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 due to low variant allele fractions (VAFs), tissue specificity, and clinical heterogeneity. To investigate the prevalence, diagnostic impact and clinical relevance of mosaic variants in participants with immune disorders. 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 clinical significance of these variants. Mosaic variants contributed to a molecular diagnosis in 1.4% (29/2064) affected participants, associated with immune disorders. Notably, 34% (10/29) of diagnostic variants were missed by standard germline analysis due to low VAFs. 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. Mosaic variants contribute significantly to the molecular diagnosis and prognosis of immune and hematological disorders and are missed by typical germline variant calling workflow.
Ghosh et al. (Sun,) studied this question.