Haploinsufficiency, de novo and biallelic missense variants in CSMD2 are associated with neurodevelopmental disorders
Year: 2026
Type: preprint
Study design: Observational Study
Abstract: ABSTRACT CUB and Sushi domains-containing CSMD proteins are involved in neuron development. Variants in the CSMD1-3 paralogs were GWAS-associated with cognition, attention-deficit hyperactivity disorder (ADHD), schizophrenia and brain structure, suggesting that these genes could be linked to neurodevelopmental disorders (NDD). Indeed, rare biallelic variants in all three CSMD paralogs were recently associated with epilepsy, while rare biallelic variants in CSMD1 were also linked with intellectual disability and cortical malformations. We identified nine individuals from eight families carrying CSMD2 biallelic missense variants in developmental delay/intellectual disability cohorts. Affected individuals presented with autism spectrum disorder (ASD), ADHD and brain anomalies. Consistent with gnomAD metrics that suggest CSMD2 haploinsufficiency, we also report two families segregating monoallelic CSMD2 frameshift variants, which complement a described de novo truncation variant in an ASD proband. We concomitantly report two phenotypically overlapping individuals with de novo CSMD2 missense variants and compare them to twelve de novo CSMD2 cases identified in published trio analyses. UK Biobank analyses showed nominally significant enrichment of ADHD, ASD and neuroticism in volunteers carrying at least one rare CSMD2 variant. In silico modelling and immunofluorescence assays showed that mutated residues in affected individuals with biallelic and de novo missense variants are clustering in two regions and that the encoded proteins showed impaired membrane localization and an increased cytoplasmic aggregation. Zebrafish crispant larvae for the orthologous csmd2 presented with microcephaly, smaller cerebellum, and reduced Purkinje cell size. Larvae also displayed decreased swimming velocity, diminished connectivity between the optic tecta, and abnormal peripheral neuronal branching. We demonstrate that rare, likely pathogenic variants in CSMD2 are associated with both autosomal recessive and dominant forms of NDD further substantiating the functional significance of CSMD paralogs in neurogenesis/synapse formation.
Source: medRxiv
Authors: Clara Pailler-Pradeau, Marianne Victoria Lemée, Caterina Cevallos, Francesca Mattioli, Jacqueline Chrast, Sissy Bassani, Hossein Darvish, Ginevra Zanni, Giovanna Stefania Colafati, Lorena Travaglini, Francesco Nicita, Shivarajan M. Amudhavalli, Caitlin Lawson, Joseph G. Gleeson, Isabella Stuewe, Liana Friedman, Maha S. Zaki, Lauren Bell, Elise Boucher Brischoux, Paul Kuentz, Nico Fuhrmann, Victoria Lampkemeyer, Christian Netzer, Thomas Smol, Catherine Vincent-Delorme, Zafar Iqbal, Mathias Toft, Tarab Zehra, Sidra Kaleem Jafri, Ambrin Fatima, Mukhtar Ullah, Zainab Akhtar, Tayyaba Shan, Sabika Firasat, Saghar Ghasemi Firouzabadi, Abbas Tafakhori, Sarina Sharbatkhori, Faezeh Jamali, Maximilian Balbach, Friedhelm Hildebrandt, Emily O’Heir, Lynn Pais, Alba Sanchis-Juan, Michael E. Talkowski, Quinten Waisfisz, Lotte Kleinendorst, Giovanna Ambrosini, Trisha Kuchta, Zoltan Kutalik, Nicolas Guex, Stylianos E. Antonarakis, Muhammad Ansar, Christelle Golzio, Alexandre Reymond
Institutions: University of Lausanne, Centre National de la Recherche Scientifique, Inserm, Institut de génétique et de biologie moléculaire et cellulaire, Université de Strasbourg, SIB Swiss Institute of Bioinformatics, Bambino Gesù Children's Hospital, Children's Mercy Hospital, University of California San Diego, Rady Children's Institute for Genomic Medicine, National Research Centre, Peoria campus of the University of Illinois System, Centre Hospitalier Universitaire de Besançon, Université Marie et Louis Pasteur, University of Cologne, Université de Lille, Centre Hospitalier Universitaire de Lille, Maladies RAres du DEveloppement embryonnaire et du MEtabolisme, Oslo University Hospital, University of Oslo, Aga Khan University, Fondation Asile des Aveugles, Quaid-i-Azam University, Tehran University of Medical Sciences, North Khorasan University of Medical Sciences, Boston Children's Hospital, Harvard University, Broad Institute, Massachusetts General Hospital, Amsterdam UMC Location University of Amsterdam, Amsterdam University Medical Centers, École Polytechnique Fédérale de Lausanne, Indiana University Health, University of Geneva, Dow University of Health Sciences
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Funders: Broad Institute, Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Université de Strasbourg, Fondation de France, Centre National de la Recherche Scientifique, Université de Lausanne, National Institutes of Health, National Human Genome Research Institute, University of Colorado School of Medicine, Anschutz Medical Campus
Awards: G1109023570, G1414796561, G164444715, G1800105685, G1923432458, Par-delà les frontières, l'Université de Strasbourg, G2255650664, G2449524460, G2694206344, Façonner les talents en formation et en recherche à l'Université de Strasbourg, G2980570810, G3310169441, G3357951378, G3730343, G399734812, G4302627264, G4381811279, Integrative Molecular and Cellular Biology, G4779185514, G4798114250, G4899307531, G5296751580, Joint Center for Mendelian Genomics, Integrative Biology : Nuclear dynamics- Regenerative medicine - Translational medicine, G6136357505, G6276897512, G6389594462, G6834175958, Chromatin remodeler CHD1L in neurogenesis and in 1q21.1 Copy Number Variant-associated neurodevelopmental phenotypes, G7804020939, G7886130148, Advancing rare disease discovery through technological and methodological approaches using an intuitive platform, seqr
OpenAlex ID: W7214904333