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The identification of a RNA splice variant in TULP1 in two siblings with early-onset photoreceptor dystrophy.
- Source :
-
Molecular genetics & genomic medicine [Mol Genet Genomic Med] 2019 Jun; Vol. 7 (6), pp. e660. Date of Electronic Publication: 2019 Apr 04. - Publication Year :
- 2019
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Abstract
- Background: 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.<br />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. Patients were clinically evaluated, including assessment of the medical history, slit-lamp biomicroscopy, and ophthalmoscopy. In addition, a functional analysis of the putative splice variant in TULP1 was performed using a midigene assay.<br />Results: Clinical assessment showed a typical early-onset photoreceptor dystrophy in both the 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. 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.<br />Conclusion: 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 TULP1 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 noncoding regions beyond the noncanonical splice sites in patients with inherited retinal diseases.<br /> (© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)
- Subjects :
- Adolescent
Child
Cone Dystrophy metabolism
Exome
Exons
Eye Proteins metabolism
Female
Frameshift Mutation
Homozygote
Humans
Male
Mutation
Pedigree
RNA
RNA Splice Sites genetics
RNA Splicing genetics
Retinal Rod Photoreceptor Cells metabolism
Siblings
Exome Sequencing methods
Cone Dystrophy genetics
Eye Proteins genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2324-9269
- Volume :
- 7
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Molecular genetics & genomic medicine
- Publication Type :
- Academic Journal
- Accession number :
- 30950243
- Full Text :
- https://doi.org/10.1002/mgg3.660