ArticleGenome medicine2017
Molecular dissection of germline chromothripsis in a developmental context using patient-derived iPS cells.
Article in Genome medicine, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 32 citations in OpenAlex.
- Structural variants in the 3D genome as drivers of disease.Nature reviews. Genetics · 2025Review
- Diversity and consequences of structural variation in the human genome.Nature reviews. Genetics · 2025Review
- Chromoanagenesis in Osteosarcoma.Biomolecules · 2025Review
- Identifying Balanced Chromosomal Translocations in Human Embryos by Oxford Nanopore Sequencing and Breakpoints Region Analysis.Frontiers in genetics · 2021Article
- The Iceberg under Water: Unexplored Complexity of Chromoanagenesis in Congenital Disorders.American journal of human genetics · 2019Review
- Insertional translocation involving an additional nonchromothriptic chromosome in constitutional chromothripsis: Rule or exception?Molecular genetics & genomic medicine · 2019Article
- On the Complexity of Mechanisms and Consequences of Chromothripsis: An Update.Frontiers in genetics · 2019Review
- Chromoanagenesis: cataclysms behind complex chromosomal rearrangements.Molecular cytogenetics · 2019Review
- Enabling multiplexed testing of pooled donor cells through whole-genome sequencing.Genome medicine · 2018Article
- Chromothripsis 18 in multiple myeloma patient with rapid extramedullary relapse.Molecular cytogenetics · 2018Article
- Review
- Mapping and phasing of structural variation in patient genomes using nanopore sequencing.Nature communications · 2017Article
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Authors and funding
17 authors at 6 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundGermline chromothripsis causes complex genomic rearrangements that are likely to affect multiple genes and their regulatory contexts. The contribution of individual rearrangements and affected genes to the phenotypes of patients with complex germline genomic rearrangements is generally unknown.
methodsTo dissect the impact of germline chromothripsis in a relevant developmental context, we performed trio-based RNA expression analysis on blood cells, induced pluripotent stem cells (iPSCs), and iPSC-derived neuronal cells from a patient with de novo germline chromothripsis and both healthy parents. In addition, Hi-C and 4C-seq experiments were performed to determine the effects of the genomic rearrangements on transcription regulation of genes in the proximity of the breakpoint junctions.
resultsSixty-seven genes are located within 1 Mb of the complex chromothripsis rearrangements involving 17 breakpoints on four chromosomes. We find that three of these genes (FOXP1, DPYD, and TWIST1) are both associated with developmental disorders and differentially expressed in the patient. Interestingly, the effect on TWIST1 expression was exclusively detectable in the patient's iPSC-derived neuronal cells, stressing the need for studying developmental disorders in the biologically relevant context. Chromosome conformation capture analyses show that TWIST1 lost genomic interactions with several enhancers due to the chromothripsis event, which likely led to deregulation of TWIST1 expression and contributed to the patient's craniosynostosis phenotype.
conclusionsWe demonstrate that a combination of patient-derived iPSC differentiation and trio-based molecular profiling is a powerful approach to improve the interpretation of pathogenic complex genomic rearrangements. Here we have applied this approach to identify misexpression of TWIST1, FOXP1, and DPYD as key contributors to the complex congenital phenotype resulting from germline chromothripsis rearrangements.
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