A novel splice-site variant in CDH23 in a patient with Usher syndrome type 1

Ophthalmic Genet. 2019 Dec;40(6):545-548. doi: 10.1080/13816810.2019.1692359. Epub 2019 Nov 22.


Background: Gene editing has shown huge potential in correcting aberrant splicing and Cas13 has been identified as being particularly suitable for targeting RNA. It has therefore become increasingly important to highlight new splice site mutations that may be correctable, particularly in genes that are too large to be encoded by AAV vectors. About 20% of Usher Type 1 cases are caused by mutations in CDH23.Purpose: To report a novel splice site mutation of CDH23 associated with Usher Type 1D.Materials and Methods: Case report.Results: A 35-year-old Caucasian female who is congenitally deaf with vestibular dysfunction presented with visual acuity of 6/12 in both eyes. Fundus examination revealed findings typical of retinitis pigmentosa with foveal preservation of photoreceptor layer. Next generation sequencing analysis revealed a novel homozygous variant, c.9319 + 1G>T in CDH23 consistent with the diagnosis of Usher Syndrome Type 1D. The c.9319 + 1G>T variant is predicted to affect splicing at the exon 65/intron 65 boundary, which highly likely leads to complete skipping of exon 65.Conclusions: We describe a case of a typical Usher Syndrome Type 1D caused by a novel splice site variant in CDH23. Currently there are no treatments for CDH23 related retinal degeneration, partly because the cDNA size of 10kb is too large for AAV vector gene augmentation therapy. Alternative strategies include CRISPR-Cas9 adenine base editors and RNA editing with CRISPR-Cas13. Single-nucleotide editing represents a promising approach for targeting this variant in CDH23 to restore the wildtype splice donor site at this position.

Keywords: CDH23; Usher syndrome; retinitis pigmentosa; splice site variant.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cadherin Related Proteins
  • Cadherins / genetics*
  • Female
  • Genotype
  • Humans
  • Mutation*
  • RNA Splicing / genetics*
  • Usher Syndromes / genetics*
  • Usher Syndromes / pathology*


  • CDH23 protein, human
  • Cadherin Related Proteins
  • Cadherins