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Phenotypes and genotypes in individuals with SMC1A variants.

  • Huisman S Department of Pediatrics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
  • Mulder PA Autism Team Northern-Netherlands, Jonx Department of Youth Mental Health and Autism, Lentis Psychiatric Institute, Groningen, the Netherlands.
  • Redeker E Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
  • Bader I Division of Clinical Genetics, Department of Pediatrics, Paracelsus Medical University Salzburg, Salzburg, Austria.
  • Bisgaard AM Kennedy Center, Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark.
  • Brooks A Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, the Netherlands.
  • Cereda A Department of Pediatrics, ASST Papa Giovanni XXIII, Bergamo, Italy.
  • Cinca C División Genetica, Hospital de Clínicas José de San Martín, Universidad de Buenos Aires, Buenos Aires, Argentina.
  • Clark D Division of Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
  • Cormier-Daire V 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.
  • Deardorff MA Division of Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
  • Diderich K Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, the Netherlands.
  • Elting M Department of Clinical Genetics, VU University Medical Center, Amsterdam, the Netherlands.
  • van Essen A MRC Human Genetics Unit, IGMM, Western General Hospital, Edinburgh, United Kingdom.
  • FitzPatrick D Department of Health Sciences, Medical Genetics, University of Milan, Milan, Italy.
  • Gervasini C Institut für Humangenetik Lübeck, Universitätsklinikum Schleswig-Holstein, Lübeck, Germany.
  • Gillessen-Kaesbach G Department of Medical Genetics, Kasturba Medical College, Manipal University, Manipal, India.
  • Girisha KM Department of Clinical Genetics, Leiden University Medical Centre, Leiden, the Netherlands.
  • Hilhorst-Hofstee Y Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.
  • Hopman S Institut für Medizinische Genetik und Humangenetik, Berlin, Germany.
  • Horn D Department of Clinical Genetics, VU University Medical Center, Amsterdam, the Netherlands.
  • Isrie M Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, the Netherlands.
  • Jansen S Kennedy Center, Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark.
  • Jespersgaard C Section for Functional Genetics, Institute of Human Genetics, University of Lübeck, Lübeck, Germany.
  • Kaiser FJ Division of Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
  • Kaur M Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, the Netherlands.
  • Kleefstra T Division of Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
  • Krantz ID Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
  • Lakeman P Autism Team Northern-Netherlands, Jonx Department of Youth Mental Health and Autism, Lentis Psychiatric Institute, Groningen, the Netherlands.
  • Landlust A Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Lessel D 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.
  • Michot C Cerebra Centre for Neurodevelopmental Disorders, School of Psychology, University of Birmingham, Birmingham, United Kingdom.
  • Moss J Division of Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
  • Noon SE Cerebra Centre for Neurodevelopmental Disorders, School of Psychology, University of Birmingham, Birmingham, United Kingdom.
  • Oliver C Institut für Humangenetik Lübeck, Universitätsklinikum Schleswig-Holstein, Lübeck, Germany.
  • Parenti I Laboratorio de Genética Clínica y Genómica Funcional, Facultad de Medicina, Universidad de Zaragoza, Zaragoza, Spain.
  • Pie J 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.
  • Ramos FJ Division of Human Genetics, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
  • Rieubland C Molecular Biology Laboratory, Istituto Auxologico Italiano, Milan, Italy.
  • Russo S UOC Pediatria, ASST Lariana, Como, Italy.
  • Selicorni A Kennedy Center, Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark.
  • Tümer Z Severinus Institute, Veldhoven, the Netherlands.
  • Vorstenbosch R Division of Craniofacial Medicine, Seattle Children's Hospital, Seattle, Washington.
  • Wenger TL Autism Team Northern-Netherlands, Jonx Department of Youth Mental Health and Autism, Lentis Psychiatric Institute, Groningen, the Netherlands.
  • van Balkom I Autism Team Northern-Netherlands, Jonx Department of Youth Mental Health and Autism, Lentis Psychiatric Institute, Groningen, the Netherlands.
  • Piening S Departments of Pediatrics, Hematology, Oncology and Department of General Nursery, Medical University of Gdansk, Gdansk, Poland.
  • Wierzba J Department of Pediatrics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
  • Hennekam RC
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  • 2017-05-27
Published in:
  • American journal of medical genetics. Part A. - 2017
Brachmann-De Lange syndrome
Cornelia de Lange syndrome
NIPBL
Rett syndrome
SMC1A
behavior
self-injurious behavior
severity score
syndrome delineation
Adolescent
Adult
Cell Cycle Proteins
Child
Child, Preschool
Chromosomal Proteins, Non-Histone
De Lange Syndrome
Exome
Humans
Infant
Infant, Newborn
Male
Middle Aged
Netherlands
Proteins
Rett Syndrome
Spasms, Infantile
Young Adult
English 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.
Language
  • English
Open access status
green
Identifiers
Persistent URL
https://folia.unifr.ch/global/documents/285534
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