De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides–Baraitser syndrome

Abstract

Purpose

Nontruncating variants in SMARCA2, encoding a catalytic subunit of SWI/SNF chromatin remodeling complex, cause Nicolaides–Baraitser syndrome (NCBRS), a condition with intellectual disability and multiple congenital anomalies. Other disorders due to SMARCA2 are unknown.

Methods

By next-generation sequencing, we identified candidate variants in SMARCA2 in 20 individuals from 18 families with a syndromic neurodevelopmental disorder not consistent with NCBRS. To stratify variant interpretation, we functionally analyzed SMARCA2 variants in yeasts and performed transcriptomic and genome methylation analyses on blood leukocytes.

Results

Of 20 individuals, 14 showed a recognizable phenotype with recurrent features including epicanthal folds, blepharophimosis, and downturned nasal tip along with variable degree of intellectual disability (or blepharophimosis intellectual disability syndrome [BIS]). In contrast to most NCBRS variants, all SMARCA2 variants associated with BIS are localized outside the helicase domains. Yeast phenotype assays differentiated NCBRS from non-NCBRS SMARCA2 variants. Transcriptomic and DNA methylation signatures differentiated NCBRS from BIS and those with nonspecific phenotype. In the remaining six individuals with nonspecific dysmorphic features, clinical and molecular data did not permit variant reclassification.

Conclusion

We identified a novel recognizable syndrome named BIS associated with clustered de novo SMARCA2 variants outside the helicase domains, phenotypically and molecularly distinct from NCBRS.

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Fig. 1: Facial appearance of individuals carrying SMARCA2 variants.
Fig. 2: Schematic representation of SMARCA2 protein and localization of variants associated with Nicolaides–Baraitser syndrome (NCBRS), blepharophimosis intellectual disability syndrome (BIS), and the nonspecific phenotypes.
Fig. 3: Phenotypic effects of SMARCA2 (Snf2) variants in S. cerevisiae.
Fig. 4: Transcriptomic and methylation analyses in individuals harboring SMARCA2 variants.

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Acknowledgements

We thank parents of our patients and particularly Anna Caccavo and Charlotte Bull. We thank the Centre de Calcul de l’Université de Bourgogne (CCUB, https://haydn2005.u-bourgogne.fr/dsi-ccub/) for technical support and management of information technology platform. This work was supported by Telethon Foundation, Telethon Undiagnosed Diseases Program (TUDP, GSP15001), FEDER, and the Czech Ministry of Health (17-29423A and 00064203 to MH and MH). This work was in part generated within the European Reference Network ITHACA. C.S. is supported by French Medical Foundation (FRM), S.E.K. by French Medical Foundation and French National Research Agency (ANR-10-LABX-49-01 GRAL), J.G. by Finovi and French National Research Agency (ANR-18-CE18-007), and C.D. by Wellcome Trust (209568/Z/17/Z). Patients identified through the Deciphering Developmental Disorders (DDD) Study are reported. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between Wellcome Trust and Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). Views expressed in this publication are those of the author(s) and not necessarily of Wellcome Trust or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12 granted by the Republic of Ireland REC). Part of the data presented here was provided through access to data and findings generated by the 100,000 Genomes Project, funded by National Institute for Health Research (NIHR) and NHS England (full acknowledgement on https://www.genomicsengland.co.uk/about-gecip/publications/).

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Correspondence to Jérôme Govin PhD or Antonio Vitobello PhD or Nicola Brunetti-Pierri MD.

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Cappuccio, G., Sayou, C., Tanno, P.L. et al. De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides–Baraitser syndrome. Genet Med (2020). https://doi.org/10.1038/s41436-020-0898-y

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Keywords

  • SMARCA2
  • Nicolaides–Baraitser syndrome
  • BIS
  • intellectual disability
  • neurodevelopmental disorder