Coffin–Siris Syndrome and the BAF Complex: Genotype–Phenotype Study in 63 Patients

Authors

  • Gijs W.E. Santen,

    Corresponding author
    1. Center for Human and Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands
    • Correspondence to: Gijs W.E. Santen, Albinusdreef 2, Postbus 9600, 2300 RC Leiden, The Netherlands. E-mail: santen@lumc.nl

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  • Emmelien Aten,

    1. Center for Human and Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands
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  • Anneke T. Vulto-van Silfhout,

    1. Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands
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  • Caroline Pottinger,

    1. All Wales Medical Genetics Service, Glan Clwyd Hospital, Rhyl, UK
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  • Bregje W.M. van Bon,

    1. Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands
    2. Nijmegen Center for Molecular Life Sciences, Institute for Genetic and Metabolic Disease, Radboud University Medical Centre, Nijmegen, The Netherlands
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  • Ivonne J.H.M. van Minderhout,

    1. Center for Human and Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands
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  • Ronelle Snowdowne,

    1. Center for Human and Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands
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  • Christian A.C. van der Lans,

    1. Center for Human and Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands
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  • Merel Boogaard,

    1. Center for Human and Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands
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  • Margot M.L. Linssen,

    1. Center for Human and Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands
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  • Linda Vijfhuizen,

    1. Center for Human and Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands
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  • Michiel J.R. van der Wielen,

    1. Center for Human and Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands
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  • M.J. (Ellen) Vollebregt,

    1. Center for Human and Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands
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  • the Coffin-Siris consortium,

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    • The members of the consortium are listed in an Appendix at the end of the article.

  • Martijn H. Breuning,

    1. Center for Human and Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands
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  • Marjolein Kriek,

    1. Center for Human and Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands
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  • Arie van Haeringen,

    1. Center for Human and Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands
    2. Department of Clinical Genetics, Juliana Children's Hospital–Haga Teaching Hospital, The Hague, The Netherlands
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  • Johan T. den Dunnen,

    1. Center for Human and Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands
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  • Alexander Hoischen,

    1. Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands
    2. Nijmegen Center for Molecular Life Sciences, Institute for Genetic and Metabolic Disease, Radboud University Medical Centre, Nijmegen, The Netherlands
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  • Jill Clayton-Smith,

    1. Manchester Biomedical Research Centre, MAHSC, St Mary's Hospital, Manchester, UK
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  • Bert B.A. de Vries,

    1. Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands
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  • Raoul C.M. Hennekam,

    1. Department of Pediatrics, Academic Medical Center, Amsterdam, The Netherlands
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    • These authors jointly directed this research.

  • Martine J. van Belzen,

    1. Center for Human and Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands
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    • These authors jointly directed this research.

  • Mariam Almureikhi,

  • Anwar Baban,

  • Mafalda Barbosa,

  • Tawfeg Ben-Omran,

  • Katherine Berry,

  • Stefania Bigoni,

  • Odile Boute,

  • Louise Brueton,

  • Ineke van der Burgt,

  • Natalie Canham,

  • Kate E. Chandler,

  • Krystyna Chrzanowska,

  • Amanda L. Collins,

  • Teresa de Toni,

  • John Dean,

  • Nicolette S. den Hollander,

  • Leigh Anne Flore,

  • Alan Fryer,

  • Alice Gardham,

  • John M. Graham Jr.,

  • Victoria Harrison,

  • Denise Horn,

  • Marjolijn C. Jongmans,

  • Dragana Josifova,

  • Sarina G. Kant,

  • Seema Kapoor,

  • Helen Kingston,

  • Usha Kini,

  • Tjitske Kleefstra,

  • Małgorzata Krajewska-Walasek,

  • Nancy Kramer,

  • Saskia M. Maas,

  • Patricia Maciel,

  • Grazia M.S. Mancini,

  • Isabelle Maystadt,

  • Shane McKee,

  • Jeff M. Milunsky,

  • Sheela Nampoothiri,

  • Ruth Newbury-Ecob,

  • Sarah M. Nikkel,

  • Michael J. Parker,

  • Luis A. Pérez-Jurado,

  • Stephen P. Robertson,

  • Caroline Rooryck,

  • Debbie Shears,

  • Margherita Silengo,

  • Ankur Singh,

  • Robert Smigiel,

  • Gabriela Soares,

  • Miranda Splitt,

  • Helen Stewart,

  • Elizabeth Sweeney,

  • May Tassabehji,

  • Beyhan Tuysuz,

  • Albertien M. van Eerde,

  • Catherine Vincent-Delorme,

  • Louise C. Wilson,

  • Gozde Yesil


  • Communicated by Maria Rita Passos-Bueno

ABSTRACT

De novo germline variants in several components of the SWI/SNF-like BAF complex can cause Coffin–Siris syndrome (CSS), Nicolaides–Baraitser syndrome (NCBRS), and nonsyndromic intellectual disability. We screened 63 patients with a clinical diagnosis of CSS for these genes (ARID1A, ARID1B, SMARCA2, SMARCA4, SMARCB1, and SMARCE1) and identified pathogenic variants in 45 (71%) patients. We found a high proportion of variants in ARID1B (68%). All four pathogenic variants in ARID1A appeared to be mosaic. By using all variants from the Exome Variant Server as test data, we were able to classify variants in ARID1A, ARID1B, and SMARCB1 reliably as being pathogenic or nonpathogenic. For SMARCA2, SMARCA4, and SMARCE1 several variants in the EVS remained unclassified, underlining the importance of parental testing. We have entered all variant and clinical information in LOVD-powered databases to facilitate further genotype–phenotype correlations, as these will become increasingly important because of the uptake of targeted and untargeted next generation sequencing in diagnostics. The emerging phenotype–genotype correlation is that SMARCB1 patients have the most marked physical phenotype and severe cognitive and growth delay. The variability in phenotype seems most marked in ARID1A and ARID1B patients. Distal limbs anomalies are most marked in ARID1A patients and least in SMARCB1 patients. Numbers are small however, and larger series are needed to confirm this correlation.

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