2. Academic Validation
  3. BICRA, a SWI/SNF Complex Member, Is Associated with BAF-Disorder Related Phenotypes in Humans and Model Organisms

BICRA, a SWI/SNF Complex Member, Is Associated with BAF-Disorder Related Phenotypes in Humans and Model Organisms

  • Am J Hum Genet. 2020 Dec 3;107(6):1096-1112. doi: 10.1016/j.ajhg.2020.11.003.
Scott Barish 1,  Tahsin Stefan Barakat 2,  Brittany C Michel 3,  Nazar Mashtalir 3,  Jennifer B Phillips 4,  Alfredo M Valencia 5,  Berrak Ugur 6,  Jeremy Wegner 4,  Tiana M Scott 7,  Brett Bostwick 8,  Undiagnosed Diseases Network,  David R Murdock 8,  Hongzheng Dai 9,  Elena Perenthaler 2,  Anita Nikoncuk 2,  Marjon van Slegtenhorst 2,  Alice S Brooks 2,  Boris Keren 10,  Caroline Nava 10,  Cyril Mignot 10,  Jessica Douglas 11,  Lance Rodan 11,  Catherine Nowak 11,  Sian Ellard 12,  Karen Stals 13,  Sally Ann Lynch 14,  Marie Faoucher 15,  Gaetan Lesca 15,  Patrick Edery 15,  Kendra L Engleman 16,  Dihong Zhou 16,  Isabelle Thiffault 16,  John Herriges 16,  Jennifer Gass 17,  Raymond J Louie 17,  Elliot Stolerman 17,  Camerun Washington 17,  Francesco Vetrini 18,  Aiko Otsubo 18,  Victoria M Pratt 18,  Erin Conboy 18,  Kayla Treat 18,  Nora Shannon 19,  Jose Camacho 20,  Emma Wakeling 21,  Bo Yuan 9,  Chun-An Chen 8,  Jill A Rosenfeld 9,  Monte Westerfield 22,  Michael Wangler 6,  Shinya Yamamoto 23,  Cigall Kadoch 24,  Daryl A Scott 25,  Hugo J Bellen 26
Affiliations

Affiliations

  • 1 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.
  • 2 Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
  • 3 Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • 4 Department of Biology, University of Oregon, Eugene, OR 97403, USA.
  • 5 Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Chemical Biology Program, Harvard University, Cambridge, MA 02138, USA.
  • 6 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA.
  • 7 Department of Microbiology and Molecular Biology, College of Life Science, Brigham Young University, Provo, UT 84602, USA.
  • 8 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • 9 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics Laboratory, Houston, TX 77030, USA.
  • 10 APHP Sorbonne Université, Département de Génétique and Centre de Référence Déficiences Intellectuelles de Causes Rares, Groupe Hospitalier Pitié-Salpêtrière, 75006 Paris, France.
  • 11 Department of Pediatrics, Boston Children's at Waltham, Waltham, MA 02453, USA.
  • 12 Exeter Genomics Laboratory, Royal Devon and Exeter NHS Foundation Trust, Exeter EX2 5DW, UK.
  • 13 Exeter Genomics Laboratory, Royal Devon and Exeter NHS Foundation Trust, Exeter EX2 5DW, UK; Institute of Biomedical and Clinical Science, College of Medicine and Health, University of Exeter, Exeter EX4 4PY, UK.
  • 14 National Centre for Medical Genetics, Our Lady's Children's Hospital, Crumlin, Dublin D12 N512, Ireland.
  • 15 Department of Medical Genetics, Lyon University Hospital, Université Claude bernard Lyon 1, Lyon 69100, France.
  • 16 Division of Clinical Genetics, Children's Mercy Hospital, University of Missouri-Kansas City School of Medicine, Kansas City, MO 64108, USA.
  • 17 Greenwood Genetic Center, 106 Gregor Mendel Cir, Greenwood, SC 29646, USA.
  • 18 Department of Clinical Medical and Molecular Genetics, Indiana University, Indianapolis, IN 46202, USA.
  • 19 Regional Genetics Service, Nottingham University Hospitals NHS Trust, Nottingham NG5 1PB, UK.
  • 20 Pediatric Genetics and Metabolism, Loma Linda University Children's Hospital, Loma Linda, CA 92354, USA.
  • 21 Clinical Genetics, Great Ormond Street Hospital, London WC1N 3JH, UK.
  • 22 Department of Biology, University of Oregon, Eugene, OR 97403, USA; Institute of Neuroscience, University of Oregon, Eugene, OR 97403, USA.
  • 23 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
  • 24 Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: [email protected].
  • 25 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: [email protected].
  • 26 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Institute of Neuroscience, University of Oregon, Eugene, OR 97403, USA; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: [email protected].
PMID: 33232675 DOI: 10.1016/j.ajhg.2020.11.003
Abstract

SWI/SNF-related intellectual disability disorders (SSRIDDs) are rare neurodevelopmental disorders characterized by developmental disability, coarse facial features, and fifth digit/nail hypoplasia that are caused by pathogenic variants in genes that encode for members of the SWI/SNF (or BAF) family of chromatin remodeling complexes. We have identified 12 individuals with rare variants (10 loss-of-function, 2 missense) in the BICRA (BRD4 interacting chromatin remodeling complex-associated protein) gene, also known as GLTSCR1, which encodes a subunit of the non-canonical BAF (ncBAF) complex. These individuals exhibited neurodevelopmental phenotypes that include developmental delay, intellectual disability, autism spectrum disorder, and behavioral abnormalities as well as dysmorphic features. Notably, the majority of individuals lack the fifth digit/nail hypoplasia phenotype, a hallmark of most SSRIDDs. To confirm the role of BICRA in the development of these phenotypes, we performed functional characterization of the zebrafish and Drosophila orthologs of BICRA. In zebrafish, a mutation of bicra that mimics one of the loss-of-function variants leads to craniofacial defects possibly akin to the dysmorphic facial features seen in individuals harboring putatively pathogenic BICRA variants. We further show that Bicra physically binds to other non-canonical ncBAF complex members, including the BRD9/7 ortholog, CG7154, and is the defining member of the ncBAF complex in flies. Like other SWI/SNF complex members, loss of Bicra function in flies acts as a dominant enhancer of position effect variegation but in a more context-specific manner. We conclude that haploinsufficiency of BICRA leads to a unique SSRIDD in humans whose phenotypes overlap with those previously reported.

Keywords

BAFopathy; CG11873; Drosophila; GLTSCR1; chromatin; developmental delay; intellectual disability; ncBAF complex; position effect variegation; zebrafish.

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