Retinal disorders

Gene: RNU6-9

Green List (high evidence)

Comment on list classification: Recurrent RNU6-9 variants (n.55_56insG & n.56_57insG) were detected in patients from 17 unrelated families with retinitis pigmentosa - 3 cases confirmed de novo, 6 suspected to be de novo. 78% of individuals with U4/U6 changes presented with first RP symptoms during childhood or adolescence. Importantly, 9 obligate carriers from these families had no visual symptoms, hinting at incomplete disease penetrance. Based on the available evidence, RNU6-9 should be promoted to Green for Retinal disorders at the next GMS update.

Created: 21 Nov 2025, 11:41 a.m. | Last Modified: 21 Nov 2025, 11:49 a.m.

Panel Version: 8.72

PMID: 39830270 Quinodoz et al., 2025
Large cohort of RP patients screened using Sanger sequencing of genes encoding U4 and U6. Reported 153 individuals across 67 families with retinitis pigmentosa, with monoallelic variants in RNU4-2 and RNU6 paralogs.

n.55_56insG insertion recurred in the RNU6 paralogs (RNU6-1, RNU6-2, RNU6-8, and RNU6-9) - 102 individuals from 47 diverse, unrelated families. Pathogenic variants were NOT detected in RNU6-7. Insertion at the same position, n.55_56insT, is reported in gnomAD in all 5 paralogs (181 alleles total).
Insertion n.56_57insG was detected in RNU6 paralogs in individuals from 6 families.

RNU6-9 specific data: n.55_56insG insertion in RNU6-9 reported in numerous patients from 14 diverse RP families - 3 cases confirmed and 6 suspected to be de novo; n.56_57insG detected in 3 unrelated adRP families (based on pre-print supplementary table 2).

Details for patients with U4 and U6 changes:
Age of onset of RP: under 12yo = 42 patients (62%); 13-19 years = 11; 20-30 years = 8; adulthood 30+ = 7 patients.
Phenotype spectrum in addition to classical RP features: ocular edema (56%), non-age-related cataract / lens opacity (24%), vitreoretinal complications (31%).

Functional effect prediction: RP-related variants identified reside in a region that critical for binding of the U4/U6 duplex to the splicing factors PRPF31, PRPF3, and PRPF8 - genes previously linked to AD retinitis pigmentosa.
Sources: Literature

Created: 21 Nov 2025, 11:40 a.m. | Last Modified: 21 Nov 2025, 11:41 a.m.

Panel Version: 8.71

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
retinitis pigmentosa, MONDO:0019200

Publications

• 39830270