Personalised genomic strategies improve diagnostic yield in inherited retinal dystrophies: a stepwise, patient-centred approach

Background : Inherited retinal dystrophies (IRDs) are genetically heterogeneous group of conditions, with approximately 40% of cases remaining unresolved after initial genetic testing. This study aimed to assess the impact of a personalised genomic approach integrating whole-exome sequencing (WES) reanalysis, whole-genome sequencing (WGS), customised gene panels and functional assays to improve diagnostic yield. Subjects/Methods : A cohort of 597 individuals with IRDs, including 525 probands and 72 affected relatives, underwent a stepwise genetic assessment. Re-evaluation included WES reanalysis, WGS and customised gene panels for unresolved cases. Variant interpretation was refined using updated classification guidelines, functional assays such as mRNA and minigene/midigene assays and segregation studies. Results : Initial genetic testing yielded a diagnostic rate of 59.6% (313/525) in probands. Re-evaluation of 101 unresolved cases resulted in 42 additional proband diagnoses and resolution of 7 familial cases, increasing the total number of new diagnoses to 49 (48.5% of re-evaluated cases). This raised the overall diagnostic yield in probands to 67.6% (355/525). Functional assays confirmed pathogenicity of variants in ABCA4 , ATF6 , REEP6 and TULP1 , while WGS enabled the identification of large structural and deep intronic variants, further enhancing molecular diagnostic accuracy. Conclusions : A patient-centred, multi-tiered genomic strategy significantly improved the diagnostic yield for IRDs, refining genotype-phenotype correlations and enabling personalised genetic counselling. Periodic re-evaluation incorporating advanced sequencing and functional assays is essential to improve IRD molecular diagnostics.