Phenotypes and genotypes in individuals with SMC1A variants

Research output: Contribution to journalArticlepeer-review


  • 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

  • University of Amsterdam
  • Autism Team Northern-Netherlands, Jonx Department of Youth Mental Health and Autism, Lentis Psychiatric Institute, Groningen, the Netherlands.
  • Division of Clinical Genetics, Department of Pediatrics, Paracelsus Medical University Salzburg, Salzburg, Austria.
  • Copenhagen University Hospitals
  • Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, the Netherlands.
  • Department of Pediatrics, ASST Papa Giovanni XXIII, Bergamo, Italy.
  • University of Buenos Aires
  • 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.
  • Vrije Universiteit Medical Centre
  • MRC Human Genetics Unit, IGMM, Western General Hospital, Edinburgh, United Kingdom.
  • University of Milan
  • Universitätsklinikum Schleswig-Holstein
  • Department of Medical Genetics, Kasturba Medical College, Manipal University, Manipal, India.
  • Department of Clinical Genetics, Leiden University Medical Centre, Leiden, the Netherlands.
  • University Medical Center Utrecht
  • Institut für Medizinische Genetik und Humangenetik, Berlin, Germany.
  • Radboud University
  • University of Lübeck
  • University Medical Center Hamburg-Eppendorf
  • University of Birmingham
  • 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.
  • Medical University of Gdansk


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