Comparative analysis of WGS and WES for genetic diagnosis in a pediatric Albanian population

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Abstract
Background Rare diseases affect over 300 million people worldwide, with more than half of these cases presenting in childhood. Despite advances in genomic technologies, significant diagnostic delays remain, particularly in underrepresented populations. Although whole-genome sequencing is expected to be more effective than whole-exome sequencing, there are currently no direct patient-level comparisons from Albania. Methods We conducted a prospective, head-to-head comparison of whole-genome sequencing and whole-exome sequencing in 72 pediatric patients from Albania with suspected rare genetic disorders. Both technologies were applied in parallel using ISO-accredited pipelines. Variants were classified according to the ACMG guidelines and assessed for clinical relevance. Primary and secondary findings, as well as dual diagnoses, were recorded and compared. Results A molecular diagnosis was achieved in 72.2% of patients. Whole genome sequencing yielded diagnostic or secondary findings in 68.1% of cases, while whole exome sequencing identified primary diagnoses in 30.6% of cases. WGS made a primary diagnosis in 37.5% of cases, resolving complex or blended phenotypes and detecting variant types that were missed by WES, including deep intronic, regulatory and structural variants. Furthermore, WGS identified medically actionable secondary findings in 15.3% of patients, providing direct information for clinical management. Overall, WGS outperformed WES across variant classes and inheritance modes. Conclusion WGS demonstrated clear diagnostic superiority over WES in this pediatric cohort, particularly in identifying complex phenotypes and structural variants. These results suggest that WGS should be considered a primary diagnostic tool and highlight the importance of ensuring equitable access to genomic technologies for underrepresented populations.

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