A new international study led by researchers at The Ottawa Hospital and Seattle Children’s Hospital has identified a novel neurodevelopmental disorder caused by mutations in the SMARCA1 gene. The findings, published in Nature Communications, offer new insights into how the brain develops and how changes in chromatin remodeling genes can lead to conditions such as autism and other intellectual disabilities.
SMARCA1 makes a protein that helps control which genes are turned on or off by organizing the DNA around genes (known as chromatin remodeling). This delicate process is crucial for brain development and for helping cells decide what type they will become. Even a small change in the SMARCA1 gene can disrupt the incorporation of the protein into the NURF complex (a protein group that rearranges chromatin structure) and its function in regulating gene expression during brain development, leading to long-lasting effects on brain growth and cognitive function.
The team of researchers from 56 institutions across 14 countries were able to identify 25 unique variants of the mutated gene in 35 affected individuals worldwide, with many having developmental delays, speech regression, macrocephaly (enlarged head size) and autism spectrum characteristics. Then, using mouse models, the team was able to examine how different types of mutations affect brain development, either by removing SMARCA1 entirely or partially. Mice with no SMARCA1 protein developed normally, but mice with a broken version of the protein had larger brains, just like some of the children. The study also found that producing a faulty version of the protein can be more disruptive than losing it entirely.
“On average, it takes ten years for an individual with a rare neurodevelopmental disorder to get a diagnosis,” says co-lead Dr. David Picketts, Deputy Scientific Director and Senior Scientist at the Ottawa Hospital Research Institute and Professor at the University of Ottawa. “Now that the gene is identified and is being studied, there’s new hope for earlier diagnosis and for the development of novel therapies.”
Dr. Ghayda Mirzaa, co-lead of the study, agrees: “This study shows that genetic variants of the SMARCA1 gene are associated with a broad spectrum of features that vary from person to person,” says Dr. Mirzaa, Associate Professor of Pediatrics and Medical Genetics at Seattle Children’s Hospital. “Delineation of this and many other neurodevelopmental disorders would not be possible without access to comprehensive genetic testing. Our hope from this work is that it will facilitate an earlier and more precise diagnosis for future families”
Authors: Ghayda M. Mirzaa, Keqin Yan, Raissa Relator, Mathieu Levesque, Pranisha Jayasinghe, Sara Timpano, Binnaz Yalcin, Stephan Collins, Alban Ziegler, Emily Pao, Nora Oyama, Elise Brischoux-Boucher, Juliette Piard, Kristin G. Monaghan, Maria. J. Guillen Sacoto, William B. Dobyns, Kristen L. Park, Daniel Martin Fernández-Mayoralas, Alberto Fernández-Jaén, Parul Jayakar, María Palomares-Bralo, Fernando Santos-Simarro, Alfredo Brusco, Vincenzo Antona, Elisa Giorgio, Malin Kvarnung, Bertrand Isidor, Solène Conrad, Benjamin Cogné, Wallid Deb, Kyra E. Stuurman, Katalin Šterbová, Noor Smal, Sarah Weckhuysen, Renske Oegema, A. Micheil Innes, Daniel. C. Koboldt, Tawfeg Ben-Omran, Rebecca C. Yeh, Michael C. Kruer, Somayeh Bakhtiari, Antigone Papavasiliou, Sébastien Moutton, Sophie Nambot, Sirisak Chanprasert, Sarah A. Paolucci, Kait Miller, Barbara Burton, Katherine Kim, Emily O’Heir, Zandre Bruwer, Kirsten. A. Donald, Tjitske Kleefstra, Amy Goldstein, Brad Angle, Kelly Bontempo, Peter Miny, Pascal Joset, Florence Demurger, Emma Hobson, Lewis Pang, Lori Carpenter, Dong Li, Dominique Bonneau, Bekim Sadikovic & David J. Picketts
Cores: Animal Behaviour (BEH); Cell Biology and Image Acquisition (CBIA); Genomic Editing and Molecular Biology Facility (GEM); Human Pluripotent StemCell Facility (HPSCF); StemCore
Funding: Canadian Institutes of Health Research, Qatar National Research Fund, National Human Genome Research Institute, National Institutes of Mental Health (National Human Genome Research Institute; National Institute of Mental Health), Simons Foundation Autism Research Initiative (SFARI), Stanley Center for Psychiatric Research at the Broad Institute, Research Foundation – Flanders, Queen Elisabeth Medical Foundation, Italian Ministry for Education, University and Research, NextGenerationEU (NGEU), Care4Rare Canada Consortium
L’Hôpital d’Ottawa est un centre universitaire de pointe dans le domaine de la recherche et de la santé et un hôpital d’enseignement fièrement affilié à l’Université d’Ottawa et soutenu par la Fondation de l’Hôpital d’Ottawa.
