Dissecting Missing Heritability in Rare Inherited Macular Dystrophies.
Beyond ABCA4/BEST1, most rare macular dystrophies remain genetically unresolved
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 (inherited macular dystrophies) within an Irish inherited retinal disease (inherited retinal disease) registry.
Retrospective review of individuals with a clinical diagnosis of macular or cone dystrophy.
232 patients with macular/cone dystrophies were identified.
ABCA4 and BEST1 accounted for most molecular diagnoses (47.4%).
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 .
Genetic resolution rates for rare inherited macular dystrophies remain lower than pan-retinal inherited retinal disease phenotypes.
Beyond ABCA4 and BEST1 , inherited macular dystrophies 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.