Rare non-coding variant rs890306703 is genetically associated with early-onset severe retinal degeneration

Three of four children from a consanguineous family with achromatopsia developed early-onset severe retinal dystrophy (EOSRD), resulting in severe visual impairment. After a comprehensive genome analysis including the retinal epigenome, we identified homozygosity for rs890306703-C as a candidate variant at the transcriptional start site of the long non-coding RNA gene (lncRNA) ENSG00000286364. CRISPR base editing of the variant and CRISPR-mediated lncRNA ablation dysregulated genes related to actin dynamics, cell adhesion and other processes important for photoreceptor health; however, the lncRNA expression remains unaffected. rs890306703-C generates new transcription factor motifs that increase transcriptional activity. We define an EOSRD-associated regulatory variant augmenting gene regulation relevant for retinal processes.