Identification of a deep intronic POLR3A variant causing inclusion of a pseudoexon derived from an Alu element in Pol III-related leukodystrophy
- 1 June 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Journal of Human Genetics
- Vol. 65 (10), 921-925
- https://doi.org/10.1038/s10038-020-0786-y
Abstract
Pseudoexon inclusion caused by deep intronic variants is an important genetic cause for various disorders. Here, we present a case of a hypomyelinating leukodystrophy with developmental delay, intellectual disability, autism spectrum disorder, and hypodontia, which are consistent with autosomal recessive POLR3-related leukodystrophy. Whole-exome sequencing identified only a heterozygous missense variant (c.1451G>A) in POLR3A. To explore possible involvement of a deep intronic variant in another allele, we performed whole-genome sequencing of the patient with variant annotation by SpliceAI, a deep-learning-based splicing prediction tool. A deep intronic variant (c.645 + 312C>T) in POLR3A, which was predicted to cause inclusion of a pseudoexon derived from an Alu element, was identified and confirmed by mRNA analysis. These results clearly showed that whole-genome sequencing, in combination with deep-learning-based annotation tools such as SpliceAI, will bring us further benefits in detecting and evaluating possible pathogenic variants in deep intronic regions.Keywords
Funding Information
- Ministry of Health, Labour and Welfare
- Takeda Science Foundation
- HUSM Grant-in-Aid from Hamamatsu University School of Medicine
This publication has 13 references indexed in Scilit:
- Predicting Splicing from Primary Sequence with Deep LearningCell, 2019
- A primer on deep learning in genomicsNature Genetics, 2018
- Are whole-exome and whole-genome sequencing approaches cost-effective? A systematic review of the literatureGenetics in Medicine, 2018
- Deep intronic mutations and human diseaseHuman Genetics, 2017
- Examining Sources of Error in PCR by Single-Molecule SequencingPLOS ONE, 2017
- In silico tools for splicing defect prediction: a survey from the viewpoint of end usersGenetics in Medicine, 2014
- Alternative splicing and evolution: diversification, exon definition and functionNature Reviews Genetics, 2010
- Multifactorial Interplay Controls the Splicing Profile of Alu-Derived ExonsMolecular and Cellular Biology, 2008
- The Birth of an Alternatively Spliced Exon: 3' Splice-Site Selection in Alu ExonsScience, 2003
- Heteroduplex Resolution Using T7 Endonuclease I in Microbial Community AnalysesBioTechniques, 2000