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Identification of a deep intronic POLR3A variant causing inclusion of a pseudoexon derived from an Alu element in Pol III-related leukodystrophy
- Source :
- Journal of Human Genetics. 65:921-925
- Publication Year :
- 2020
- Publisher :
- Springer Science and Business Media LLC, 2020.
-
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.
- Subjects :
- Male
0301 basic medicine
Autism Spectrum Disorder
Mutation, Missense
Alu element
Genes, Recessive
Laryngomalacia
030105 genetics & heredity
Biology
medicine.disease_cause
Deep intronic variants
03 medical and health sciences
Deep Learning
Alu Elements
Cerebellum
Exome Sequencing
Genetics
medicine
Humans
Protein Isoforms
Missense mutation
Amino Acid Sequence
RNA, Messenger
Allele
Pseudo-exon inclusion
Genetics (clinical)
Exome sequencing
Whole genome sequencing
Mutation
SpliceAI
Sequence Homology, Amino Acid
Whole Genome Sequencing
POLR3A
Leukodystrophy
Infant, Newborn
RNA Polymerase III
medicine.disease
Introns
Hereditary Central Nervous System Demyelinating Diseases
030104 developmental biology
whole-genome sequencing
RNA splicing
Muscle Hypotonia
Agenesis of Corpus Callosum
Atrophy
Sequence Alignment
Pseudogenes
Subjects
Details
- ISSN :
- 1435232X and 14345161
- Volume :
- 65
- Database :
- OpenAIRE
- Journal :
- Journal of Human Genetics
- Accession number :
- edsair.doi.dedup.....cbeed14f867c24d7ccd122e98dad27e7