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.

Birmingham Women's NHS Foundation Trust Birmingham UK

Cambridge University Hospitals NHS Foundation Trust Cambridge Biomedical Campus Cambridge UK

Centre de génétique humaine Université de Franche Comté Besançon France

Centre de Référence Déficiences Intellectuelles de Causes Rares CHU Dijon Dijon France

Clinical Genetics Great Ormond Street Hospital for Children NHS Foundation Trust London UK

CPDPN Pôle mère enfant Maison de Santé Protestante Bordeaux Bagatelle Talence France

Dell Children's Medical Group Austin TX USA

Department of Biology and Medical Genetics Charles University Prague 2nd Faculty of Medicine and University Hospital Motol Prague Czech Republic

Department of Genetics and Metabolism Children's National Medical Center Washington DC USA

Department of Genetics and Reproduction Centre Hospitalo Universitaire Grenoble Alpes Grenoble France

Department of Genetics Robert Debré Hospital AP HP Paris France

Department of Genome Sciences University of Washington School of Medicine Seattle WA USA

Department of Medical and Molecular Genetics King's College London UK

Department of Medical Genetics Osaka Women's and Children's Hospital Osaka Japan

Department of Medical Genetics Poitiers University Hospital Poitiers France

Department of Pathology and Laboratory Medicine Western University London Canada

Department of Pediatrics and Translational Genetics Academic Medical Center University of Amsterdam Amsterdam The Netherlands

Department of Pediatrics The University of Texas at Austin Dell Medical School Austin TX USA

Department of Precision Medicine University of Campania Luigi Vanvitelli Naples Italy

Department of Translational Medicine Federico 2 University Naples Italy

Howard Hughes Medical Institute University of Washington Seattle WA USA

Inserm U1209 CNRS UMR 5309 Univ Grenoble Alpes Institute for Advanced Biosciences Grenoble France

Inserm UMR 1231 GAD Genetics of Developmental disorders Université de Bourgogne Franche Comté FHU TRANSLAD Dijon France

Institut de Génétique et de Biologie Moléculaire et Cellulaire Illkirch France

Institute of Medical Genetics Tokyo Women's Medical University Tokyo Japan

Manchester Centre for Genomic Medicine Manchester UK

Medical Genetics Unit Hospital Pediátrico Centro Hospitalar e Universitário de Coimbra Coimbra Portugal

Molecular Genetics Laboratory Victoria Hospital London Health Sciences Centre London ON Canada

Oxford Centre for Genomic Medicine Oxford University Hospitals NHS Foundation Trust Oxford UK

Reference Center for Developmental Anomalies Department of Medical Genetics Bordeaux University Hospital Bordeaux France

Service de Génétique clinique CHU de Rennes Univ Rennes Institut de Génétique et Développement de Rennes UMR 6290 Rennes France

Service de Génétique Moléculaire et Génomique BMT HC « Jean Dausset » Rennes France

Telethon Institute of Genetics and Medicine Pozzuoli Italy

The Francis Crick Institute London UK

Tokyo Women's Medical University Institute of Integrated Medical Sciences Tokyo Japan

UF Innovation en diagnostic génomique des maladies rares CHU Dijon Dijon France

University Clinic of Genetics Faculty of Medicine Universidade de Coimbra Coimbra Portugal

University Hospitals Bristol NHS Foundation Trust University of Bristol Bristol UK

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