Identification of novel driver risk genes in CNV loci associated with neurodevelopmental disorders

• Published in: HGG advances 2024-07, Vol.5 (3), p.100316, Article 100316
• Main Authors: Azidane, Sara, Gallego, Xavier, Durham, Lynn, Cáceres, Mario, Guney, Emre, Pérez-Cano, Laura
• Format: Article
• Language: English
• Subjects: autism spectrum disorder; Autism Spectrum Disorder - genetics; burden testing; Copy number variants; Decipher database; DNA Copy Number Variations - genetics; dosage-sensitive genes; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; iHART cohort; neurodevelopmental disorders; Neurodevelopmental Disorders - genetics; Protein Interaction Maps - genetics; risk genes and pathways; SFARI database; structural variants
• ISSN: 2666-2477; 2666-2477
• DOI: 10.1016/j.xhgg.2024.100316

Copy-number variants (CNVs) are genome-wide structural variations involving the duplication or deletion of large nucleotide sequences. While these types of variations can be commonly found in humans, large and rare CNVs are known to contribute to the development of various neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD). Nevertheless, given that these NDD-risk CNVs cover broad regions of the genome, it is particularly challenging to pinpoint the critical gene(s) responsible for the manifestation of the phenotype. In this study, we performed a meta-analysis of CNV data from 11,614 affected individuals with NDDs and 4,031 control individuals from SFARI database to identify 41 NDD-risk CNV loci, including 24 novel regions. We also found evidence for dosage-sensitive genes within these regions being significantly enriched for known NDD-risk genes and pathways. In addition, a significant proportion of these genes was found to (1) converge in protein-protein interaction networks, (2) be among most expressed genes in the brain across all developmental stages, and (3) be hit by deletions that are significantly over-transmitted to individuals with ASD within multiplex ASD families from the iHART cohort. Finally, we conducted a burden analysis using 4,281 NDD cases from Decipher and iHART cohorts, and 2,504 neurotypical control individuals from 1000 Genomes and iHART, which resulted in the validation of the association of 162 dosage-sensitive genes driving risk for NDDs, including 22 novel NDD-risk genes. Importantly, most NDD-risk CNV loci entail multiple NDD-risk genes in agreement with a polygenic model associated with the majority of NDD cases. [Display omitted] We conducted a meta-analysis of CNV data, unveiling 24 new CNV loci associated with risk for neurodevelopmental disorders (NDDs). We provide evidence for the contribution of dosage-sensitive genes within these loci, including the validation of 22 novel risk genes and new gene-phenotype associations, advancing molecular characterization and NDD genetic diagnoses.