DOI: 10.18413/2658-6533-2025-11-4-0-1

Common CNVs modulate phenotypes in neurodevelopmental disorders (autism and intellectual disability): focus on SHANK3 and CHAMP1

Ivan Y. Iourov
Oksana S. Kurinnaia
Maria M. Iuditskaia
Efim S. Karpachev
Kirill S. Vasin
Victoria Y. Voinova
Ekaterina V. Semina
Yuri B. Yurov
Yulia A. Chaika
Svetlana G. Vorsanova

Background: Common copy number variations (CNVs) are rarely considered as causative in genomic research dedicated to uncovering mechanisms of neurodevelopmental diseases. However, analyzing complex systems of interactions between individual genomic variations indicates that at least minimal phenotypic effects of common CNVs should exist. Here, we have tested this idea focusing on CNVs affecting SHANK3 and CHAMP1 genes. The aim of the study:The analysis of common CNVs affecting SHANK3 and CHAMP1 genes in a neurodevelopmental cohort (intellectual disability, autism, epilepsy) to uncover possible effects on the phenotypic outcome. Materials and methods: CNVswere evaluated in aneurodevelopmental cohort of 780 children with intellectual disability, autism, epilepsy and congenital anomalies by molecular karyotyping using a high-resolution SNP array technique. Original bioinformatic methods were used to address the effect of CNVs affecting SHANK3 and CHAMP1. Results: CNVs involving SHANK3 and CHAMP1 were observed in 44 (5.6%) and 6 (0.8%) individuals, respectively. SHANK3 CNVs have been associated with specific language problems in 36 (82%) out of 44 individuals. CHAMP1 CNVs were all associated with chromosomal instability, which had been proposed as a cause of more severe clinical manifestations. Bioinformatic analysis has confirmed these modulating effects of common CNVs on phenotypes in neurodevelopmental diseases. Conclusion: Our data allowed to propose a pathogenetic model for brain disfunction in ID and ASD, which is based on an idea that common CNVs add/exacerbate phenotypic traits produced by the main genetic defect (chromosomal aberration or gene mutation). Thus, it appears that mechanisms of neurodevelopmental diseases are more complex than previously recognized even in cases associated with a well-described genomic pathology

Keywords: copy number variations, autism, intellectual disability, neurodevelopmental disorders, phenotype, SHANK3, CHAMP1.

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Iourov IY, Kurinnaia OS, Iuditskaia ME, et al. Common CNVs modulate phenotypes in neurodevelopmental disorders (autism and intellectual disability): focus on SHANK3 and CHAMP1. Research Results in Biomedicine. 2025;11(4):596-606. DOI: 10.18413/2658-6533-2025-11-4-0-1

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