ArticleGenome medicine2018
Complex structural variants in Mendelian disorders: identification and breakpoint resolution using short- and long-read genome sequencing.
Article in Genome medicine, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 105 papers.
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Who cites it
105 citing papers in PubMed.
- Rare disease genomics in an era of human pangenomics and telomere-to-telomere genome references.European journal of human genetics : EJHG · 2026Review
- Structural variant discovery and diagnostic impact in rare diseases from short-read and long-read sequencing.medRxiv : the preprint server for health sciences · 2026Article
- GrassSV - hybrid method to detect structural variants in high throughput DNA-seq data.PLoS computational biology · 2026Article
- Compound heterozygous structural variants resulting in CNTNAP2 biallelic loss-of-function: rare mechanisms unveiled by genome sequencing.Human genomics · 2026Article
- Long-read Sequencing in Inherited Retinal Dystrophies: A Systematic Review.Ophthalmology science · 2026Review
- TMC6/8-associated epidermodysplasia verruciformis: germline variants and a complex structural alteration in a skin cancer predisposition syndrome.European journal of human genetics : EJHG · 2026Article
- The biomedical landscape of genomic structural variation in the qatari population.Nature communications · 2026Article
- Long-read genome sequencing resolves the breakpoints of a chromosome 8;22 balanced translocation in NF2-related schwannomatosis.Scientific reports · 2025Article
- Complex de novo structural variants are an underestimated cause of rare disorders.Nature communications · 2025Article
- insilicoSV: a flexible grammar-based framework for structural variant simulation and placement.Bioinformatics (Oxford, England) · 2025Article
- The continued promise of genomic technologies and software in neurogenetics.Journal of neuromuscular diseases · 2025Review
- NGS Approaches in Clinical Diagnostics: From Workflow to Disease-Specific Applications.International journal of molecular sciences · 2025Review
- Article
- Diversity and consequences of structural variation in the human genome.Nature reviews. Genetics · 2025Review
- Enhanced identification of novel pathogenic variants in hereditary hearing loss through physical phasing with integrated short and long-read sequencing data.Molecular genetics and genomics : MGG · 2025Article
- Long-Read Whole-Genome Sequencing as a Tool for Variant Detection in Inherited Retinal Dystrophies.International journal of molecular sciences · 2025Article
- Unraveling undiagnosed rare disease cases by HiFi long-read genome sequencing.Genome research · 2025Article
- Benchmarking long-read structural variant calling tools and combinations for detecting somatic variants in cancer genomes.Scientific reports · 2025Article
- De novo and somatic structural variant discovery with SVision-pro.Nature biotechnology · 2025Article
- SUMMER: an integrated nanopore sequencing pipeline for variants detection and clinical annotation on the human genome.Functional & integrative genomics · 2025Article
45 more citing papers are in PubMed but not listed here.
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Authors and funding
22 authors.
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No grant is acknowledged in the PubMed record.
Abstract
backgroundStudies have shown that complex structural variants (cxSVs) contribute to human genomic variation and can cause Mendelian disease. We aimed to identify cxSVs relevant to Mendelian disease using short-read whole-genome sequencing (WGS), resolve the precise variant configuration and investigate possible mechanisms of cxSV formation.
methodsWe performed short-read WGS and analysis of breakpoint junctions to identify cxSVs in a cohort of 1324 undiagnosed rare disease patients. Long-read WGS and gene expression analysis were used to resolve one case.
resultsWe identified three pathogenic cxSVs: a de novo duplication-inversion-inversion-deletion affecting ARID1B, a de novo deletion-inversion-duplication affecting HNRNPU and a homozygous deletion-inversion-deletion affecting CEP78. Additionally, a de novo duplication-inversion-duplication overlapping CDKL5 was resolved by long-read WGS demonstrating the presence of both a disrupted and an intact copy of CDKL5 on the same allele, and gene expression analysis showed both parental alleles of CDKL5 were expressed. Breakpoint analysis in all the cxSVs revealed both microhomology and longer repetitive elements.
conclusionsOur results corroborate that cxSVs cause Mendelian disease, and we recommend their consideration during clinical investigations. We show that resolution of breakpoints can be critical to interpret pathogenicity and present evidence of replication-based mechanisms in cxSV formation.
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