Molecular Diagnostic Yield and Genotype-Phenotype Spectrum of Inherited Eye Diseases in a Tertiary Health Center in Türkiye

OBJECTIVES: To describe ophthalmic phenotypes prompting genetic testing and to calculate the molecular diagnostic yield retrospectively in a real-world tertiary health center cohort.


METHODS: This retrospective observational study employed a phenotype-first review of archived clinical genetic testing records. Unique individuals with documented ocular manifestations were identified and deduplicated using demographic and phenotype consistency rather than laboratory patient number alone. Patients were assigned one primary molecular outcome: Phenotype-concordant pathogenic or likely pathogenic diagnosis, candidate/variant of uncertain significance/partial finding, unresolved, or secondary/non-diagnostic pathogenic or likely pathogenic finding. Variants of uncertain significance, single pathogenic alleles for recessive disorders, and unphased biallelic variants were not counted as definitive diagnoses.
RESULTS: Among 33 unique individuals, phenotype-concordant molecular diagnoses were established in 18.2% (6/33), while candidate, variant of uncertain significance, or partial findings were more frequent at 54.5% (18/33). Diagnoses involved REEP6, TYR, PTEN, BRPF1, and CACNA1F. An additional patient with albinism carried two heterozygous TYR pathogenic or likely pathogenic variants, but phase was not established; confirmation in trans would increase the yield to 21.2%. Excluding a CACNA1F case with a nonspecific archived phenotype reduced the yield to 15.2%.
DISCUSSION AND CONCLUSION: The conservative molecular diagnostic yield was 18.2%, with candidate and partial findings substantially outnumbering definitive diagnoses. This gap underscores the importance of phenotype concordance, inheritanceaware interpretation, and segregation analysis in real-world ophthalmic genetics, where unresolved cases represent a reanalysis cohort rather than a diagnostic dead end.

Keywords: Ophthalmic Genetics, genetic testing, molecular diagnostic yield, genotype–phenotype correlation, inherited eye diseases, albinism, inherited retinal disease