Diagnostic utility of clinical genome reanalysis in rare pediatric disorders using long-read sequencing

N/A (pediatric multi-gene genomic reanalysis)

Genomic reanalysis by LRS (PacBio HiFi) in undiagnosed pediatric cases after WES or short-read WGS: detection of missed SVs, tandem repeat expansions (STRs), variants in difficult regions (dark genes), and improved phasing; comparison of diagnostic yields

Evaluation of the diagnostic gain from genomic reanalysis by long-read sequencing (LRS, PacBio HiFi) in pediatric cases undiagnosed after standard WES or short-read WGS. LRS detects additional variants through several mechanisms: complex structural variants (SVs) missed, tandem repeat expansions (STRs) in NDD genes, variants in difficult-access regions (dark genes), and improved haplotypic phasing for recessive variants. These results document the clinical utility of LRS as a second-line approach after failed standard diagnosis.

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LRS reanalysis is the most effective diagnostic extension strategy available for post-WES/WGS negative pediatric cases. STR and dark gene detection (SMN1, PMS2, GBA) is particularly valuable. Integrate into unresolved case reanalysis protocols after 18-24 months.

HGG Advances (Cell Press) +2; additional LRS yield in WGS-negative pediatric cases +3; SV + STR + dark genes detected +2; impact on unresolved cases +1