Biallelic Variants Are Associated with Isolated Retinitis Pigmentosa.

A class of retinal dystrophies known as retinitis pigmentosa (RP) is caused by the loss of photoreceptor cells. RP can be genetically transmitted as an autosomal dominant, autosomal recessive, or -linked trait. About one-third of genes implicated in retinal degeneration encode for proteins whose functional dysregulation affects the "connecting cilium" in photoreceptors, altering its structure and function. Here we report on a 33-year-old woman who was referred for clinical genetic testing following a previous diagnosis of degenerative retinopathy, which was not informative. She was enrolled in a research program dedicated to undiagnosed retinal disorders, where a whole genome sequencing approach was employed to understand the underlying genetic basis. The genomic analysis documented the occurrence of compound heterozygosity for two functionally relevant missense variants in , which encodes a protein with a well-documented role in SNARE-mediated trafficking and ciliogenesis. Confocal microscopy analysis showed elongated cilia in patient-derived and -depleted fibroblasts compared to control cells. Real-time PCR analyses showed a consistent significant reduction of mRNA levels in patient-derived and -depleted cells, both in basal conditions and after treatment with Smoothened agonist, SAG, indicating Sonic hedgehog signaling dysregulation. Collectively, these data suggest that biallelic loss-of-function variants of may cause photoreceptor degeneration and underlie isolated RP.