July 2019
Volume 60, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2019
The identification of a RNA splice variant in TULP1 in two siblings with early-onset photoreceptor dystrophy
Author Affiliations & Notes
  • Susanne Roosing
    Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands
    Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, Netherlands
  • Sanne K Verbakel
    Department of Ophthalmology, Radboud University Medical Center, Nijmegen, Netherlands
    Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, Netherlands
  • Zeinab Fadaie
    Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands
    Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, Netherlands
  • Jeroen Klevering
    Department of Ophthalmology, Radboud University Medical Center, Nijmegen, Netherlands
    Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, Netherlands
  • Maria M. van Genderen
    Bartiméus Diagnostic Center for Complex Visual Disorders, Nijmegen, Netherlands
    Department of Ophthalmology, University Medical Center Utrecht, Nijmegen, Netherlands
  • Ilse Feenstra
    Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands
    Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, Netherlands
  • Frans P Cremers
    Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands
    Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, Netherlands
  • Carel C B Hoyng
    Department of Ophthalmology, Radboud University Medical Center, Nijmegen, Netherlands
    Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, Netherlands
  • Footnotes
    Commercial Relationships   Susanne Roosing, None; Sanne Verbakel, None; Zeinab Fadaie, None; Jeroen Klevering, None; Maria van Genderen, None; Ilse Feenstra, None; Frans Cremers, None; Carel Hoyng, None
  • Footnotes
    Support  the Foundation Fighting Blindness USA Project Program Award grant no. PPA-0517-0717-RAD
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 423. doi:
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to authenticated users only.
      Sign In or Create an Account ×
    • Get Citation

      Susanne Roosing, Sanne K Verbakel, Zeinab Fadaie, Jeroen Klevering, Maria M. van Genderen, Ilse Feenstra, Frans P Cremers, Carel C B Hoyng; The identification of a RNA splice variant in TULP1 in two siblings with early-onset photoreceptor dystrophy. Invest. Ophthalmol. Vis. Sci. 2019;60(9):423.

      Download citation file:


      © ARVO (1962-2015); The Authors (2016-present)

      ×
  • Supplements
Abstract

Purpose :
Early-onset photoreceptor dystrophies are a major cause of irreversible visual impairment in children and young adults. This clinically heterogeneous group of disorders can be caused by mutations in many genes. Nevertheless, to date, 30-40% of cases remain genetically unexplained. In view of expanding therapeutic options, it is essential to obtain a molecular diagnosis in these patients as well. In this study, we aimed to identify the genetic cause in two siblings with genetically unexplained retinal disease.

Methods : Whole exome sequencing was performed to identify the causative variants in two siblings in whom a single pathogenic variant in TULP1 was found previously. In addition, a functional analysis of the putative splice variant in TULP1 was performed using a midigene assay. Patients were clinically evaluated, including assessment of the medical history, slit-lamp biomicroscopy, and ophthalmoscopy.

Results : Clinical assessment showed a typical early-onset photoreceptor dystrophy in both patients. Whole exome sequencing identified two pathogenic variants in TULP1, a c.1445G>A (p.(Arg482Gln)) missense mutation and an intronic c.718+23G>A variant. No biallelic pathogenic variants were identified in other known retinal disease associated genes in either patient. Segregation analysis confirmed that both siblings were compound heterozygous for the TULP1 c.718+23G>A and c.1445G>A variants, while the unaffected parents were heterozygous. The midigene assay for the c.718+23G>A variant confirmed an elongation of exon 7 leading to a frameshift.

Conclusions : Here, we report the first near exon RNA splice variant that is not present in a consensus splice site sequence in TULP1, which was found in a compound heterozygous manner with a previously described pathogenic variant in two patients with an early-onset photoreceptor dystrophy. We provide proof of pathogenicity for this splice variant by performing an in vitro midigene splice assay, and highlight the importance of analysis of non-coding regions beyond the non-canonical splice sites in patients with inherited retinal diseases.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×