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. 2013 Nov;34(11):1519-28.
doi: 10.1002/humu.22394. Epub 2013 Aug 30.

Coffin-Siris syndrome and the BAF complex: genotype-phenotype study in 63 patients

Gijs W E Santen  1 , 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; Coffin-Siris consortium; Martijn H Breuning, Marjolein Kriek, Arie van Haeringen, Johan T den Dunnen, Alexander Hoischen, Jill Clayton-Smith, Bert B A de Vries, Raoul C M Hennekam, Martine J van Belzen
Collaborators, Affiliations

Coffin-Siris syndrome and the BAF complex: genotype-phenotype study in 63 patients

Gijs W E Santen et al. Hum Mutat. 2013 Nov.

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.

Keywords: ARID1A; ARID1B; BAF; CSS; Coffin-Siris; NBS; Nicolaides-Baraitser; SMARCA2; SMARCA4; SMARCB1; SMARCE1; SWI/SNF; genotype-phenotype; mosaicism.

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