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PubMed · 42150613

Molecular diagnostic yield and barriers in inherited retinal diseases: a retrospective cohort study.

Angel Gao·Yi F Zhai·Rita Kodida·Brian G Ballios
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Abstract

OBJECTIVE: To evaluate the diagnostic yield of panel-based genetic testing for inherited retinal diseases (IRDs) and identify barriers to molecular resolution. DESIGN: Retrospective cohort. PARTICIPANTS: A total of 404 patients with clinically confirmed IRDs who were evaluated at the Adult Inherited Retinal Dystrophy Service, Ontario, Canada (October 2021-September 2024). METHODS: Patients underwent targeted massive parallel sequencing panel testing. Diagnostic yield was calculated, and unresolved cases were reviewed. Associations between yield, phenotype, ethnicity, and sex were assessed using χ² analysis. RESULTS: Of 685 referrals, 570 had confirmed IRDs. After we excluded 140 pending results and 26 patients who declined testing, 404 patients were analyzed. At referral, 94 patients (23.2%) had a previous molecular diagnosis, and 138 (34.0%) were diagnosed through clinic-initiated testing, giving an overall yield of 57.4%. Yield varied significantly by phenotype (χ², P = 1.4 × 10⁻⁶), from 94.4% in vitelliform macular dystrophies to 25.0% in vitreoretinopathies, with no sex association (P = 1.0). Disease-causing variants were identified in 83 IRD-associated genes, most frequently ABCA4, USH2A, and BEST1. Of 172 unresolved cases, 62 (36.0%) had negative panels, and 110 (63.9%) were inconclusive, including 30 with unphased pathogenic variants in recessive genes and 10 with high-suspicion variants of uncertain significance. Key barriers included limited family availability for phasing, restricted access to functional assays, and lack of public coverage for whole-exome or whole-genome sequencing. CONCLUSIONS: Massive parallel sequencing-based panel testing achieved a 57% diagnostic yield in this IRD population. Success was strongly phenotype-dependent with substantial heterogeneity. Whole-exome sequencing, whole-genome sequencing, family segregation, and functional genomics could improve diagnostic outcomes and management.

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HumansRetrospective StudiesMaleFemaleGenetic TestingAdultMiddle AgedPhenotypeEye Diseases, HereditaryRetinal DiseasesHigh-Throughput Nucleotide SequencingYoung AdultAdolescentMutationAgedJournal Article

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Angel Gao, Yi F Zhai, Rita Kodida, Brian G Ballios. 2026-06-05. Molecular diagnostic yield and barriers in inherited retinal diseases: a retrospective cohort study.. https://doi.org/10.1016/j.jcjo.2026.04.026

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Journal Article resourceAdolescent subjectAdult subjectAged subjectFemale subjectHumans subjectJournal Article subjectMale subjectMiddle Aged subjectMutation subjectPhenotype subject

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