Phenotypes and genotypes in individuals with SMC1A variants

Research output: Contribution to journalArticle


  • Sylvia Huisman
  • Paul A Mulder
  • Egbert Redeker
  • Ingrid Bader
  • Anne-Marie Bisgaard
  • Alice Brooks
  • Anna Cereda
  • Constanza Cinca
  • Dinah Clark
  • Valerie Cormier-Daire
  • Matthew A Deardorff
  • Karin Diderich
  • Mariet Elting
  • Anthonie van Essen
  • David Fitz Patrick
  • Cristina Gervasini
  • Gabriele Gillessen-Kaesbach
  • Katta M Girisha
  • Yvonne Hilhorst-Hofstee
  • Saskia Hopman
  • Denise Horn
  • Mala Isrie
  • Sandra Jansen
  • Cathrine Jespersgaard
  • Frank J Kaiser
  • Maninder Kaur
  • Tjitske Kleefstra
  • Ian D Krantz
  • Phillis Lakeman
  • Annemiek Landlust
  • Davor Lessel
  • Caroline Michot
  • Jo Moss
  • Sarah E Noon
  • Ilaria Parenti
  • Juan Pie
  • Feliciano J Ramos
  • Claudine Rieubland
  • Silvia Russo
  • Angelo Selicorni
  • Zeynep Tümer
  • Rieneke Vorstenbosch
  • Tara L Wenger
  • Ingrid van Balkom
  • Sigrid Piening
  • Jolanta Wierzba
  • Raoul C Hennekam

Colleges, School and Institutes

External organisations

  • Department of Pediatrics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
  • Autism Team Northern-Netherlands, Jonx Department of Youth Mental Health and Autism, Lentis Psychiatric Institute, Groningen, the Netherlands.
  • Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
  • Division of Clinical Genetics, Department of Pediatrics, Paracelsus Medical University Salzburg, Salzburg, Austria.
  • Kennedy Center, Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark.
  • Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, the Netherlands.
  • Department of Pediatrics, ASST Papa Giovanni XXIII, Bergamo, Italy.
  • División Genetica, Hospital de Clínicas José de San Martín, Universidad de Buenos Aires, Buenos Aires, Argentina.
  • Division of Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
  • Department of Medical Genetics, Reference Center for Skeletal Dysplasia, INSERM UMR 1163, Laboratory of Molecular and Physiopathological Bases of Osteochondrodysplasia, Paris Descartes-Sorbonne Paris Cité University, AP-HP, Institut Imagine, and Hôpital Universitaire Necker-Enfants Malades, Paris, France.
  • Department of Clinical Genetics, VU University Medical Center, Amsterdam, the Netherlands.
  • MRC Human Genetics Unit, IGMM, Western General Hospital, Edinburgh, United Kingdom.
  • Department of Health Sciences, Medical Genetics, University of Milan, Milan, Italy.
  • Institut für Humangenetik Lübeck, Universitätsklinikum Schleswig-Holstein, Lübeck, Germany.
  • Department of Medical Genetics, Kasturba Medical College, Manipal University, Manipal, India.
  • Department of Clinical Genetics, Leiden University Medical Centre, Leiden, the Netherlands.
  • Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.
  • Institut für Medizinische Genetik und Humangenetik, Berlin, Germany.
  • Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, the Netherlands.
  • Section for Functional Genetics, Institute of Human Genetics, University of Lübeck, Lübeck, Germany.
  • Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Cerebra Centre for Neurodevelopmental Disorders, School of Psychology, University of Birmingham, Birmingham, United Kingdom.
  • Laboratorio de Genética Clínica y Genómica Funcional, Facultad de Medicina, Universidad de Zaragoza, Zaragoza, Spain.
  • Unidad de Genética Clínica, Servicio de Pediatría, Hospital Clínico Universitario "Lozano Blesa" CIBERER-GCV02 and Departamento de Pediatría, Facultad de Medicina, Universidad de Zaragoza, Zaragoza, Spain.
  • Division of Human Genetics, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
  • Molecular Biology Laboratory, Istituto Auxologico Italiano, Milan, Italy.
  • UOC Pediatria, ASST Lariana, Como, Italy.
  • Severinus Institute, Veldhoven, the Netherlands.
  • Division of Craniofacial Medicine, Seattle Children's Hospital, Seattle, Washington.
  • Departments of Pediatrics, Hematology, Oncology and Department of General Nursery, Medical University of Gdansk, Gdansk, Poland.


SMC1A encodes one of the proteins of the cohesin complex. SMC1A variants are known to cause a phenotype resembling Cornelia de Lange syndrome (CdLS). Exome sequencing has allowed recognizing SMC1A variants in individuals with encephalopathy with epilepsy who do not resemble CdLS. We performed an international, interdisciplinary study on 51 individuals with SMC1A variants for physical and behavioral characteristics, and compare results to those in 67 individuals with NIPBL variants. For the Netherlands all known individuals with SMC1A variants were studied, both with and without CdLS phenotype. Individuals with SMC1A variants can resemble CdLS, but manifestations are less marked compared to individuals with NIPBL variants: growth is less disturbed, facial signs are less marked (except for periocular signs and thin upper vermillion), there are no major limb anomalies, and they have a higher level of cognitive and adaptive functioning. Self-injurious behavior is more frequent and more severe in the NIPBL group. In the Dutch group 5 of 13 individuals (all females) had a phenotype that shows a remarkable resemblance to Rett syndrome: epileptic encephalopathy, severe or profound intellectual disability, stereotypic movements, and (in some) regression. Their missense, nonsense, and frameshift mutations are evenly spread over the gene. We conclude that SMC1A variants can result in a phenotype resembling CdLS and a phenotype resembling Rett syndrome. Resemblances between the SMC1A group and the NIPBL group suggest that a disturbed cohesin function contributes to the phenotype, but differences between these groups may also be explained by other underlying mechanisms such as moonlighting of the cohesin genes.


Original languageEnglish
JournalAmerican Journal of Medical Genetics. Part A
Early online date26 May 2017
Publication statusE-pub ahead of print - 26 May 2017


  • behavior, Brachmann-De Lange syndrome, Cornelia de Lange syndrome, NIPBL, Rett syndrome, self-injurious behavior, severity score, SMC1A, syndrome delineation