Integrating genome and transcriptome analysis to decipher balanced structural variants in unsolved cases of neurodevelopmental disorders.

Introduction: Balanced chromosomal abnormalities (BCAs) are structural variations that can underlie a wide spectrum of neurodevelopmental disorders, often remaining undetected by conventional diagnostic approaches. Whole-genome sequencing (WGS) allows for base-pair resolution of structural variants across the entire genome, making it a powerful tool to detect cryptic chromosomal rearrangements and refine breakpoint mapping. RNA sequencing (RNA-Seq), by enabling the detection of gene expression changes and fusion transcripts, provides complementary functional insights into the consequences of genomic alterations. This study integrated WGS and RNA-Seq to precisely characterize the breakpoints and assess the functional impact of Materials and methods: Short read WGS was used to identify the chromosomal breakpoints and gene disruptions caused by BCAs. RNA-Seq on blood RNA was employed to detect differential gene expression and potential fusion transcripts of disrupted genes. Results: In the first case, the inversion inv(8) (p11.2q13) disrupted two genes at the breakpoints, namely, Conclusion: These findings highlight the crucial role of WGS in identifying disease-associated BCAs and underscore the complementary value of RNA-Seq in assessing their functional consequences. This integrated approach enhanced diagnostic accuracy and clinical management, paving the way for more comprehensive and personalized care in these two patients.