title: STAG1mutations cause a novel cohesinopathy characterised by unspecific syndromic intellectual disability.
abstract: Cohesinopathies are rare neurodevelopmental disorders arising from a dysfunction in the cohesin pathway, which enables chromosome segregation and regulates gene transcription. So far, eight genes from this pathway have been reported in human disease.STAG1belongs to the STAG subunit of the core cohesin complex, along with five other subunits. This work aimed to identify the phenotype ascribed toSTAG1mutations.
  
  
  
  Among patients referred for intellectual disability (ID) in genetics departments worldwide, array-comparative genomic hybridisation (CGH), gene panel, whole-exome sequencing or whole-genome sequencing were performed following the local diagnostic standards.
  
  
  
  A mutation inSTAG1was identified in 17 individuals from 16 families, 9 males and 8 females aged 2-33 years. Four individuals harboured a small microdeletion encompassingSTAG1; three individuals from two families had an intragenicSTAG1deletion. Six deletions were identified by array-CGH, one by whole-exome sequencing. Whole-exome sequencing found de novo heterozygous missense or frameshiftSTAG1variants in eight patients, a panel of genes involved in ID identified a missense and a frameshift variant in two individuals. The 17 patients shared common facial features, with wide mouth and deep-set eyes. Four individuals had mild microcephaly, seven had epilepsy.
  
  
  
  We report an international series of 17 individuals from 16 families presenting with syndromic unspecific ID that could be attributed to aSTAG1deletion or point mutation. This first series reporting the phenotype ascribed to mutation inSTAG1highlights the importance of data sharing in the field of rare disorders.
authors.affiliation: Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), Centre Hospitalier Universitaire Dijon, Dijon, France.|Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'Interrégion Est, Centre Hospitalier Universitaire Dijon, Dijon, France.
authors.forename: Daphné
authors.identifier: 0000-0002-2193-8685
authors.initials: D
authors.lastname: Lehalle
authors.affiliation: Laboratoire de Cytogénétique, Centre Hospitalier Universitaire Dijon, Dijon, France.|Equipe GAD, EA4271, Faculté de Médecine, Université de Bourgogne Franche-Comté, Dijon, France.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Mosca-Boidron
authors.affiliation: GeneDx, 207 Perry Parkway, Gaithersburg, Maryland, USA.
authors.forename: Amber
authors.initials: A
authors.lastname: Begtrup
authors.affiliation: Service de génétique clinique, CHU Lille, Lille, France.
authors.forename: Odile
authors.initials: O
authors.lastname: Boute-Benejean
authors.affiliation: Genetic Department, University Hospital La Pitié Salpêtrière, Paris, France.
authors.forename: Perrine
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authors.lastname: Charles
authors.affiliation: GeneDx, 207 Perry Parkway, Gaithersburg, Maryland, USA.
authors.forename: Megan T
authors.initials: MT
authors.lastname: Cho
authors.affiliation: Department of Clinical Genetics, Cambridge University Hospitals, Cambridge, UK.
authors.forename: Amanda
authors.initials: A
authors.lastname: Clarkson
authors.affiliation: Epilepsy Center, NYU Langone Medical Center, New York, New York, USA.
authors.forename: Orrin
authors.initials: O
authors.lastname: Devinsky
authors.affiliation: Equipe GAD, EA4271, Faculté de Médecine, Université de Bourgogne Franche-Comté, Dijon, France.
authors.forename: Yannis
authors.initials: Y
authors.lastname: Duffourd
authors.affiliation: Laboratoire de Cytogénétique, Centre Hospitalier Universitaire Dijon, Dijon, France.|Equipe GAD, EA4271, Faculté de Médecine, Université de Bourgogne Franche-Comté, Dijon, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Duplomb-Jego
authors.affiliation: Laboratoire de biologie moléculaire, CHU Strasbourg, Strasbourg, France.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Gérard
authors.affiliation: Genetic Department, University Hospital La Pitié Salpêtrière, Paris, France.
authors.forename: Aurélia
authors.initials: A
authors.lastname: Jacquette
authors.affiliation: Laboratoire de Cytogénétique, Centre Hospitalier Universitaire Dijon, Dijon, France.|Equipe GAD, EA4271, Faculté de Médecine, Université de Bourgogne Franche-Comté, Dijon, France.
authors.forename: Paul
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authors.lastname: Kuentz
authors.affiliation: Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), Centre Hospitalier Universitaire Dijon, Dijon, France.|Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'Interrégion Est, Centre Hospitalier Universitaire Dijon, Dijon, France.
authors.forename: Alice
authors.initials: A
authors.lastname: Masurel-Paulet
authors.affiliation: Clinical Genetics Center, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors.forename: Carey
authors.initials: C
authors.lastname: McDougall
authors.affiliation: Department of Clinical Genetics, Bordeaux, France.
authors.forename: Sébastien
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authors.lastname: Moutton
authors.affiliation: Department of Human Genetics and Centre for Developmental Disabilities, KU University Hospital Leuven, Leuven, Belgium.
authors.forename: Hilde
authors.initials: H
authors.lastname: Olivié
authors.affiliation: Department of Clinical Genetics, Cambridge University Hospitals, Cambridge, UK.
authors.forename: Soo-Mi
authors.initials: SM
authors.lastname: Park
authors.affiliation: Institute of Medical Genetics, University of Zurich, Schwerzenbach-Zurich, Switzerland.
authors.forename: Anita
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authors.lastname: Rauch
authors.affiliation: Centre for Human Genetics, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Nicole
authors.initials: N
authors.lastname: Revencu
authors.affiliation: Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), Centre Hospitalier Universitaire Dijon, Dijon, France.|Laboratoire de Cytogénétique, Centre Hospitalier Universitaire Dijon, Dijon, France.|Equipe GAD, EA4271, Faculté de Médecine, Université de Bourgogne Franche-Comté, Dijon, France.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Rivière
authors.affiliation: University of Minnesota Children's Hospital, Minneapolis, Minnesota, USA.
authors.forename: Karol
authors.initials: K
authors.lastname: Rubin
authors.affiliation: Department of Clinical Genetics, Cambridge University Hospitals, Cambridge, UK.
authors.forename: Ingrid
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authors.affiliation: Oxford Centre for Genomic Medicine Nuffield Orthopaedic Centre, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 7HE.
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Shears
authors.affiliation: Service de génétique clinique, CHU Lille, Lille, France.|Univ. Lille, RADEME (Research team on rare developmental and metabolic diseases), Lille, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Smol
authors.affiliation: Department of Clinical Genetics, Cambridge University Hospitals, Cambridge, UK.
authors.forename: Ana Lisa
authors.initials: AL
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authors.affiliation: Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: Paulien
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authors.lastname: Terhal
authors.affiliation: Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), Centre Hospitalier Universitaire Dijon, Dijon, France.|Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'Interrégion Est, Centre Hospitalier Universitaire Dijon, Dijon, France.|Equipe GAD, EA4271, Faculté de Médecine, Université de Bourgogne Franche-Comté, Dijon, France.
authors.forename: Julien
authors.identifier: 0000-0001-9271-3961
authors.initials: J
authors.lastname: Thevenon
authors.affiliation: Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: Koen
authors.initials: K
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authors.affiliation: Service de génétique clinique, CHU Lille, Lille, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Vincent-Delorme
authors.affiliation: Department of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Marjolein H
authors.initials: MH
authors.lastname: Willemsen
authors.affiliation: Department of Pediatrics, Texas Tech University Health Science Center, Lubbock, Texas, USA.
authors.forename: Golder N
authors.initials: GN
authors.lastname: Wilson
authors.affiliation: Department of Clinical Genetics, Bordeaux, France.
authors.forename: Elaine
authors.initials: E
authors.lastname: Zackai
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universitat Erlangen-Nurnberg, Erlangen, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Zweier
authors.affiliation: Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), Centre Hospitalier Universitaire Dijon, Dijon, France.|Laboratoire de Cytogénétique, Centre Hospitalier Universitaire Dijon, Dijon, France.|Equipe GAD, EA4271, Faculté de Médecine, Université de Bourgogne Franche-Comté, Dijon, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Callier
authors.affiliation: Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), Centre Hospitalier Universitaire Dijon, Dijon, France.|Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'Interrégion Est, Centre Hospitalier Universitaire Dijon, Dijon, France.|Equipe GAD, EA4271, Faculté de Médecine, Université de Bourgogne Franche-Comté, Dijon, France.
authors.forename: Christel
authors.initials: C
authors.lastname: Thauvin-Robinet
authors.affiliation: Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), Centre Hospitalier Universitaire Dijon, Dijon, France.|Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'Interrégion Est, Centre Hospitalier Universitaire Dijon, Dijon, France.|Equipe GAD, EA4271, Faculté de Médecine, Université de Bourgogne Franche-Comté, Dijon, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Faivre
mesh_terms: D000328:Adult; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D055028:Comparative Genomic Hybridization; D005260:Female; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D013577:Syndrome; D000073359:Exome Sequencing; D000097722:Cohesins
chemical_list: D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D009687:Nuclear Proteins; D000097722:Cohesins; C108522:STAG1 protein, human
keywords: Cohesin; Intellectual disability; STAG1; datasharing