Bi-allelic variants in FSD1L cause retinitis pigmentosa with or without neurological involvement

Retinitis pigmentosa (RP) is an inherited retinal disease (IRD) characterized usually by progressive photoreceptor degeneration, leading to night blindness, peripheral visual field loss, and can progress to central vision impairment in some individuals. Despite advances in genomic diagnostics, many individuals with RP remain without a molecular diagnosis. We identified bi-allelic ultra-rare variants in fibronectin type II and Spry domain-containing protein 1-like (FSD1L) in six individuals with RP with or without neurological features from four unrelated families. FSD1L encodes a cytoplasmic protein, variants of which have not previously been associated with Mendelian disease. The gene is expressed in both human and mouse retinas that are enriched in cone and rod photoreceptors. Immunofluorescence and ultrastructure expansion microscopy show that FSD1L localizes along the photoreceptor microtubule axoneme, including the connecting cilium and outer segment, supporting a possible role in intracellular trafficking. A retina-enriched isoform of FSD1L includes an alternatively spliced exon (exon 10b), which we characterize as absent in minigene assays and affected individual-derived lymphocytes due to a deep intronic 26 nt deletion. Together, these findings support the association between bi-allelic disruption of FSD1L and IRD.