only by WGS. Of these 12 variants missed by WES, two candidates had variants that are likely to solve the respective case after undergoing manual curation. WGS resulted in a larger number of variants predicted as pathogenic/likely pathogenic in patients with musculoskeletal phenotypes, including variants potentially capable of solving their respective cases. WGS showed particular advantage in detecting CNVs. This study demonstrates that WGS is a promising method for improving our understanding of musculoskeletal disorders marked by genetic and phenotypic heterogeneity.