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

Neurodevelopmental disorders (NDDs) represent a group of heterogeneous conditions, the etiology of which involves a variety of genetic factors. Human accelerated regions (HARs) are highly conserved genomic elements across mammalian genomes that have accumulated human-specific sequence changes. There is a growing interest in studying HARs in relation to NDDs.

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 involvement of HARs affected by copy number variants (CNVs) in NDDs among 821 children. We demonstrate that HARs are susceptible to deletions in contrast to duplications.

We identified three recurrent HAR loci that may play a role in neurodevelopmental impairment: HAR_Merge50-02689 (20.58%, EDA), HAR_Merge50-01379 (13.64%, ERBB4) and HAR_Merge50-01486 (8.04%, intergenic region near CYYR1 and ADAMTS1). Additionally, HARs affected by CNVs in our cohort are largely located in genomic regions that rarely occur in population databases, show notable frequency deviations compared to other clinical datasets, and are associated with genes carrying pathogenic or likely pathogenic variants (e.g., HARs associated with RBFOX1, DOC2B, ZMYND11, AFF2, OPHN1), suggesting the involvement in NDD pathogenesis. Our study sheds light on the possible functional significance of HARs in the evolution and functioning of the human central nervous system, providing new opportunities for understanding their potential contribution to the pathogenesis of NDDs.

One may assume future research to highlight the complex regulatory processes within the genome associated with HARs, which might be used for molecular diagnosis and the development of therapeutic interventions. This work was supported by the MSHE RF (the Federal Scientific and Technical Programme for Genetic Technologies Development for 2019–2030, Agreement № 075-15-2025-474). Pankratova contributed equally to this work.

Federal State Budgetary Scientific Institution «Russian Mental Health Research Centre», Moscow, Russia, 115522 Maria E. Chaika Veltischev Research and Clinical Institute for Pediatrics and Pediatric Surgery of the Pirogov Russian National Research Medical University of the Russian Ministry of Health, Moscow, Russia, 117513 Maria E. Iourov The authors declare no conflict of interest.

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