Monogenic Intellectual Disability: Gene-Phenotype Relationships and Molecular Mechanisms

Intellectual disability encompasses limitations in intellectual functioning and adaptive behaviour, with syndromic and non-syndromic presentations and highly variable clinical trajectories. Genomic technologies have transformed clinical genetics by accelerating gene discovery and expanding gene–phenotype associations in monogenic forms of ID. However, diagnostic yield remains limited by extensive genetic heterogeneity and persistent knowledge gaps, leaving many individuals without a definitive molecular diagnosis and complicating clinical management, prognosis, and genetic counselling. Establishing robust gene–phenotype links often requires the identification of individuals with overlapping phenotypes and coordinated data sharing, while causal inference and variant reclassification frequently depend on functional validation. Moreover, the growing availability of cellular and animal models provides an opportunity to bridge genomic findings with mechanistic insight and translational advances.The goal of this Research Topic is to advance the understanding of monogenic intellectual disability by promoting the identification of gene–phenotype relationships and their functional validation. Despite major advances in genomic technologies, many candidate genes and variants identified in individuals with intellectual disability remain insufficiently validated, limiting clinical interpretation and genetic counselling. This Research Topic aims to foster studies that strengthen causal gene–phenotype relationships through robust functional and clinical evidence. This collection seeks to clarify how pathogenic variants disrupt neurodevelopmental processes and contribute to clinical heterogeneity. Ultimately, the Research Topic aims to support more accurate molecular diagnoses, improve variant interpretation, inform genetic counselling and clinical management, and identify pathways and mechanisms that may serve as future therapeutic targets.This Research Topic is part of the Human and Medical Genomics section and is devoted to the genetic investigation of monogenic intellectual disability, with a particular focus on publishing evidence supporting candidate disease genes identified through genomic approaches, as well as mechanistic insights derived from functional studies.The main aim of this Research Topic is to strengthen the causal links between specific genes and distinct forms of intellectual disability, while deepening the understanding of the molecular and cellular mechanisms underlying pathogenic variants. By integrating genomic discoveries with functional validation, this collection seeks to contribute to improved genetic counselling, clinical management, and the identification of potential therapeutic targets.We welcome submissions addressing, but not limited to: gene/genotype –phenotype relationships, variant interpretation, functional characterization of disease-associated variants, development and characterisation of cellular and animal disease models, cellular and molecular mechanisms, and translational implications for clinical genetics.The following article types will be considered: Original Research, Case Report, Brief Research Report, Hypothesis and Theory, Mini Review, Perspective, Review, and Systematic Review. Topic editors: Laura Machado Lara Carvalho, Maria Isabel Melaragno Source: https://www.frontiersin.org/research-topics/77646/monogenic-intellectual-disability-gene-phenotype-relationships-and-molecular-mechanisms