A Novel Copy Number Variation in PRPF31 Causes Dominant Rod-Cone Dystrophy By Haploinsufficiency

Abstract Background and Objectives: Rod-cone dystrophy (RCD), also known as Retinitis Pigmentosa, is the most common group of retinal dystrophies, affecting around 1:4,000 individuals worldwide. Herein, our objective was to identify the genetic cause of RCD in two Lebanese families with distinct inheritance patterns and explore the potential role of PRPF31 haploinsufficiency. Methods The study combined next-generation sequencing, real-time PCR (qPCR), and chromosomal microarray to identify, validate, and delineate the causative copy number variations (CNVs) identified in both families of this study. gene expression analysis using qPCR and Western Blot were conducted to assess the PRPF31 variant's impact on gene expression levels. Results A novel heterozygous deletion (701 bp) spanning exons 6 and 7 of PRPF31 was identified in the first family (F11), leading to autosomal dominant RCD through haploinsufficiency, evidenced by reduced mRNA and total absence of protein expression levels in the affected individuals (F11:III.2 and F11:II.1). A rare previously reported homozygous deletion in MERTK was found in the second family (F26), causing autosomal recessive RCD. These findings highlight the diversity of CNVs contributing to RCD and the critical role of haploinsufficiency in autosomal dominant RCD pathogenesis. Conclusion The current study expands the mutational spectrum associated with PRPF31 and MERTK genes in RCD, underscoring the importance of CNVs in its etiology. Identifying haploinsufficiency as a disease mechanism in PRPF31-related autosomal dominant RCD represents a stepping stone for future analyses regarding gene augmentation therapies.