Phenotypic Complexity and Diagnostic Utility of Exome Sequencing in ASD: Real-World Insights from Colombia

Abstract

Autism spectrum disorder (ASD) is a genetically heterogeneous condition; however, genomic data from Latin American populations remain limited. We investigated the molecular and phenotypic landscape of ASD in 916 Colombian patients who underwent whole-exome sequencing (WES) between 2022 and 2025. Clinical and genomic data were retrospectively analyzed, and phenotypes were standardized using Human Phenotype Ontology (HPO) terms. Variants were classified per ACMG/ClinGen guidelines, and we assessed phenotypic burden, predictors of molecular diagnosis, copy number variants (CNVs), and functional convergence of candidate genes. A molecular diagnosis was identified in 112 patients (12.2%), including 82 with variants in ASD-associated genes or regions and 30 with findings related to other clinical features. We identified 16 novel pathogenic/likely pathogenic variants, along with 10 CNVs. Among trio-based patients, 70.9% of molecular diagnoses were de novo. Higher phenotypic burden was associated with molecular diagnosis, and global developmental delay was the strongest predictor after correction for multiple testing. Functional enrichment analysis of candidate genes showed convergence on pathways related to neuronal development, synaptic function, and ion transport. These findings highlight the genetic and phenotypic heterogeneity of ASD and support the value of integrating standardized genomic and phenotypic characterization in Colombian populations.