Biallelic RDH11 variants cause syndromic retinitis pigmentosa with early-onset cataracts and neurodevelopmental delay: a multicenter case series

Abstract Biallelic variants in the RDH11 gene, a retinol dehydrogenase involved in the visual cycle and systemic retinoid homeostasis, were initially implicated in a rare condition characterized by retinal dystrophy, early-onset cataract, neurodevelopmental anomalies and myopathy, through single-family reports, with this association more recently being confirmed in a larger study. Here, we further establish the pathogenic role of RDH11 by presenting a large multi-center cohort, comprising eight individuals from seven unrelated families. Comprehensive genetic analysis identified homozygous variants in all affected subjects, including two novel variants, strongly supporting loss-of-function as the primary disease mechanism. Detailed clinical phenotyping defined a consistent and severe multisystem disorder. Ophthalmologically, the hallmark features include bilateral congenital or early-childhood cataracts requiring surgical intervention, accompanied by retinitis pigmentosa (RP). In terms of extra-ocular involvement, the cohort exhibited a high prevalence of neurodevelopmental delay, including intellectual disability, autistic spectrum disorder and learning difficulties. These features were frequently accompanied by congenital microcephaly, intrauterine and postnatal growth restriction, facial dysmorphisms, and dental anomalies. By significantly expanding both the mutational and phenotypic spectrum of RDH11 -related disease, our findings provide independent replication of this gene-disease association and definitively support RDH11 as a bona fide syndromic RP gene.