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

Gerarda Cappuccio (1) , Camille Sayou (2) , Pauline Le Tanno , Emilie Tisserant (3) , Ange-Line Bruel (3) , Sara El Kennani , Joaquim Sá , Karen Low , Cristina Dias , Marketa Havlovicova , Miroslava Hančárová (4) , Evan Eichler (5) , Françoise Devillard (6) , Sébastien Moutton , Julien Van-Gils (7) , Christèle Dubourg (8) , Sylvie Odent (8) , Bénédicte Gérard (9) , Amélie Piton (9) , Toshiyuki Yamamoto , Nobuhiko Okamoto , Helen Firth , Kay Metcalfe , Anna Moh , Kimberly Chapman , Erfan Aref-Eshghi (10) , Jennifer Kerkhof (10) , Annalaura Torella , Vincenzo Nigro , Laurence Perrin , Juliette C Piard (11) , Gwenaël Le Guyader , Thibaud Jouan (12, 3) , Christel Thauvin-Robinet (13, 3) , Yannis Duffourd (3) , Jaya George-Abraham , Catherine Buchanan , Denise Williams , Usha Kini , Kate Wilson , Sérgio Sousa , Raoul C M Hennekam (14) , Bekim Sadikovic (10) , Julien Thevenon (15) , Jérôme Govin (2) , Antonio Vitobello (12, 3) , Nicola Brunetti-Pierri (1)

1 University of Naples Federico II = Università degli studi di Napoli Federico II
2 IAB - Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble)
3 LNC - Lipides - Nutrition - Cancer [Dijon - U1231]
4 University Hospital Motol [Prague]
5 University of Washington [Seattle]
6 CHU - Centre Hospitalier Universitaire [Grenoble]
7 UB - Université de Bordeaux
8 IGDR - Institut de Génétique et Développement de Rennes
9 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
10 LHSC - London Health Sciences Center
11 UFC - Université de Franche-Comté
12 Equipe GAD (LNC - U1231)
13 CHU Dijon - Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand
14 AMC - Academic Medical Center - Academisch Medisch Centrum [Amsterdam]
15 Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon)

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.

Keywords: BIS; Nicolaides–Baraitser syndrome; SMARCA2; intellectual disability; neurodevelopmental disorder

Domains: Life Sciences [q-bio]

Gerarda Cappuccio, Camille Sayou, Pauline Le Tanno, Emilie Tisserant, Ange-Line Bruel, 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. Genetics in Medicine, 2020, 22 (11), pp.1838-1850. ⟨10.1038/s41436-020-0898-y⟩. ⟨hal-02928068⟩