Variants in RNU4-2 or RNU6 paralogs account for 2% of individuals with non-syndromic autosomal dominant retinitis pigmentosa in a large French cohort

Background Rod-cone dystrophy, also known as retinitis pigmentosa (RP), is a genetically heterogeneous group of retinal disorders with progressive rod then cone photoreceptor loss, leading to severe visual impairment. Approximately forty genes have been associated with autosomal dominant RP, yet nearly 10% of individuals in our French cohort remain genetically unsolved. Recently, heterozygous and biallelic inherited variants and de novo variants in small nuclear RNA (snRNA) genes have been identified in individuals with recessive neurodevelopmental disorders as well as with RP. U4 and U6 snRNAs associate with U5 snRNA and other proteins to form the tri-small nuclear ribonucleoproteins (tri-snRNPs) complex, a central component of the major spliceosome. Notably, RP-associated variants cluster in regions distinct from those implicated in neurodevelopmental disorders and affect domains involved in tri-snRNP assembly with PRPF3, PRPF8 and PRPF31, which are also associated with RP. Methods Genome and direct Sanger sequ encing combined with a candidate gene approach was performed in a French cohort of 395 autosomal dominant RP families and 418 genetically unsolved cases with RP, who underwent comprehensive ophthalmic examinations, including standard-of-care retinal imaging and functional assessments. Results We identified heterozygous inherited variants in RNU4-2 and RNU6 paralogs in eight unrelated non-syndromic autosomal dominant RP families, which co-segregated with the phenotype in available family members. Conclusions Our findings revealed that 2% of our genetically solved individuals with autosomal dominant RP carry variants in RNU4-2 or RNU6 paralogs. This represents 6% of all individuals having variants in gene s coding for the spliceosome multi-subunit complex, highlighting the importance of screening snRNA genes in individuals of RP.