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Identification of synonymous pathogenic variants in monogenic disorders by integrating exome with transcriptome sequencing.
Journal of Molecular Diagnostics : JMD 2024 January 26
Exome sequencing (ES) is becoming a first-tier clinical diagnostic test for Mendelian diseases, drastically reducing the time and cost of diagnostic odyssey and improving the diagnosis rate. Despite its success, ES faces practical challenges in assessing the pathogenicity of numerous intronic and synonymous variants, leaving a significant proportion of patients undiagnosed. In this study, a whole blood transcriptome database was constructed, which demonstrated the expression profile of 2,981 OMIM disease genes in blood samples. Meanwhile, a workflow integrating exome sequencing, blood transcriptome sequencing, and in silico prediction tools to identify and validate splicing-altering intronic or synonymous variants was proposed. Following this pipeline, seven synonymous variants in eight patients were discovered. Of these, the functional evidence of c.981G>A (PIGN), c.1161A>G (ALPL), c.858G>A (ATP6AP2) and c.1011G>T (MTHFR) have not been previously reported. RNA-seq validation confirmed that these variants induced aberrant splicing, expanding the disease-causing variants spectrum of these genes. Overall, this study shows the feasibility of combining multi-omics data to identify splicing-altering variants, especially the power of RNA-seq. It also reveals that synonymous variants, which are often overlooked in standard diagnostic approaches, comprise an important portion of unresolved genetic diseases.
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