外显子组测序检测到的嵌合变异的临床相关性

Background: Mosaic variants represent a significant but underrecognized contributor to human disease such as cancer and immune diseases. Despite advances in genetic diagnostics, mosaic variant detection remains challenging as a result of low variant allele fractions, tissue specificity, and clinical heterogeneity. Objective: We investigated the prevalence, diagnostic impact, and clinical relevance of mosaic variants in participants with immune disorders. Methods: Exome sequencing of blood and/or saliva was performed in 2655 participants, including 2064 affected participants. Mosaic variants were detected using two algorithms, LoFreq2 and Mutect2. A subset of the detected variants was orthogonally validated. Clinical data were retrospectively analyzed to assess the clinical significance of these variants. Results: Mosaic variants associated with immune disorders contributed to a molecular diagnosis in 29 (1.4%) of 2064 affected participants. Notably, 10 (34%) of 29 of diagnostic variants were missed by standard germline analysis as a result of low variant allele fractions. Clinically relevant parental mosaicism was ascertained in two families. Enrichment of mosaic variants was observed in clonal hematopoiesis-related genes driven by older age and GATA2 deficiency, with prognostic implications for hematologic disorders. Finally, chemotherapy drug resistance variants in NRAS, KRAS, and IDH2 were identified, demonstrating the potential for mosaic variant detection to inform treatment strategies. Conclusion: Mosaic variants contribute significantly to the molecular diagnosis and prognosis of immune and hematologic disorders and are missed by typical germline variant-calling workflow.