Resolving unsolved whole-genome sequencing data in paediatric neurological disorders: a cohort study.

OBJECTIVE

To resolve unsolved whole-genome sequencing (WGS) data in individuals with paediatric neurological disorders.

DESIGN

A cohort study method using updated bioinformatic tools, new analysis targets, clinical information and literature databases was employed to reanalyse existing unsolved genome data.

PARTICIPANTS

From January 2016 to September 2023, a total of 615 individuals who aged under 18 years old, exhibited neurological disorders and received singleton WGS were recruited. 364 cases were unsolved during initial WGS analysis, in which 102 consented to reanalyse existing singleton WGS data.

RESULTS

Median duration for reanalysis after initial negative WGS results was 2 years and 4 months. The diagnostic yield was 29 of 102 individuals (28.4%) through reanalysis. New disease gene discovery and new target acquisitions contributed to 13 of 29 solved cases (44.8%). The reasons of non-detected causative variants during initial WGS analysis were variant reclassification in 9 individuals (31%), analytical issue in 9 (31%), new emerging disease-gene association in 8 (27.6%) and clinical update in 3 (10.3%). The 29 new diagnoses increased the cumulative diagnostic yield of clinical WGS in the entire study cohort to 45.5% after reanalysis.

CONCLUSIONS

Unsolved paediatric WGS individuals with neurological disorders could obtain molecular diagnoses through reanalysis within a timeframe of 2-2.5 years. New disease gene, structural variations and deep intronic splice variants make a significant contribution to diagnostic yield. This approach can provide precise genetic counselling to positive reanalysis results and end a diagnostic odyssey.