Haploinsufficiency, de novo and biallelic missense variants in CSMD2 are associated with neurodevelopmental disorders
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.
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BibTeX
@misc{paillerpradeau2026haploinsufficiency,
title = {{Haploinsufficiency, de novo and biallelic missense variants in CSMD2 are associated with neurodevelopmental disorders}},
author = {C. Pailler-Pradeau and M. V. Lemee and C. Cevallos and F. Mattioli and J. Chrast and S. Bassani and H. Darvish and G. Zanni and G. S. Colafati and L. Travaglini and F. Nicita and S. M. Amudhavalli and C. Lawson and J. G. Gleeson and I. Stuewe and L. Friedman and M. S. Zaki and L. Bell and E. Boucher Brischoux and P. Kuentz and N. Fuhrmann and V. Lampkemeyer and C. Netzer and T. Smol and C. Vincent-Delorme and Z. Iqbal and M. Toft and T. Zehra and S. K. Jafri and A. Fatima and M. Ullah and Z. Akhtar and T. Shan and S. Firasat and S. G. Firouzabadi and A. Tafakhori and S. Sharbatkhori and F. Jamali and M. Balbach and F. Hildebrandt and E. O'Heir and L. Pais and A. Sanchis-Juan},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.24.26361611},
url = {https://www.medrxiv.org/content/10.64898/2026.09.24.26361611v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Haploinsufficiency, de novo and biallelic missense variants in CSMD2 are associated with neurodevelopmental disorders
AU - C. Pailler-Pradeau
AU - M. V. Lemee
AU - C. Cevallos
AU - F. Mattioli
AU - J. Chrast
AU - S. Bassani
AU - H. Darvish
AU - G. Zanni
AU - G. S. Colafati
AU - L. Travaglini
AU - F. Nicita
AU - S. M. Amudhavalli
AU - C. Lawson
AU - J. G. Gleeson
AU - I. Stuewe
AU - L. Friedman
AU - M. S. Zaki
AU - L. Bell
AU - E. Boucher Brischoux
AU - P. Kuentz
AU - N. Fuhrmann
AU - V. Lampkemeyer
AU - C. Netzer
AU - T. Smol
AU - C. Vincent-Delorme
AU - Z. Iqbal
AU - M. Toft
AU - T. Zehra
AU - S. K. Jafri
AU - A. Fatima
AU - M. Ullah
AU - Z. Akhtar
AU - T. Shan
AU - S. Firasat
AU - S. G. Firouzabadi
AU - A. Tafakhori
AU - S. Sharbatkhori
AU - F. Jamali
AU - M. Balbach
AU - F. Hildebrandt
AU - E. O'Heir
AU - L. Pais
AU - A. Sanchis-Juan
PY - 2026
DA - 2026/09/24
PB - medRxiv
DO - 10.64898/2026.09.24.26361611
UR - https://www.medrxiv.org/content/10.64898/2026.09.24.26361611v1
AB - 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.
ER -