Biallelic variants in CSMD1 are implicated in a neurodevelopmental disorder with intellectual disability and variable cortical malformations

• Published in: Cell death & disease Vol. 15; no. 5; pp. 379 - 15
• Main Authors: Werren, Elizabeth A, Peirent, Emily R, Jantti, Henna, Guxholli, Alba, Srivastava, Kinshuk Raj, Orenstein, Naama, Narayanan, Vinodh, Wiszniewski, Wojciech, Dawidziuk, Mateusz, Gawlinski, Pawel, Umair, Muhammad, Khan, Amjad, Khan, Shahid Niaz, Geneviève, David, Lehalle, Daphné, van Gassen, K L I, Giltay, Jacques C, Oegema, Renske, van Jaarsveld, Richard H, Rafiullah, Rafiullah, Rappold, Gudrun A, Rabin, Rachel, Pappas, John G, Wheeler, Marsha M, Bamshad, Michael J, Tsan, Yao-Chang, Johnson, Matthew B, Keegan, Catherine E, Srivastava, Anshika, Bielas, Stephanie L
• Format: Journal Article
• Language: English
• Published: England Springer Nature B.V 30.05.2024; Nature Publishing Group
• Subjects: Alleles; Brain architecture; Brain research; Cell Differentiation - genetics; Central nervous system; Child; Child development; Child, Preschool; Complement system; Disease; Embryo cells; Female; Forebrain; Genetics; Genomics; Humans; Immune response; Innate immunity; Intellectual disabilities; Intellectual Disability - genetics; Intellectual Disability - pathology; Lectins; Life sciences; Male; Malformations of Cortical Development - genetics; Malformations of Cortical Development - pathology; Medicine; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mental disorders; Microencephaly; Nervous system; Neurodevelopmental disorders; Neurodevelopmental Disorders - genetics; Organoids; Pediatrics; Polymicrogyria; Risk factors; Stem cells; Synaptogenesis; Tumor Suppressor Proteins; Zoology
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-024-06768-6

CSMD1 (Cub and Sushi Multiple Domains 1) is a well-recognized regulator of the complement cascade, an important component of the innate immune response. CSMD1 is highly expressed in the central nervous system (CNS) where emergent functions of the complement pathway modulate neural development and synaptic activity. While a genetic risk factor for neuropsychiatric disorders, the role of CSMD1 in neurodevelopmental disorders is unclear. Through international variant sharing, we identified inherited biallelic CSMD1 variants in eight individuals from six families of diverse ancestry who present with global developmental delay, intellectual disability, microcephaly, and polymicrogyria. We modeled CSMD1 loss-of-function (LOF) pathogenesis in early-stage forebrain organoids differentiated from CSMD1 knockout human embryonic stem cells (hESCs). We show that CSMD1 is necessary for neuroepithelial cytoarchitecture and synchronous differentiation. In summary, we identified a critical role for CSMD1 in brain development and biallelic CSMD1 variants as the molecular basis of a previously undefined neurodevelopmental disorder.