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      Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy

      research-article
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      Nature Communications
      Nature Publishing Group UK
      Genomic instability, Neurodevelopmental disorders, Chromosomes, DNA replication

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Embryonic development is dictated by tight regulation of DNA replication, cell division and differentiation. Mutations in DNA repair and replication genes disrupt this equilibrium, giving rise to neurodevelopmental disease characterized by microcephaly, short stature and chromosomal breakage. Here, we identify biallelic variants in two components of the RAD18-SLF1/2-SMC5/6 genome stability pathway, SLF2 and SMC5, in 11 patients with microcephaly, short stature, cardiac abnormalities and anemia. Patient-derived cells exhibit a unique chromosomal instability phenotype consisting of segmented and dicentric chromosomes with mosaic variegated hyperploidy. To signify the importance of these segmented chromosomes, we have named this disorder Atelís (meaning - incomplete) Syndrome. Analysis of Atelís Syndrome cells reveals elevated levels of replication stress, partly due to a reduced ability to replicate through G-quadruplex DNA structures, and also loss of sister chromatid cohesion. Together, these data strengthen the functional link between SLF2 and the SMC5/6 complex, highlighting a distinct role for this pathway in maintaining genome stability.

          Abstract

          The SMC5/6 complex is critical for genome stability. Here, the authors identify mutations in SLF2 and SMC5 as cause of Atelís Syndrome characterized by microcephaly, short stature, anemia, segmented chromosomes and mosaic variegated hyperploidy.

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          Most cited references75

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          CHOPCHOP v3: expanding the CRISPR web toolbox beyond genome editing

          Abstract The CRISPR–Cas system is a powerful genome editing tool that functions in a diverse array of organisms and cell types. The technology was initially developed to induce targeted mutations in DNA, but CRISPR–Cas has now been adapted to target nucleic acids for a range of purposes. CHOPCHOP is a web tool for identifying CRISPR–Cas single guide RNA (sgRNA) targets. In this major update of CHOPCHOP, we expand our toolbox beyond knockouts. We introduce functionality for targeting RNA with Cas13, which includes support for alternative transcript isoforms and RNA accessibility predictions. We incorporate new DNA targeting modes, including CRISPR activation/repression, targeted enrichment of loci for long-read sequencing, and prediction of Cas9 repair outcomes. Finally, we expand our results page visualization to reveal alternative isoforms and downstream ATG sites, which will aid users in avoiding the expression of truncated proteins. The CHOPCHOP web tool now supports over 200 genomes and we have released a command-line script for running larger jobs and handling unsupported genomes. CHOPCHOP v3 can be found at https://chopchop.cbu.uib.no
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            GeneMatcher: a matching tool for connecting investigators with an interest in the same gene.

            Here, we describe an overview and update on GeneMatcher (http://www.genematcher.org), a freely accessible Web-based tool developed as part of the Baylor-Hopkins Center for Mendelian Genomics. We created GeneMatcher with the goal of identifying additional individuals with rare phenotypes who had variants in the same candidate disease gene. We also wanted to facilitate connections to basic scientists working on orthologous genes in model systems with the goal of connecting their work to human Mendelian phenotypes. Meeting these goals will enhance the identification of novel Mendelian genes. Launched in September, 2013, GeneMatcher now has 2,178 candidate genes from 486 submitters spread across 38 countries entered in the database (June 1, 2015). GeneMatcher is also part of the Matchmaker Exchange (http://matchmakerexchange.org/) with an Application Programing Interface enabling submitters to query other databases of genetic variants and phenotypes without having to create accounts and data entries in multiple systems.
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              CHOPCHOP v2: a web tool for the next generation of CRISPR genome engineering

              In just 3 years CRISPR genome editing has transformed biology, and its popularity and potency continue to grow. New CRISPR effectors and rules for locating optimum targets continue to be reported, highlighting the need for computational CRISPR targeting tools to compile these rules and facilitate target selection and design. CHOPCHOP is one of the most widely used web tools for CRISPR- and TALEN-based genome editing. Its overarching principle is to provide an intuitive and powerful tool that can serve both novice and experienced users. In this major update we introduce tools for the next generation of CRISPR advances, including Cpf1 and Cas9 nickases. We support a number of new features that improve the targeting power, usability and efficiency of CHOPCHOP. To increase targeting range and specificity we provide support for custom length sgRNAs, and we evaluate the sequence composition of the whole sgRNA and its surrounding region using models compiled from multiple large-scale studies. These and other new features, coupled with an updated interface for increased usability and support for a continually growing list of organisms, maintain CHOPCHOP as one of the leading tools for CRISPR genome editing. CHOPCHOP v2 can be found at http://chopchop.cbu.uib.no
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                Author and article information

                Contributors
                lecaignec.c@chu-toulouse.fr
                eridavis@luriechildrens.org
                g.s.stewart@bham.ac.uk
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                4 November 2022
                4 November 2022
                2022
                : 13
                : 6664
                Affiliations
                [1 ]GRID grid.6572.6, ISNI 0000 0004 1936 7486, Institute of Cancer and Genomic Sciences, , University of Birmingham, ; Birmingham, UK
                [2 ]GRID grid.413808.6, ISNI 0000 0004 0388 2248, Advanced Center for Genetic and Translational Medicine (ACT-GeM), Stanley Manne Children’s Research Institute, , Ann & Robert H Lurie Children’s Hospital of Chicago, ; Chicago, IL USA
                [3 ]GRID grid.420112.4, ISNI 0000 0004 0607 7017, National Institute for Biotechnology and Genetic Engineering (NIBGE-C), Faisalabad, , Pakistan Institute of Engineering and Applied Sciences (PIEAS), ; Islamabad, Pakistan
                [4 ]GRID grid.277151.7, ISNI 0000 0004 0472 0371, Service de Génétique Médicale, , CHU Nantes, ; Nantes Cedex 1, France
                [5 ]GRID grid.5254.6, ISNI 0000 0001 0674 042X, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, , University of Copenhagen, ; Copenhagen, Denmark
                [6 ]GRID grid.17635.36, ISNI 0000000419368657, Department of Biochemistry, Molecular Biology and Biophysics, , University of Minnesota, ; Minneapolis, MN USA
                [7 ]GRID grid.12082.39, ISNI 0000 0004 1936 7590, Genome Damage and Stability Centre, Science Park Road, , University of Sussex, Falmer, ; Brighton, UK
                [8 ]GRID grid.418987.b, ISNI 0000 0004 1764 2181, Department of Chromosome Science, National Institute of Genetics, , Research Organization of Information and Systems (ROIS), ; Mishima, Shizuoka Japan
                [9 ]GRID grid.189509.c, ISNI 0000000100241216, Center for Human Disease Modeling, , Duke University Medical Center, ; Durham, NC USA
                [10 ]GRID grid.5515.4, ISNI 0000000119578126, Hospital Infantil Universitario Niño Jesús, CIBER de fisiopatología de la obesidad y nutrición (CIBEROBN), Instituto de Salud Carlos III, , Universidad Autónoma de Madrid, ; Madrid, Spain
                [11 ]The Community Health Clinic, Topeka, IN USA
                [12 ]GRID grid.11951.3d, ISNI 0000 0004 1937 1135, Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, , University of the Witwatersrand, ; Johannesburg, South Africa
                [13 ]GRID grid.4305.2, ISNI 0000 0004 1936 7988, MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, Western General Hospital, , The University of Edinburgh, ; Edinburgh, Scotland
                [14 ]GRID grid.13097.3c, ISNI 0000 0001 2322 6764, Department of Medical and Molecular Genetics, Faculty of Life Science and Medicine, Guy’s Hospital, , King’s College London, ; London, UK
                [15 ]Bioscientia Institute for Medical Diagnostics, Human Genetics, Ingelheim, Germany
                [16 ]GRID grid.415298.3, ISNI 0000 0004 0573 8549, King Fahad Military Medical Complex, ; Dhahran, Saudi Arabia
                [17 ]GRID grid.418961.3, ISNI 0000 0004 0472 2713, Regeneron Genetics Center, , Regeneron Pharmaceuticals Inc., ; Tarrytown, NY USA
                [18 ]GRID grid.9486.3, ISNI 0000 0001 2159 0001, International Laboratory for Human Genome Research, , Universidad Nacional Autónoma de México, ; Querétaro, México
                [19 ]GRID grid.418640.f, Clinic for Special Children, ; Strasburg, PA USA
                [20 ]GRID grid.412966.e, ISNI 0000 0004 0480 1382, Department of Clinical Genetics, , Maastricht University Medical Center, ; Maastricht, The Netherlands
                [21 ]GRID grid.275033.0, ISNI 0000 0004 1763 208X, Department of Genetics, , The Graduate University for Advanced Studies (SOKENDAI), ; Mishima, Shizuoka Japan
                [22 ]GRID grid.239826.4, ISNI 0000 0004 0391 895X, Clinical Genetics Department, , Guy’s Hospital, ; London, UK
                [23 ]GRID grid.470126.6, ISNI 0000 0004 1767 0473, Department of Rare Disease Genomics, , Yokohama City University Hospital, ; Yokohama, Japan
                [24 ]GRID grid.268441.d, ISNI 0000 0001 1033 6139, Department of Human Genetics, , Yokohama City University Graduate School of Medicine, ; Yokohama, Japan
                [25 ]GRID grid.410804.9, ISNI 0000000123090000, Department of Paediatrics, , Jichi Medical University School of Medicine, ; Tochigi, Japan
                [26 ]GRID grid.429045.e, ISNI 0000 0004 0500 5230, IMDEA Alimentación/IMDEA Food, ; Madrid, Spain
                [27 ]GRID grid.412966.e, ISNI 0000 0004 0480 1382, Department of Clinical Genetics and GROW-School for Oncology and Developmental Biology, , Maastricht University Medical Center, ; Maastricht, The Netherlands
                [28 ]GRID grid.508721.9, Centre Hospitalier Universitaire Toulouse, Service de Génétique Médicale and ToNIC, Toulouse NeuroImaging Center, Inserm, UPS, , Université de Toulouse, ; Toulouse, France
                [29 ]GRID grid.16753.36, ISNI 0000 0001 2299 3507, Department of Pediatrics; Department of Cell and Developmental Biology, Feinberg School of Medicine, , Northwestern University, ; Chicago, IL USA
                Author information
                http://orcid.org/0000-0003-0909-4341
                http://orcid.org/0000-0001-8690-5828
                http://orcid.org/0000-0003-3012-8788
                http://orcid.org/0000-0002-3286-7990
                http://orcid.org/0000-0002-2912-8273
                http://orcid.org/0000-0001-8169-8735
                http://orcid.org/0000-0001-5766-659X
                http://orcid.org/0000-0002-8218-0089
                http://orcid.org/0000-0003-3096-8795
                http://orcid.org/0000-0003-4178-1838
                http://orcid.org/0000-0003-0376-7736
                http://orcid.org/0000-0002-8539-8753
                http://orcid.org/0000-0002-2085-5773
                http://orcid.org/0000-0002-0570-2031
                http://orcid.org/0000-0002-9736-7137
                http://orcid.org/0000-0002-7657-1649
                http://orcid.org/0000-0001-7634-9207
                http://orcid.org/0000-0002-4540-5277
                http://orcid.org/0000-0002-1320-1165
                http://orcid.org/0000-0001-5826-0276
                http://orcid.org/0000-0001-9846-6500
                http://orcid.org/0000-0002-7818-7595
                http://orcid.org/0000-0003-1783-619X
                http://orcid.org/0000-0002-6623-709X
                http://orcid.org/0000-0002-0598-653X
                http://orcid.org/0000-0002-2412-8397
                http://orcid.org/0000-0002-0960-3241
                Article
                34349
                10.1038/s41467-022-34349-8
                9636423
                36333305
                4120626c-77af-44e0-9cc2-4fd0d2fb0f4f
                © The Author(s) 2022

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 11 November 2021
                : 21 October 2022
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100000289, Cancer Research UK (CRUK);
                Award ID: C17422/A25154
                Award ID: C17183/A23303
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100001279, Great Ormond Street Hospital Charity (GOSH);
                Award ID: V5019
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100000329, Novo Nordisk UK Research Foundation;
                Award ID: NNF14CC0001
                Award Recipient :
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                © The Author(s) 2022

                Uncategorized
                genomic instability,neurodevelopmental disorders,chromosomes,dna replication
                Uncategorized
                genomic instability, neurodevelopmental disorders, chromosomes, dna replication

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