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Deep-intronic ABCA4 variants explain missing heritability in Stargardt disease and allow correction of splice defects by antisense oligonucleotides
- Source :
- Genetics in Medicine, 21(8), 1751-1760. Nature Publishing Group, Genetics in Medicine, 21(8), 1751-1760. Lippincott Williams & Wilkins, Genetics in Medicine, GENETICS IN MEDICINE
- Publication Year :
- 2019
- Publisher :
- Lippincott Williams & Wilkins, 2019.
-
Abstract
- Purpose: Using exome sequencing, the underlying variants in many persons with autosomal recessive diseases remain undetected. We explored autosomal recessive Stargardt disease (STGD1) as a model to identify the missing heritability.Methods: Sequencing of ABCA4 was performed in 8 STGD1 cases with one variant and p.Asn1868Ile in trans, 25 cases with one variant, and 3 cases with no ABCA4 variant. The effect of intronic variants was analyzed using in vitro splice assays in HEK293T cells and patient-derived fibroblasts. Antisense oligonucleotides were used to correct splice defects.Results: In 24 of the probands (67%), one known and five novel deep-intronic variants were found. The five novel variants resulted in messenger RNA pseudoexon inclusions, due to strengthening of cryptic splice sites or by disrupting a splicing silencer motif. Variant c.769-784C>T showed partial insertion of a pseudoexon and was found in cis with c.5603A>T (p.Asn1868Ile), so its causal role could not be fully established. Variant c.4253+43G>A resulted in partial skipping of exon 28. Remarkably, antisense oligonucleotides targeting the aberrant splice processes resulted in (partial) correction of all splicing defects.Conclusion: Our data demonstrate the importance of assessing noncoding variants in genetic diseases, and show the great potential of splice modulation therapy for deep-intronic variants.
- Subjects :
- 0301 basic medicine
antisense oligonucleotide
030105 genetics & heredity
ABCA4
Exon
Missing heritability problem
Medicine and Health Sciences
Protein Isoforms
Genetics(clinical)
Child
Genetics (clinical)
Exome sequencing
POPULATION
Genetics
education.field_of_study
Exons
Middle Aged
3. Good health
Pedigree
Stargardt disease
RNA splicing
Adult
Adolescent
RNA Splicing
Population
Biology
Polymorphism, Single Nucleotide
Article
03 medical and health sciences
Young Adult
REVEALS
medicine
Humans
splice
education
Gene
Aged
MUTATIONS
deep-intronic variant
Biology and Life Sciences
IN-VITRO
Oligonucleotides, Antisense
medicine.disease
GENE
Introns
030104 developmental biology
HEK293 Cells
Mutation
missing heritability
ATP-Binding Cassette Transporters
Subjects
Details
- ISSN :
- 15300366 and 10983600
- Volume :
- 21
- Issue :
- 8
- Database :
- OpenAIRE
- Journal :
- Genetics in Medicine
- Accession number :
- edsair.doi.dedup.....289b1faa5a30558c06f691696f4e3d71