BICRA, a SWI/SNF Complex Member, Is Associated with BAF-Disorder Related Phenotypes in Humans and Model Organisms PMID: 33232675

ADC Targets in Oncology

2026-04-10

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

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].

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.