Decoding the Genetic Origins of Neurodevelopmental Disorders: De Novo Variants, Genomic Sequencing, and Precision Approaches to Early Diagnosis
DOI:
https://doi.org/10.64784/396Palabras clave:
neurodevelopmental disorders, de novo genetic variants, whole-exome sequencing, whole-genome sequencing, genotype–phenotype correlation, intellectual disability, autism spectrum disorder, pediatric genomics, early molecular diagnosis, precision medicineResumen
Neurodevelopmental disorders represent a heterogeneous group of conditions characterized by alterations in cognitive, behavioral, motor, and neurological development, frequently associated with complex genetic mechanisms. Among these, de novo genetic variants have emerged as major contributors to severe developmental phenotypes, including intellectual disability, global developmental delay, autism spectrum disorder, and developmental epileptic encephalopathies. This review examines the molecular contribution of newly arising genetic variants, the diagnostic performance of next-generation sequencing technologies, genotype–phenotype correlations, and the clinical implications of early molecular identification. A structured narrative review was developed using 20 foundational and contemporary scientific publications, complemented by recent evidence concerning clinical utility, with particular attention to international investigations and Latin American contributions. The reviewed evidence indicates that pathogenic de novo coding variants account for an estimated 42% of severe developmental disorders in a major genomic cohort, while exome sequencing demonstrates an overall diagnostic yield of approximately 36% across neurodevelopmental populations. Evidence from Brazil further illustrates the relevance of newly arising variants in genetically heterogeneous pediatric cohorts. Molecular findings reveal convergence among genes involved in chromatin remodeling, transcriptional regulation, synaptic organization, and neuronal excitability, highlighting the complexity of genotype–phenotype relationships. Furthermore, positive genomic diagnoses may contribute to modifications in clinical management, although improvements in long-term developmental outcomes remain insufficiently established. Persistent challenges include uncertain variant classification, incomplete molecular characterization, unequal population representation, and limited access to genomic technologies. The integration of genomic sequencing, comprehensive clinical phenotyping, genetic counseling, and multidisciplinary pediatric care constitutes a fundamental strategy for improving etiological diagnosis and supporting individualized management. Expanded international collaboration and longitudinal research are necessary to strengthen clinical translation and equitable access to precision genomic medicine.
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