Determinants of Disease Penetrance in -Associated Retinopathy.

Retinitis pigmentosa 11 (RP11) is caused by dominant mutations in , however a significant proportion of mutation carriers do not develop retinopathy. Here, we investigated the relationship between polymorphism, repeat copy number and disease penetrance in RP11 patients and non-penetrant carriers (NPCs). We further characterized and expression in fibroblasts from eight RP11 patients and one NPC from a family carrying the c.1205C>T variant. Retinal organoids (ROs) and retinal pigment epithelium (RPE) were differentiated from induced pluripotent stem cells derived from RP11 patients, an NPC and a control subject. All RP11 patients were homozygous for the 3-copy repeat in the promoter, while 3/5 NPCs carried a 4-copy repeat. The rs4806718 genotype did not correlate with disease penetrance. expression declined with age in adult cadaveric retina. and expression was reduced in RP11 fibroblasts, RO and RPE compared with controls. Both RP11 and NPC RPE displayed shortened primary cilia compared with controls, however a subpopulation of cells with normal cilia lengths was present in NPC RPE monolayers. Our results indicate that RP11 non-penetrance is associated with the inheritance of a 4-copy repeat, but not with polymorphisms.