The mosaic genome: De novo variations driving neurodevelopment in autism spectrum disorder, intellectual disability, and epilepsy 

• Author Details:   
• Sudakshina Deb ^*

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Neurodevelopmental disorders (NDDs) such as Autism Spectrum Disorder (ASD), Intellectual Disability (ID), and Epilepsy (EP) are complex conditions caused by disruptions in brain development that are typically mediated by rare genetic mutations. Of these, de novo mutations (DNMs)—not inherited but spontaneous—have become the key drivers. These mutations, more likely to be pathogenic than inherited mutations, may arise from either gametogenesis or early embryonic development and in some cases result in mosaicism, where only some of the genes carry the mutations.

This is a review of the molecular etiology, mutation pattern, and pathogenicity of DNMs and mosaic variants in ASD, ID, and EP. With denovo-db curated databases and functional network analysis via the STRING database, the article addresses the type of DNMs (missense, frameshift, splice-site, etc.), where they occur on the chromosome, and the recurrent genes involved like CHD8, SCN2A, SYNGAP1, and GRIN2B. Interestingly, an unprecedentedly high proportion of these DNMs are CpG transition mutations, commonly linked to methylation instability and paternal age or environmental stress.

The paper also acknowledges the manner in which overlap between DNMs of such disorders generates shared molecular networks that include chromatin remodeling, synaptic function, and ion channel regulation. The findings are consistent with the hypothesis that shared genetic architecture explains differential NDD phenotypes, with DNMs as primary markers of early developmental derangements.

Through the translation of genomic data to functional gene assessment, the review presents a convergent summary of spontaneous and mosaic genetic variants' capacity to drive neurodevelopmental processes to the onset and comorbidity of ASD, ID, and EP. It emphasizes the importance of ongoing whole-exome and whole-genome sequencing research in the discovery of actionable mutations and the identification of future therapeutic targets.