Multimodal imaging provides insights into phenotype and disease progression in inherited retinal disorders. Congenital achromatopsia (ACHM), a cone dysfunction syndrome, has been long considered a stable condition, but recent evidence suggests structural progression. With gene replacement strategies under development for ACHM, there is a critical need for imaging biomarkers to define progression patterns and follow therapy. Using semiquantitative plots, near-infrared (NIR-AF) and short-wavelength autofluorescence (SW-AF) were explored and correlated with clinical characteristics and retinal structure on optical coherence tomography (OCT). In sixteen ACHM patients with genetic confirmation (CNGA3, n = 8; CNGB3, n = 7; PDE6C, n = 1), semiquantitative plots allowed the detailed analysis of autofluorescence patterns, even in poorly fixating eyes. Twelve eyes showed perifoveal hyperautofluorescent rings on SW-AF, and 7 eyes had central hypoautofluorescent areas on NIR-AF, without association between these alterations (P = 0.57). Patients with central NIR-AF hypoautofluorescence were older (P = 0.004) and showed more advanced retinal alterations on OCT than those with normal NIR-AF (P = 0.051). NIR-AF hypoautofluorescence diameter was correlated to patient age (r = 0.63, P = 0.009), size of ellipsoid zone defect on OCT (r = 0.67, P = 0.005), but not to the size of SW-AF hyperautofluorescence (P = 0.27). These results demonstrate the interest of NIR-AF as imaging biomarker in ACHM, suggesting a relationship with age and disease progression.

X-linked cone dysfunction disorders such as Blue Cone Monochromacy and X-linked Cone Dystrophy are characterized by complete loss (of) or reduced L- and M- cone function due to defects in the OPN1LW/OPN1MW gene cluster. Here we investigated 24 affected males from 16 families with either a structurally intact gene cluster or at least one intact single (hybrid) gene but harbouring rare combinations of common SNPs in exon 3 in single or multiple OPN1LW and OPN1MW gene copies. We assessed twelve different OPN1LW/MW exon 3 haplotypes by semi-quantitative minigene splicing assay. Nine haplotypes resulted in aberrant splicing of ≥20% of transcripts including the known pathogenic haplotypes (i.e. 'LIAVA', 'LVAVA') with absent or minute amounts of correctly spliced transcripts, respectively. De novo formation of the 'LIAVA' haplotype derived from an ancestral less deleterious 'LIAVS' haplotype was observed in one family with strikingly different phenotypes among affected family members. We could establish intrachromosomal gene conversion in the male germline as underlying mechanism. Gene conversion in the OPN1LW/OPN1MW genes has been postulated, however, we are first to demonstrate a de novo gene conversion within the lineage of a pedigree.