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

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.

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.

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.

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. Competing Interest Statement The authors have declared no competing interest. Funding Statement This study did not receive any funding Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The National Ethics Committee of Albania, under the Ministry of Health and Social Protection. Ethical approval was granted. Approval number: 303/15. Informed consent was obtained from all participants and/or their legal guardians before enrolment, and the relevant consent forms have been archived. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability All data produced in the present study are available upon reasonable request to the authors