Copy number variants (CNV) interfere with human Accelerated Regions (HARs) to cause neurodevelopmental disorders: a large-scale cohort study

Neurodevelopmental disorders (NDDs) represent a group of heterogeneous conditions, the etiology of which involves genetic contributors. HARs are highly conserved genomic elements across mammals that have accumulated human-specific sequence changes. There is a growing interest in studying Human Accelerated Regions (HARs) in relation to these disorders. These regions are thought to contribute both to the evolution of higher cognitive functions in humans and to an increased susceptibility to NDDs. This is the first study to assess the contribution of HARs affected by CNVs in 821 children with NDDs. We demonstrate that HARs are susceptible to structural variations (deletions and duplications). We identified three recurrent HAR loci most strongly associated with neurodevelopmental impairment: HAR_Merge50-02702, HAR_Merge50-02080, and HAR_Merge50-02689. Additionally, we found that HARs disrupted by CNVs form coordinated functional clusters corresponding to genomic regions that harbor extremely rare or entirely absent CNVs in the general population (e.g., HARs associated with RBFOX1, DOC2B, ZMYND11, AFF2, OPHN1 ). Our study reinforces the importance of HARs in the evolution and functioning of the human central nervous system and provides new evidence supporting the functional relevance to neurodevelopmental disorders. We anticipate that future research will elucidate the complex regulatory processes within the genome and will identify specific HARs that may be used for diagnostic purposes and developing therapeutic interventions.