The Mosaic Genome: De Novo Variations Driving Neurodevelopment in Autism Spectrum Disorder, Intellectual Disability, and Epilepsy

Authors: Sudakshina Deb

DOI: 10.18231/j.ijn.11927.1759983172

Keywords: De novo mutations, neurodevelopmental disorders, autism spectrum disorder, intellectual disability, epilepsy, whole exome sequencing, whole genome sequencing, mosaicism, DNA methylation, environmental mutagens, chromatin remodeling, gene ontology, synaptic plasticity, paternal age effect, missense mutations, CpG transitions, ion channel genes, shared genetic architecture, genetic overlap.

Abstract: Neurodevelopmental disorders (NDDs), such as Autism Spectrum Disorder (ASD), Intellectual Disability (ID), and Epilepsy (EP), are defined by cognitive, behavioral, and communication impairments caused by extensive genetic and environmental etiologies. The strongest genetic risk factors are de novo mutations (DNMs)—unplanned, non-transmitted mutations that arise during gametogenesis or during early embryonic development. With the growing application of next-generation sequencing, that is, whole genome sequencing (WGS) and whole exome sequencing (WES), DNMs have emerged as prime actors in NDD etiology. This review covers the etiology, causes, and implications of de novo mutations (DNMs) with respect to their location within coding and non-coding regulatory parts of the genome. Methylation-catalyzed transitions of CpG, paternal age, oxidative stress, and exposure to environmental mutagens are processes that are involved in the frequency of DNMs. Notably, DNMs are primarily missense mutations with a higher frequency of transitions, particularly C>T and G>A, but not transversions. By employing extensive genomic databases, the study identifies DNM hotspots in chromosomes and their correlation with genes such as CHD8, SYNGAP1, SCN2A, ARID1B, and GRIN2B, which are involved in ASD, ID, and EP. Gene ontology analysis identifies that DNMs inhibit important neurodevelopmental functions such as chromatin remodeling, synaptic signaling, and ion channel regulation. Additionally, this study identifies a strong genetic overlap across ASD, ID, and EP, and 123 genes are identified to be shared in being affected by DNMs, which create robust protein interaction networks. These results confirm the hypothesis that DNMs not only individually contribute uniquely to each condition but are also responsible for their common pathophysiology. In summary, de novo mutations are important genomic signatures in the etiology and pathogenesis of neurodevelopmental disorders. Ongoing integrative genomic studies are crucial in unmasking their pathogenicity as well as in informing precision medicine approaches in the diagnosis and management of neurodevelopmental disorders.