Copy number variants (CNVs) interfere with human accelerated regions (HARs) in neurodevelopmental disorders: a large-scale cohort study

Abstract

ABSTRACT Neurodevelopmental disorders (NDDs) represent a heterogeneous group of conditions affecting the central nervous system, the etiology of which involves a wide range of factors, including genetic contributors. A proportion of this genetic component is mediated by copy number variations (CNVs) - deletions and duplications of genomic segments that are associated with a broad spectrum of neurodevelopmental and neuropsychiatric phenotypes. In recent years, there has also been growing interest in studying Human Accelerated Regions (HARs) in relation to these disorders. HARs are highly conserved genomic elements across mammals that have accumulated human-specific sequence changes. These regions are thought to contribute both to the evolution of higher cognitive functions in humans and, paradoxically, to an increased susceptibility to NDDs. Thus, both HARs and CNVs are expected to play key roles in the genetic architecture and pathogenesis of NDDs. However, despite active research on HARs and CNVs separately, integrative studies examining copy-number–driven disruptions specifically within HARs in patients with neurodevelopmental disorders have been extremely limited. This is the first study to assess the contribution of CNVs affecting HARs in 821 children with NDDs. Our bioinformatic evaluation of CNV profiles in this clinical cohort demonstrated that HARs are indeed susceptible to structural alterations in the form of deletions and duplications, supporting the notion that CNVs have shaped the evolution of these regions. Our findings further indicate that HARs, overall, are less frequently affected by duplications compared to other genomic regions. 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 ). These same genes exhibit a high haploinsufficiency index (HI = 3) according to ClinGen, highlighting their dosage sensitivity. Analysis of the most frequently affected HARs confirmed that their associated genes are significantly enriched for core NDD phenotypes. The absence of a direct correlation with genomic instability suggests that HARs represent functionally vulnerable elements and that compensatory mechanisms may restrict the accumulation of additional structural damage in these regions. Taken together, 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 of HAR-associated disruptions in neurodevelopmental disorders. We anticipate that future research will further elucidate the complex regulatory processes within the genome and help identify specific HAR regions that may be informative for diagnostic purposes and the development of targeted therapeutic approaches.