Cell Death and Disease (May 2024)
Biallelic variants in CSMD1 are implicated in a neurodevelopmental disorder with intellectual disability and variable cortical malformations
- Elizabeth A. Werren,
- Emily R. Peirent,
- Henna Jantti,
- Alba Guxholli,
- Kinshuk Raj Srivastava,
- Naama Orenstein,
- Vinodh Narayanan,
- Wojciech Wiszniewski,
- Mateusz Dawidziuk,
- Pawel Gawlinski,
- Muhammad Umair,
- Amjad Khan,
- Shahid Niaz Khan,
- David Geneviève,
- Daphné Lehalle,
- K. L. I. van Gassen,
- Jacques C. Giltay,
- Renske Oegema,
- Richard H. van Jaarsveld,
- Rafiullah Rafiullah,
- Gudrun A. Rappold,
- Rachel Rabin,
- John G. Pappas,
- Marsha M. Wheeler,
- Michael J. Bamshad,
- Yao-Chang Tsan,
- Matthew B. Johnson,
- Catherine E. Keegan,
- Anshika Srivastava,
- Stephanie L. Bielas
Affiliations
- Elizabeth A. Werren
- Department of Human Genetics, University of Michigan Medical School
- Emily R. Peirent
- Neuroscience Graduate Program, University of Michigan
- Henna Jantti
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
- Alba Guxholli
- Department of Human Genetics, University of Michigan Medical School
- Kinshuk Raj Srivastava
- Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute
- Naama Orenstein
- Schneider Children’s Medical Center of Israel
- Vinodh Narayanan
- Center for Rare Childhood Disorders, Translational Genomics Research Institute
- Wojciech Wiszniewski
- Department of Molecular and Medical Genetics, Oregon Health and Science University
- Mateusz Dawidziuk
- Department of Medical Genetics, Institute of Mother and Child
- Pawel Gawlinski
- Department of Medical Genetics, Institute of Mother and Child
- Muhammad Umair
- Medical Genomics Research Department, King Abdullah International Medical Research Center, King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs
- Amjad Khan
- Department of Molecular and Medical Genetics, Oregon Health and Science University
- Shahid Niaz Khan
- Department of Zoology, Kohat University of Science and Technology
- David Geneviève
- Montpellier University, Inserm Unit U1183, Reference Center for Rare Diseases and Developmental Anomalies, CHU
- Daphné Lehalle
- Sorbonne University, Department of Medical Genetics, Hospital Armand Trousseau
- K. L. I. van Gassen
- Department of Genetics, University Medical Centre Utrecht, Utrecht University
- Jacques C. Giltay
- Department of Genetics, University Medical Centre Utrecht, Utrecht University
- Renske Oegema
- Department of Genetics, University Medical Centre Utrecht, Utrecht University
- Richard H. van Jaarsveld
- Department of Genetics, University Medical Centre Utrecht, Utrecht University
- Rafiullah Rafiullah
- Department of Biotechnology, Faculty of Life Sciences, BUITEMS
- Gudrun A. Rappold
- Department of Human Molecular Genetics, Institute of Human Genetics, Ruprecht-Karls-University
- Rachel Rabin
- Department of Pediatrics, NYU Grossman School of Medicine
- John G. Pappas
- Department of Pediatrics, NYU Grossman School of Medicine
- Marsha M. Wheeler
- Department of Genome Sciences, University of Washington
- Michael J. Bamshad
- Department of Pediatrics, University of Washington
- Yao-Chang Tsan
- Division of Cardiovascular Medicine, University of Michigan
- Matthew B. Johnson
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
- Catherine E. Keegan
- Department of Human Genetics, University of Michigan Medical School
- Anshika Srivastava
- Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences
- Stephanie L. Bielas
- Department of Human Genetics, University of Michigan Medical School
- DOI
- https://doi.org/10.1038/s41419-024-06768-6
- Journal volume & issue
-
Vol. 15,
no. 5
pp. 1 – 15
Abstract
Abstract 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.
