Expanding beyond the exome: identifying pediatric patients best suited for genome sequencing

This study aimed to compare the diagnostic yield of genome sequencing (GS) versus exome sequencing (ES) in a pediatric population, with a focus on determining whether GS offers a significant advantage over ES in identifying genetic variants. A retrospective analysis of prospectively allocated pediatric patients was performed on 297 pediatric patients who underwent next-generation sequencing. Of these, 59.6% (177) underwent only ES, 32.3% (96) underwent only GS, and 8.1% (24) had both tests. Diagnostic positivity rates were compared between ES and GS, and subgroup analyses were performed based on clinical characteristics. GS demonstrated a higher positivity rate (51.7%) compared to ES (42.8%), with a 95.8% concordance between tests in patients who underwent both. However, the added diagnostic yield of GS was less than 10%. Greater GS positivity was identified in a group of children with neurological, musculoskeletal, growth disorder and craniofacial anomalies. Deep intronic variants were identified in two cases that underwent GS, but only one had also undergone ES. Limitations in medical record completeness and data quality were noted, which could affect the study’s generalizability. GS offered a modest increase in diagnostic yield over ES, particularly for detecting deep intronic variants. Some conditions had greater GS positivity, but the interpretation deserves caution as issues regarding homogeneity and sample selection may have influenced this result.