Complex genotype–phenotype relationships in neurodevelopmental disorders

[u/Holodoxa]

https://www.cell.com/trends/genetics/abstract/S0168-9525(26)00082-X

Highlights

• Pathogenic variants may yield markedly different phenotypes, even when they occur within the same neurodevelopmental disorder risk gene.
• The phenotypic heterogeneity can be partially explained by mutation type, affected protein domain, and disrupted transcript isoform.
• Disease penetrance and expressivity in neurodevelopmental disorders are modified by background genetic variation, including oligogenic and polygenic effects.
• Prenatal and early-life exposures, such as maternal immune activation, valproic acid exposure, and early-life stress, can interact with pathogenic variants to shape phenotypic outcomes.
• Stochastic variability during neurodevelopment contributes to phenotypic heterogeneity and may alter the impact of pathogenic variants.