Fig 1. Overview of the patient stratification, the lines of genetic investigation performed and the strategy used to prioritize genes for functional follow-up.

(A). HARBOR patients were separated at baseline into two groups based on the size of their Low-Luminance Deficit (LLD): patients in quartile 1 (Q1) had the smallest drop in vision under low-luminance and patients in quartile 4 (Q4) had the biggest deficit. (B). Lines of genetic investigation and top-line results. (C) For functional analysis follow-up, top genetic hits were prioritized based on different criteria such as being the causal gene at the locus (presence of coding variants), the rare variants (RV) identified being enriched in Q1 patients, the gene playing a role in a biological pathway associated with AMD pathophysiology, and providing a potential biomarker opportunity. For the top hits, gene expression in human retina or RPE/choroid (bulk RNA sequencing, data from Orozco et al. [17]) and in different human ocular cell types (single cell RNA sequencing, data from Gautam et al. [18]) were also analyzed. AR: autosomal recessive; FPLD5: Familial Partial Lipodystrophy type 5. RGCs: Retinal Ganglion Cells. RPE: Retinal Pigment Epithelium.