Coffin-siris syndrome and the BAF complex: Genotype-phenotype study in 63 patients

Gijs W E Santen, Emmelien Aten, Anneke T. Vulto-van Silfhout, Caroline Pottinger, Bregje W M van Bon, Ivonne J H M van Minderhout, Ronelle Snowdowne, Christian A C van der Lans, Merel Boogaard, Margot M L Linssen, Linda Vijfhuizen, Michiel J R van der Wielen, M. J Ellen Vollebregt, Martijn H. Breuning, Marjolein Kriek, Arie van Haeringen, Johan T. den Dunnen, Alexander Hoischen, Jill Clayton-Smith, Bert B A de VriesRaoul C M Hennekam, Martine J. van Belzen, 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, Victoria Harrison, Denise Horn, Marjolijn C. Jongmans, Dragana Josifova, Sarina G. Kant, Seema Kapoor, Helen Kingston, Usha Kini, Tjitske Kleefstra, Krajewska-Walasek Malgorzata Krajewska-Walasek, Nancy Kramer, Saskia M. Maas, Patricia Maciel, M. S Mancini Grazia, 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, I. Karen Temple, Beyhan Tuysuz, Albertien M. van Eerde, Catherine Vincent-Delorme, Louise C. Wilson, Gozde Yesil

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1519-1528
Number of pages10
JournalHuman Mutation
Volume34
Issue number11
DOIs
Publication statusPublished - Nov 2013

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Keywords

  • ARID1A
  • ARID1B
  • BAF
  • Coffin-Siris
  • CSS
  • Genotype-phenotype
  • Mosaicism
  • NBS
  • Nicolaides-Baraitser
  • SMARCA2
  • SMARCA4
  • SMARCB1
  • SMARCE1
  • SWI/SNF

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Santen, G. W. E., Aten, E., Vulto-van Silfhout, A. T., Pottinger, C., van Bon, B. W. M., van Minderhout, I. J. H. M., Snowdowne, R., van der Lans, C. A. C., Boogaard, M., Linssen, M. M. L., Vijfhuizen, L., van der Wielen, M. J. R., Vollebregt, M. J. E., Breuning, M. H., Kriek, M., van Haeringen, A., den Dunnen, J. T., Hoischen, A., Clayton-Smith, J., ... Yesil, G. (2013). Coffin-siris syndrome and the BAF complex: Genotype-phenotype study in 63 patients. Human Mutation, 34(11), 1519-1528. https://doi.org/10.1002/humu.22394