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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.
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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.
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.
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.
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.
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