Identifying genetic causes and establishing a diagnostic approach for WES-negative pediatric population with neurodevelopmental disorder

Optical Genome Mapping and long-read sequencing (Illumina Complete Long Reads) as second-tier testing for WES-negative neurodevelopmental disorders

Optical Genome Mapping (OGM) and long-read Illumina Complete Long Reads (ICLR) were applied to 87 children with unexplained global developmental delay/intellectual disability despite prior WES. Six patients carried pathogenic/likely pathogenic variants (4 structural variants, 2 SNVs), for additional diagnostic yields of 4.71% (OGM) and 6.98% (ICLR). OGM was effective for complex rearrangements and repetitive regions, whereas ICLR better detected noncoding SNVs and provided precise breakpoint resolution. The authors propose a stepwise diagnostic strategy positioning ICLR as an early second-tier test for WES-negative neurodevelopmental disorders.

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The study addresses a major practical question: what to do after a negative WES in a neurodevelopmental disorder? Positioning ICLR as second-line testing, ahead of or alongside OGM, is justified by its ability to capture both noncoding SNVs and SV breakpoints. This is the expected trajectory — from WES toward long-read genome — where the gain lies in accessing uncovered regions, not in panel extension.