Dissecting Missing Heritability in Rare Inherited Macular Dystrophies

To describe the genetic resolution rate, molecular findings, and genotype-phenotype correlations of non-ABCA4 and non-BEST1 inherited macular dystrophies (IMDs) within an Irish inherited retinal disease (IRD) registry.

Retrospective review of individuals with a clinical diagnosis of macular or cone dystrophy. Comprehensive phenotyping (dilated ocular biomicroscopy, multimodal retinal imaging, visual electrophysiology) and genetic testing (panel-based next-generation sequencing, single-gene testing, whole exome/genome sequencing, WES/WGS). Variants were interpreted using ACMG AMP criteria, and genotype-phenotype match was confirmed through multidisciplinary review.

232 patients with macular/cone dystrophies were identified. ABCA4 and BEST1 accounted for most molecular diagnoses (47.4%). Removing ABCA4 and BEST1, 59.0% of IMDs were genetically unresolved, higher than the rate in general IRD cohorts. Deep phenotyping enabled diagnostic reclassification in 13/72 (18.1%), namely achromatopsia, congenital stationary night blindness, and oculocutaneous albinism. Further genetic testing resolved 35/72 (48.6%) of those unresolved on first-line testing, with PRPH2 being most prevalent (n = 12), followed by GUCY2D, CRB1, PROM1, and CRX. Characteristic phenotypic signatures-such as CRB1-associated retinal thickening and retinoschisis or PROM1-associated Stargardt-like changes-supported known genotype-phenotype correlations.

Genetic resolution rates for rare IMDs remain lower than pan-retinal IRD phenotypes. Beyond ABCA4 and BEST1, IMDs exhibit substantial genetic and phenotypic heterogeneity (24 genotypes in this cohort), with low molecular diagnostic rates despite comprehensive sequencing approaches. Detailed multimodal phenotyping (i.e., structural, functional and extra-ocular) is essential to refine diagnosis, guide genetic testing and interpret candidate variants. Genetic testing is challenging when the retinal phenotype is advanced (i.e., atrophy) or lacks pathognomonic features. Meticulous phenotyping (functional, structural and systemic) and broader genomic strategies (e.g., WES/WGS) may further increase diagnostic yield, though gene panel content is constantly improving. Consistently improving molecular diagnostic rates will ensure equitable access to emerging gene-specific therapies.