Clinical manifestations of dual‐gene variants in retinitis pigmentosa
Lasse Wolfram, Jan‐Philipp Bodenbender, David A. Merle, Milda Reith, Anton Sonntag, Krunoslav Stingl, Tobias B. Haack, Theresia Zuleger, Bernd Wissinger, Laura Kühlewein, Katarina Stingl, Susanne KohlAbstract
Purpose
Retinitis pigmentosa (RP) is an inherited retinal disease (IRD), whereby each affected individual typically harbours pathogenic variants in a single causative gene, yet the disorder exhibits marked genetic heterogeneity, with more than 100 genes reported to underlie RP. Dual‐gene defect constellations are rare but may modify disease presentation, complicating diagnosis, prognosis and therapeutic decision‐making. This study aimed to characterize the clinical and genetic effects of dual‐gene variants in patients with RP as the lead diagnosis.
Methods
We retrospectively analysed 10 affected individuals and their parents from eight families with confirmed dual‐genotype constellations in RP‐associated genes. Ophthalmic evaluation included best‐corrected visual acuity (BCVA), visual fields, multimodal imaging, electroretinography (ERG) and full‐field stimulus threshold testing (FST). Genetic analyses comprised whole genome sequencing and targeted segregation studies; for the latter, long‐read sequencing was used to clarify cis/trans variant configuration.
Results
Genes involved were CEP290 , RCBTB1 , ABCA4 , PDE6A , CRB1 , EYS , PRPH2 , MYO7A , RS1 , USH2A , MT‐TL1 , RHO and BEST1 , in various genotype constellations. Phenotypes ranged from early‐onset severe rod‐cone dystrophy to late‐onset mild RP, largely reflecting gene‐specific effects (e.g. EYS > CRB1 > PRPH2 ) and their interactions. Long‐read sequencing revealed ABCA4 variants in cis , explaining asymptomatic carriers and informing gene therapy eligibility. Functional retinal testing highlighted gene‐specific patterns, including macular preservation in EYS ‐driven RP and Best disease‐associated macular changes.
Conclusion
Dual‐gene variant constellations contribute to heterogeneous RP phenotypes. Integrating comprehensive genetic analysis with detailed clinical assessment is critical to define gene‐specific contributions, inform prognosis, guide clinical management and determine eligibility for emerging gene‐based therapies.