Revealing the impact of partial gene duplications in ASH1L: integration of optical genome mapping and RNA sequencing.

INTRODUCTION: Partial gene duplications are structural variants that are challenging to interpret, particularly in the context of neurodevelopmental disorders. The ASH1L gene, associated with autism spectrum disorders and cognitive impairment, exemplifies the complexity of such variants. This study explores the integration of Optical Genome Mapping (OGM) with traditional cytogenetic techniques and RNA sequencing to enhance the characterization of de novo partial gene duplications. METHODS: Initial detection of the duplication was performed using array comparative genomic hybridization (CGH) and exome sequencing, which were insufficient to resolve the detailed structure or predict functional impacts. OGM was employed to clarify the structural arrangement, while RNA sequencing assessed the expression profile of the ASH1L gene. RESULTS: OGM identified a tandem arrangement of two duplications at 1q22. One duplication resulted in a 3-exon intragenic duplication with a predicted frameshift effect, which conventional methods had misinterpreted as a single event. RNA sequencing revealed no reduction in ASH1L mRNA levels despite the frameshift, suggesting the non-activation of the nonsense-mediated decay (NMD) system. DISCUSSION: These findings challenge conventional views on the functional consequences of structural variants. The study demonstrates the capability of OGM to uncover complex genomic rearrangements that evade detection by traditional methods. Integrating advanced genomic tools enhances diagnostic precision and broadens our understanding of the pathogenicity of structural variants in developmental disorders.