ArticleNature communications2022
Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy.
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Article in Nature communications, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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30citing papers in PubMed
6.9field-weighted citation impact, top 3% of its field
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Who cites it
30 citing papers in PubMed, 38 citations in OpenAlex.
- The Multifunctional SMC5/6 Complex in Genome Stability, Antiviral Restriction, and Human Disease.Current issues in molecular biology · 2026Review
- SLF2 and SMC5 dysfunction drives HSC aging and predisposes to MDS, defining a new inherited bone marrow failure syndrome.Leukemia · 2026Article
- Disruption of the structural maintenance of chromosomes 5/6 complex enables tumor mutagenesis.NAR cancer · 2026Article
- A manually curated gene-phenotype catalogue for progeroid syndromes and premature aging.Aging · 2026Article
- Molecular determinants of Smc5/6 association with DNA junctions.Nature communications · 2026Article
- Assessing SMC Complex Function in Replication Fork Progression with DNA Fiber Assays.Methods in molecular biology (Clifton, N.J.) · 2026Article
- Structural and mechanistic perspectives on Nse5/6 regulation of the Smc5/6 complex.Frontiers in molecular biosciences · 2026Review
- Investigation of DNA Damage Response Genes Validates the Role of DNA Repair in Pediatric Cancer Risk and IdentifiesJournal of clinical oncology : official journal of the American Society of Clinical Oncology · 2025Article
- RecessiveDiagnostics (Basel, Switzerland) · 2025Article
- Bi-allelic deleterious variants in SNAPIN, which encodes a retrograde dynein adaptor, cause a prenatal-onset neurodevelopmental disorder.American journal of human genetics · 2025Article
- Pathogenic variants in TMEM184B cause a neurodevelopmental syndrome associated with alteration of metabolic signaling.American journal of human genetics · 2025Article
- Characterization of a PNLIP variant identified in Amish pediatric patients with congenital pancreatic lipase deficiency.Journal of lipid research · 2025Article
- Pathogenic variants inmedRxiv : the preprint server for health sciences · 2025Article
- RNA methyltransferase SPOUT1/CENP-32 links mitotic spindle organization with the neurodevelopmental disorder SpADMiSS.Nature communications · 2025Article
- Mosaic variegated aneuploidy in development, ageing and cancer.Nature reviews. Genetics · 2024Review
- Update on Recommendations for Cancer Screening and Surveillance in Children with Genomic Instability Disorders.Clinical cancer research : an official journal of the American Association for Cancer Research · 2024Review
- Structural mechanisms of SLF1 interactions with Histone H4 and RAD18 at the stalled replication fork.Nucleic acids research · 2024Article
- The SMC5/6 complex prevents genotoxicity upon APOBEC3A-mediated replication stress.The EMBO journal · 2024Article
- RAD18 directs DNA double-strand break repair by homologous recombination to post-replicative chromatin.Nucleic acids research · 2024Article
- Crucial role of the NSE1 RING domain in Smc5/6 stability and FANCM-independent fork progression.Cellular and molecular life sciences : CMLS · 2024Article
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Authors and funding
48 authors at 20 institutions in 11 countries.
Laura J Grange *Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.ORCID 0000-0003-0909-4341
John J Reynolds *Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.ORCID 0000-0001-8690-5828
Farid Ullah *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.
Bertrand Isidor *Service de Génétique Médicale, CHU Nantes, Nantes Cedex 1, France.
Robert F ShearerNovo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.ORCID 0000-0003-3012-8788
Xenia LatypovaService de Génétique Médicale, CHU Nantes, Nantes Cedex 1, France.
Ryan M BaxleyDepartment of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA.ORCID 0000-0002-3286-7990
Antony W OliverGenome Damage and Stability Centre, Science Park Road, University of Sussex, Falmer, Brighton, UK.ORCID 0000-0002-2912-8273
Anil GaneshInstitute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
Sophie L CookeInstitute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.ORCID 0000-0001-8169-8735
Satpal S JhujhInstitute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.ORCID 0000-0001-5766-659X
Gavin S McNeeInstitute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
Robert HollingworthInstitute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
Martin R HiggsInstitute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.ORCID 0000-0002-8218-0089
Toyoaki NatsumeDepartment of Chromosome Science, National Institute of Genetics, Research Organization of Information and Systems (ROIS), Mishima, Shizuoka, Japan.
Tahir KhanCenter for Human Disease Modeling, Duke University Medical Center, Durham, NC, USA.ORCID 0000-0003-3096-8795
Gabriel Á Martos-MorenoHospital Infantil Universitario Niño Jesús, CIBER de fisiopatología de la obesidad y nutrición (CIBEROBN), Instituto de Salud Carlos III, Universidad Autónoma de Madrid, Madrid, Spain.
Sharon ChuppThe Community Health Clinic, Topeka, IN, USA.
Christopher G MathewSydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.ORCID 0000-0003-4178-1838
David ParryMRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, Western General Hospital, The University of Edinburgh, Edinburgh, Scotland.ORCID 0000-0003-0376-7736
Michael A SimpsonDepartment of Medical and Molecular Genetics, Faculty of Life Science and Medicine, Guy's Hospital, King's College London, London, UK.ORCID 0000-0002-8539-8753
Nahid NahavandiBioscientia Institute for Medical Diagnostics, Human Genetics, Ingelheim, Germany.
Zafer YükselBioscientia Institute for Medical Diagnostics, Human Genetics, Ingelheim, Germany.ORCID 0000-0002-2085-5773
Mojgan DrasdoBioscientia Institute for Medical Diagnostics, Human Genetics, Ingelheim, Germany.
Anja KronBioscientia Institute for Medical Diagnostics, Human Genetics, Ingelheim, Germany.
Petra VogtBioscientia Institute for Medical Diagnostics, Human Genetics, Ingelheim, Germany.
Annemarie JonassonBioscientia Institute for Medical Diagnostics, Human Genetics, Ingelheim, Germany.
Saad Ahmed SethKing Fahad Military Medical Complex, Dhahran, Saudi Arabia.ORCID 0000-0002-0570-2031
Claudia Gonzaga-JaureguiRegeneron Genetics Center, Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA.
Karlla W BrigattiClinic for Special Children, Strasburg, PA, USA.
Alexander P A StegmannDepartment of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.ORCID 0000-0002-9736-7137
Masato KanemakiDepartment of Genetics, The Graduate University for Advanced Studies (SOKENDAI), Mishima, Shizuoka, Japan.ORCID 0000-0002-7657-1649
Dragana JosifovaClinical Genetics Department, Guy's Hospital, London, UK.ORCID 0000-0001-7634-9207
Yuri UchiyamaDepartment of Rare Disease Genomics, Yokohama City University Hospital, Yokohama, Japan.ORCID 0000-0002-4540-5277
Yukiko OhDepartment of Paediatrics, Jichi Medical University School of Medicine, Tochigi, Japan.
Akira MorimotoDepartment of Paediatrics, Jichi Medical University School of Medicine, Tochigi, Japan.
Hitoshi OsakaDepartment of Paediatrics, Jichi Medical University School of Medicine, Tochigi, Japan.ORCID 0000-0002-1320-1165
Zineb AmmousThe Community Health Clinic, Topeka, IN, USA.
Jesús ArgenteHospital Infantil Universitario Niño Jesús, CIBER de fisiopatología de la obesidad y nutrición (CIBEROBN), Instituto de Salud Carlos III, Universidad Autónoma de Madrid, Madrid, Spain.ORCID 0000-0001-5826-0276
Naomichi MatsumotoDepartment of Rare Disease Genomics, Yokohama City University Hospital, Yokohama, Japan.ORCID 0000-0001-9846-6500
Constance T R M StumpelDepartment of Clinical Genetics and GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands.
Alexander M R TaylorInstitute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.ORCID 0000-0002-7818-7595
Andrew P JacksonMRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, Western General Hospital, The University of Edinburgh, Edinburgh, Scotland.
Anja-Katrin BielinskyDepartment of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA.ORCID 0000-0003-1783-619X
Niels MailandNovo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.ORCID 0000-0002-6623-709X
Cedric Le CaignecCentre Hospitalier Universitaire Toulouse, Service de Génétique Médicale and ToNIC, Toulouse NeuroImaging Center, Inserm, UPS, Université de Toulouse, Toulouse, France. lecaignec.c@chu-toulouse.fr.ORCID 0000-0002-0598-653X
Erica E DavisAdvanced 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. eridavis@luriechildrens.org.ORCID 0000-0002-2412-8397
Grant S StewartInstitute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK. g.s.stewart@bham.ac.uk.ORCID 0000-0002-0960-3241
University of Birmingham · GBJichi Medical University · JPGénétique Médicale & Génomique Fonctionelle · FRGuy's Hospital · GBInstituto de Salud Carlos III · ESMaastricht University · NLUniversity of Copenhagen · DKUniversity of Minnesota · USWestern General Hospital · GBYokohama City University Hospital · JPAutonomous University of Queretaro · MXClinic for Special Children · USDuke Medical Center · USKing Fahd Military Medical Complex · SALurie Children's Hospital · USNational Institute of Genetics · JPNorthwestern University · USThe Graduate University for Advanced Studies, SOKENDAI · JPUniversité Toulouse III - Paul Sabatier · FRUniversity of Sussex · GB
Funding
Functional Dissection of CNVs in Neurodevelopmental TraitsR01MH106826 · NIMH · LURIE CHILDREN'S HOSPITAL OF CHICAGO · PI DAVIS, ERICA ELLEN · 2015 to 2025
$4.6MThe role of DNA damage tolerance pathways in human cellsR01GM134681 · NIGMS · UNIVERSITY OF VIRGINIA · PI George Lucian Moldovan, Claudia M Nicolae · 2019 to 2026
$3.0MMechanistic insight into genome stability pathwaysR35GM141805 · NIGMS · UNIVERSITY OF VIRGINIA · PI Anja-Katrin Bielinsky · 2021 to 2026
$2.9MMedical Research Council MC_UU_00007/5Medical Research Council MR/P018955/1NIGMS NIH HHS R01 GM134681NIGMS NIH HHS R35 GM141805NIMH NIH HHS R01 MH106826
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.
Indexed as
Cell Cycle ProteinsMicrocephalyChromosomal Proteins, Non-HistoneChromosomesDNA-Binding ProteinsDNA RepairGenomic InstabilityHumansUbiquitin-Protein LigasesCell Cycle ProteinsChromosomal Proteins, Non-HistoneDNA-Binding ProteinsRAD18 protein, humanSMC5 protein, humanUbiquitin-Protein Ligases
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