Genome sequencing reveals novel pathogenic deep-intronic PCDH15 variants, amenable to antisense oligonucleotide-based splice correction

A groundbreaking study has uncovered two previously unknown genetic mutations linked to Usher syndrome, a rare condition causing hearing and vision loss. Researchers analyzed genetic data from probands diagnosed with Usher syndrome and identified two deep-intronic variants in the PCDH15 gene, c.3983+3635A G and c.3123-1728A G. These variants were deemed likely pathogenic and were found to disrupt the pre-mRNA splicing process, resulting in a premature stop codon and the production of a truncated protein.

Through laboratory experiments using minigene splice assays and iPSC-derived photoreceptor precursor cells, scientists demonstrated that both mutations lead to the inclusion of a pseudoexon, causing the premature termination of protein translation. To address this issue, researchers designed antisense oligonucleotides (ASOs) to correct the aberrant pre-mRNA splicing caused by these deep-intronic variants.

Initial tests showed that these ASOs successfully restored normal splicing patterns, indicating their potential as a future therapeutic strategy for halting the progression of retinitis pigmentosa in patients with these novel genetic mutations. This research sheds new light on Usher syndrome caused by deep-intronic pathogenic variants in PCDH15 and represents the first application of an ASO-mediated splice correction approach for this specific patient population.