ArticlePLoS genetics2022
Massively parallel reporter assays discover de novo exonic splicing mutants in paralogs of Autism genes.
Article in PLoS genetics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 35 citations in OpenAlex.
- An in vivo parallelized reporter assay to uncover tissue-specific splicing regulatory sequences in a multicellular animal.Nucleic acids research · 2026Article
- RNA-based discovery and correction of splicing defects caused byMolecular therapy. Nucleic acids · 2026Article
- Article
- Multiplexed assays of variant effect for clinical variant interpretation.Nature reviews. Genetics · 2026Review
- Review
- Generative Design of Cell Type-Specific RNA Splicing Elements for Programmable Gene Regulation.bioRxiv : the preprint server for biology · 2025Article
- Core splicing architecture and early spliceosomal recognition determine microexon sensitivity to SRRM3/4.Nature structural & molecular biology · 2025Article
- Article
- Joint, multifaceted genomic analysis enables diagnosis of diverse, ultra-rare monogenic presentations.Nature communications · 2025Article
- Single Antisense Oligonucleotides Correct Diverse Splicing Mutations in Hotspot Exons.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Functional impact of splicing variants in the elaboration of complex traits in cattle.Nature communications · 2025Article
- Data-driven insights to inform splice-altering variant assessment.American journal of human genetics · 2025Article
- Decoding biology with massively parallel reporter assays and machine learning.Genes & development · 2024Review
- SpliceVarDB: A comprehensive database of experimentally validated human splicing variants.American journal of human genetics · 2024Article
- A second hotspot for pathogenic exon-skipping variants in CDC45.European journal of human genetics : EJHG · 2024Article
- All exons are not created equal-exon vulnerability determines the effect of exonic mutations on splicing.Nucleic acids research · 2024Article
- Strategies for dissecting the complexity of neurodevelopmental disorders.Trends in genetics : TIG · 2024Review
- Combined bioinformatic and splicing analysis of likely benign intronic and synonymous variants reveals evidence for pathogenicity.Genetics in medicine open · 2024Article
- Benchmarking splice variant prediction algorithms using massively parallel splicing assays.Genome biology · 2023Article
- Nonsynonymous Synonymous Variants Demand for a Paradigm Shift in Genetics.Current genomics · 2023Review
Corrections and comments
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
Abstract
To determine the contribution of defective splicing in Autism Spectrum Disorders (ASD), the most common neurodevelopmental disorder, a high throughput Massively Parallel Splicing Assay (MaPSY) was employed and identified 42 exonic splicing mutants out of 725 coding de novo variants discovered in the sequencing of ASD families. A redesign of the minigene constructs in MaPSY revealed that upstream exons with strong 5' splice sites increase the magnitude of skipping phenotypes observed in downstream exons. Select hits were validated by RT-PCR and amplicon sequencing in patient cell lines. Exonic splicing mutants were enriched in probands relative to unaffected siblings -especially synonymous variants (7.5% vs 3.5%, respectively). Of the 26 genes disrupted by exonic splicing mutations, 6 were in known ASD genes and 3 were in paralogs of known ASD genes. Of particular interest was a synonymous variant in TNRC6C - an ASD gene paralog with interactions with other ASD genes. Clinical records of 3 ASD patients with TNRC6C variant revealed respiratory issues consistent with phenotypes observed in TNRC6 depleted mice. Overall, this study highlights the need for splicing analysis in determining variant pathogenicity, especially as it relates to ASD.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.