ArticlePLoS genetics2009
Disease-causing 7.4 kb cis-regulatory deletion disrupting conserved non-coding sequences and their interaction with the FOXL2 promotor: implications for mutation screening.
Article in PLoS genetics, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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38 citing papers in PubMed, 93 citations in OpenAlex.
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- Blepharophimosis, Ptosis, Epicanthus Inversus Syndrome: New Report with a 197-kb Deletion Upstream ofMolecular syndromology · 2019Article
- Novel long-range regulatory mechanisms controlling PKD2 gene expression.BMC genomics · 2018Article
- Promoter Capture Hi-C: High-resolution, Genome-wide Profiling of Promoter Interactions.Journal of visualized experiments : JoVE · 2018Article
- Conserved non-coding elements: developmental gene regulation meets genome organization.Nucleic acids research · 2017Review
- The Shh Topological Domain Facilitates the Action of Remote Enhancers by Reducing the Effects of Genomic Distances.Developmental cell · 2016Article
- A genome-wide association scan in admixed Latin Americans identifies loci influencing facial and scalp hair features.Nature communications · 2016Article
- The complexity of epigenetic diseases.The Journal of pathology · 2016Review
- Long-Range Chromatin Interactions.Cold Spring Harbor perspectives in biology · 2015Review
- A genome-wide association study identifies multiple loci for variation in human ear morphology.Nature communications · 2015Article
- A large genomic deletion leads to enhancer adoption by the lamin B1 gene: a second path to autosomal dominant adult-onset demyelinating leukodystrophy (ADLD).Human molecular genetics · 2015Article
- On human disease-causing amino acid variants: statistical study of sequence and structural patterns.Human mutation · 2015Article
- Molecular and clinical analyses of 16q24.1 duplications involving FOXF1 identify an evolutionarily unstable large minisatellite.BMC medical genetics · 2014Article
- Disruption of long-range gene regulation in human genetic disease: a kaleidoscope of general principles, diverse mechanisms and unique phenotypic consequences.Human genetics · 2014Review
- An individual with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) and additional features expands the phenotype associated with mutations in KAT6B.American journal of medical genetics. Part A · 2014Article
- Chromatin and epigenetic features of long-range gene regulation.Nucleic acids research · 2013Review
- Haploinsufficiency at the human IFNGR2 locus contributes to mycobacterial disease.Human molecular genetics · 2013Article
- Reference-assisted chromosome assembly.Proceedings of the National Academy of Sciences of the United States of America · 2013Article
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Authors and funding
21 authors at 8 institutions in 7 countries.
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Abstract
To date, the contribution of disrupted potentially cis-regulatory conserved non-coding sequences (CNCs) to human disease is most likely underestimated, as no systematic screens for putative deleterious variations in CNCs have been conducted. As a model for monogenic disease we studied the involvement of genetic changes of CNCs in the cis-regulatory domain of FOXL2 in blepharophimosis syndrome (BPES). Fifty-seven molecularly unsolved BPES patients underwent high-resolution copy number screening and targeted sequencing of CNCs. Apart from three larger distant deletions, a de novo deletion as small as 7.4 kb was found at 283 kb 5' to FOXL2. The deletion appeared to be triggered by an H-DNA-induced double-stranded break (DSB). In addition, it disrupts a novel long non-coding RNA (ncRNA) PISRT1 and 8 CNCs. The regulatory potential of the deleted CNCs was substantiated by in vitro luciferase assays. Interestingly, Chromosome Conformation Capture (3C) of a 625 kb region surrounding FOXL2 in expressing cellular systems revealed physical interactions of three upstream fragments and the FOXL2 core promoter. Importantly, one of these contains the 7.4 kb deleted fragment. Overall, this study revealed the smallest distant deletion causing monogenic disease and impacts upon the concept of mutation screening in human disease and developmental disorders in particular.
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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.