Genome sequencing finds deep-intronic PCDH15 variants in unsolved Usher syndrome cases
A preprint reports two novel deep-intronic variants in PCDH15 that disrupt splicing in Usher syndrome patients who had previously received no genetic diagnosis, and demonstrates antisense oligonucleotide rescue in a minigene model.
A preprint posted to bioRxiv on 20 August 2026 describes the identification of two novel deep-intronic pathogenic variants in PCDH15 — the gene encoding protocadherin-15 — in patients with a clinical diagnosis of Usher syndrome who had not received a molecular diagnosis through standard testing panels.
Usher syndrome is the most common cause of combined hereditary deafness and visual impairment (retinitis pigmentosa), and is caused by pathogenic variants in several genes including PCDH15 (Usher syndrome type 1F). Approximately 10–15% of clinically diagnosed Usher syndrome patients remain genetically unresolved even after comprehensive panel testing, representing a significant challenge for genetic counselling and for access to emerging therapeutic trials.
The researchers, who analysed genome sequencing data from a cohort of clinically presenting probands, identified two intronic variants — c.3983+3635A>G and c.3123-1728A>G — located far from canonical splice sites and therefore undetected by exon-focused sequencing approaches. Both variants were classified as likely pathogenic under published frameworks and were predicted computationally to alter PCDH15 pre-mRNA splicing. A minigene splice assay provided experimental confirmation of the splicing defect.
Critically, the authors report that antisense oligonucleotide (ASO) treatment in the minigene system corrected the aberrant splicing, raising the possibility of an RNA-targeted therapeutic approach for patients carrying these variants. This is consistent with a broader research trend exploring ASO-based splice correction for deep-intronic variants across multiple genetic conditions.
This work is a preprint and has not yet been peer-reviewed. Findings should be interpreted accordingly.
Plain-language version
For patients, families, and general readers. Educational only — not medical advice.
Usher syndrome is a rare inherited condition that causes deafness from birth and gradual loss of vision. Some people who have Usher syndrome do not get a genetic result from standard DNA tests, which can make it harder to access future treatments or receive accurate genetic counselling.
Researchers have now used a more detailed type of DNA test called genome sequencing to find two previously unknown genetic changes deep inside the PCDH15 gene in patients who had no previous genetic explanation for their condition. These changes are hidden far from the usual places that standard tests look, which is why they were missed before.
The study also showed — in a laboratory cell model — that a type of molecule called an antisense oligonucleotide could correct the effect of these changes on how the gene is read. This is an early-stage finding in cells, not in people, but researchers say it suggests a possible future treatment direction.
This is a preprint, meaning it has not yet been checked by independent scientific reviewers.
This is an educational summary, not medical advice. If anything here raises questions for you, please speak with your GP or a clinical professional.
Sources
Read the original reporting — these are the public sources this summary draws from.
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Primary sourcePreprint bioRxiv (Cold Spring Harbor Laboratory) · 2026-08-24Genome sequencing reveals novel pathogenic deep-intronic PCDH15 variants, amenable to antisense oligonucleotide-based splice correction