ArticleEuropean journal of human genetics : EJHG2013
Deep-intronic ATM mutation detected by genomic resequencing and corrected in vitro by antisense morpholino oligonucleotide (AMO).
Article in European journal of human genetics : EJHG, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 36 citations in OpenAlex.
- Digenic Inheritance of Mutations in Homologous Recombination Genes in Cancer Patients.Journal of personalized medicine · 2024Article
- Early-Onset Ovarian Cancer <30 Years: What Do We Know about Its Genetic Predisposition?International journal of molecular sciences · 2023Review
- Deep intronic founder mutations identified in theProceedings of the National Academy of Sciences of the United States of America · 2023Article
- The Power of Clinical Diagnosis for Deciphering Complex Genetic Mechanisms in Rare Diseases.Genes · 2023Review
- Case Report: Biallelic Loss of Function ATM due to Pathogenic Synonymous and Novel Deep Intronic Variant c.1803-270T > G Identified by Genome Sequencing in a Child With Ataxia-Telangiectasia.Frontiers in genetics · 2022Article
- Transposon clusters as substrates for aberrant splice-site activation.RNA biology · 2021Article
- Analysis of Pathogenic Pseudoexons Reveals Novel Mechanisms Driving Cryptic Splicing.Frontiers in genetics · 2021Article
- Targeting Alternative Splicing as a Potential Therapy for Episodic Ataxia Type 2.Biomedicines · 2020Review
- Deep Intronic Mutation in SERPING1 Caused Hereditary Angioedema Through Pseudoexon Activation.Journal of clinical immunology · 2020Article
- Recent advances in primary immunodeficiency: from molecular diagnosis to treatment.F1000Research · 2020Review
- Splicing profile by capture RNA-seq identifies pathogenic germline variants in tumor suppressor genes.NPJ precision oncology · 2020Article
- Atm reactivation reverses ataxia telangiectasia phenotypes in vivo.Cell death & disease · 2018Article
- Updated genetic testing of Italian patients referred with a clinical diagnosis of primary hyperoxaluria.Journal of nephrology · 2017Article
- Oligonucleotide therapies for disorders of the nervous system.Nature biotechnology · 2017Article
- CADD score has limited clinical validity for the identification of pathogenic variants in noncoding regions in a hereditary cancer panel.Genetics in medicine : official journal of the American College of Medical Genetics · 2016Article
- Pseudoexons provide a mechanism for allele-specific expression of APC in familial adenomatous polyposis.Oncotarget · 2016Article
- Small-scale high-throughput sequencing-based identification of new therapeutic tools in cystic fibrosis.Genetics in medicine : official journal of the American College of Medical Genetics · 2015Article
- Pure and syndromic optic atrophy explained by deep intronic OPA1 mutations and an intralocus modifier.Brain : a journal of neurology · 2014Article
- Exon-skipping antisense oligonucleotides to correct missplicing in neurogenetic diseases.Nucleic acid therapeutics · 2014Review
- Role of pseudoexons and pseudointrons in human cancer.International journal of cell biology · 2013Review
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Recent development of next-generation DNA sequencing (NGS) techniques is changing the approach to search for mutations in human genetic diseases. We applied NGS to study an A-T patient in which one of the two expected mutations was not found after DHPLC, cDNA sequencing and MLPA screening. The 160-kb ATM genomic region was divided into 31 partially overlapping fragments of 4-6 kb and amplified by long-range PCR in the patient and mother, who carried the same mutation by segregation. We identified six intronic variants that were shared by the two genomes and not reported in the dbSNP(132) database. Among these, c.1236-405C>T located in IVS11 was predicted to be pathogenic because it affected splicing. This mutation creates a cryptic novel donor (5') splice site (score 1.00) 405 bp upstream of the exon 12 acceptor (3') splice site. cDNA analysis showed the inclusion of a 212-bp non-coding 'pseudoexon' with a premature stop codon. We validated the functional effect of the splicing mutation using a minigene assay. Using antisense morpholino oligonucleotides, designed to mask the cryptic donor splice-site created by the c.1236-405C>T mutation, we abrogated the aberrant splicing product to a wild-type ATM transcript, and in vitro reverted the functional ATM kinase impairment of the patients' lymphoblasts. Resequencing is an effective strategy for identifying rare splicing mutations in patients for whom other mutation analyses have failed (DHPLC, MLPA, or cDNA sequencing). This is especially important because many of these patients will carry rare splicing variants that are amenable to antisense-based correction.
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