Expanding the Variant Spectrum of MED13L-Associated Neurodevelopmental Disorder: Insights from the 100k Genomes Project

Background: An estimated 2–5% of infants are born with significant congenital defects and/or go on to develop severe neurodevelopmental disorders in early childhood, with a substantial proportion attributed to underlying genetic causes. Variants in the MED13L gene have been linked to a syndromic neurodevelopmental disorder characterized by developmental delay, intellectual disability, and, in some cases, congenital heart defects. However, the pathogenicity of many MED13L variants—particularly missense changes—remains poorly understood. Methods: This study analyzed clinically and genomically annotated data from the 100,000 Genomes Project (Genomics England), focusing on individuals with rare MED13L variants. A structured pipeline was developed to extract, filter, and interpret missense and truncating variants using the Interactive Variant Analysis (IVA) tool and associated resources. Detailed clinical phenotypes were manually cross-referenced through the Participant Explorer, and variants were classified following ACMG guidelines. Results: After filtering, eight probands were identified with clinically relevant, previously unreported, MED13L variants: five variants of uncertain significance (VUS) and three likely pathogenic. Despite differences in classification, both VUS and likely pathogenic variants were associated with a consistent neurodevelopmental phenotype. One additional patient carried an intronic MED13L variant with predicted spliceogenic potential and presented with a congenital heart defect, raising the possibility of a regulatory effect on cardiac gene expression. Notably, four of the eight individuals also harbored additional pathogenic or likely pathogenic variants in other genes known to contribute to neurodevelopmental phenotypes, illustrating potential genetic heterogeneity. The study also identified a disproportionately high rate of VUS among individuals of non-European ancestry, highlighting challenges in variant interpretation due to underrepresentation in population databases. Conclusions: This work emphasizes the value of large-scale genomic datasets in refining variant classification and improving diagnostic accuracy. It highlights the complexity of interpreting MED13L variants, the importance of considering genetic heterogeneity, and the need for increased diversity in genomic reference databases. Findings underscore the necessity of trio sequencing and functional studies to reclassify VUS and advance understanding of MED13L-associated syndromes.