Abstract

Whole-genome sequencing (WGS) has emerged as a powerful genomic tool for diagnosing rare Mendelian 
disorders, offering substantial gains in clinical validity and clinical utility compared with traditional single-gene or 
panel-based approaches. By simultaneously interrogating the full genome, WGS improves diagnostic yield—often 
exceeding prior testing and enabling identification of pathogenic variants that inform prognosis, treatment 
selection, surveillance strategies, and reproductive counselling. Evidence shows that genomic diagnoses frequently 
lead to measurable changes in patient management and facilitate cascade testing for at-risk relatives. However, 
technical limitations such as incomplete coverage, challenges in variant interpretation, confirmatory testing 
requirements, and bioinformatic bottlenecks continue to affect implementation. Broader adoption also raises 
ethical, legal, and social considerations, including data privacy, consent, incidental findings, equitable access, and 
health-system readiness. From a population-health perspective, lessons from diagnostic use suggest that WGS 
could inform targeted screening strategies for severe, actionable Mendelian conditions, though robust economic 
evaluations, longitudinal outcome data, and standardized interpretation frameworks remain necessary. Overall, 
WGS provides a clinically valuable platform for rare disease diagnosis while offering important insights for future 
population screening policies and genomic governance.