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A novel hypomorphic splice variant in EIF2B5 gene is associated with mild ovarioleukodystrophy
- Source :
- Dipòsit Digital de la UB, Universidad de Barcelona, Annals of Clinical and Translational Neurology, Vol 7, Iss 9, Pp 1574-1579 (2020), Dipòsit Digital de Documents de la UAB, Universitat Autònoma de Barcelona, Annals of Clinical and Translational Neurology, Annals of Clinical and Translational Neurology, Wiley, 2020, 7 (9), pp.1574-1579. ⟨10.1002/acn3.51131⟩, r-IGTP. Repositorio Institucional de Producción Científica del Instituto de Investigación Germans Trias i Pujol, instname
- Publication Year :
- 2020
-
Abstract
- Objective: To identify the genetic cause in an adult ovarioleukodystrophy patient resistant to diagnosis. Methods: We applied whole-exome sequencing (WES) to a vanishing white matter disease patient associated with premature ovarian failure at 26 years of age. We functionally tested an intronic variant by RT-PCR on patient's peripheral blood mononuclear cells (PBMC) and by minigene splicing assay. Results: WES analysis identified two novel variants in theEIF2B5gene: c.725A > G (p.Tyr242Cys) and an intronic noncanonical mutation (c.1156 + 13G>A). This intronic mutation resulted into generation of various isoforms both in patient's PBMC and in the minigene splicing assay, showing that similar to 20% residual wild-type isoform is still expressed by the intronic-mutated allele alone, concordant with an hypomorphic effect of this variant. Conclusion: We report two novel variants inEIF2B5, one of them a noncanonical intronic splice variant, located at a +13 intronic position. This position is mutated only in 0.05% of ClinVar intronic mutations described so far. Furthermore, we illustrate how minigene splicing assay may be advantageous when validating splice-altering variants, in this case highlighting the coexistence of wild-type and mutated forms, probably explaining this patient's milder, late-onset phenotype.
- Subjects :
- 0301 basic medicine
Adult
[SDV]Life Sciences [q-bio]
Neurosciences. Biological psychiatry. Neuropsychiatry
medicine.disease_cause
Ovary diseases
03 medical and health sciences
0302 clinical medicine
Diagnòstic
Leukoencephalopathies
Diagnosis
Exome Sequencing
Intronic Mutation
Medicine
Humans
Ovarian Diseases
Allele
RC346-429
Gene
Research Articles
Genetics
Malalties de l'ovari
Mutation
business.industry
General Neuroscience
Alternative splicing
Phenotype
Magnetic Resonance Imaging
[SDV] Life Sciences [q-bio]
Eukaryotic Initiation Factor-2B
030104 developmental biology
RNA splicing
Female
Neurology (clinical)
Neurology. Diseases of the nervous system
business
030217 neurology & neurosurgery
Research Article
Minigene
RC321-571
Subjects
Details
- ISSN :
- 23289503
- Volume :
- 7
- Issue :
- 9
- Database :
- OpenAIRE
- Journal :
- Annals of clinical and translational neurology
- Accession number :
- edsair.doi.dedup.....b5807af8652b13985c1d8a5b720a6b08