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

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. Autosomal dominant RP has been associated with about thirty genes, while approximately 10% of our French autosomal dominantRP cohort remain genetically unsolved. Recently, several variants in small nuclear RNA (snRNA) genes have been identified in cases with autosomal recessive and autosomal recessive neurodevelopmental disorders as well as autosomal dominant RP. These snRNAs undergo post-transcriptional modifications and, in association with proteins and other snRNAs, assemble into small nuclear ribonucleoproteins that are components of the spliceosome. By performing genome and direct Sanger sequencing, combined with a candidate gene approach, we identified heterozygous 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. RNU4-2 and RNU6 encode U4 and U6, snRNA, respectively, forming with U5, the tri-sn ribonucleoprotein (RNP) complex, representing the core of the major spliceosome. Interestingly, variants in autosomal dominant RP cases cluster in distinct locations than variants implicated in neurodevelopmental disorders, affecting regions important for tri-snRNP complex assembly with PRPF3, PRPF8 and PRPF31, also implicated in RP. Together, our findings revealed that 2% of our genetically solved cases with autosomal dominant RP carry variants in RNU4-2 or RNU6 paralogs. This represents 6% of all cases having variants in genes coding for the multisubunit complex, highlighting the importance of screening snRNA genes in cases of RP.