Clinical relevance of mosaic variants detected by exome sequencing.
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Ghosh Rajarshi, Fazal Zeeshan, Oler Andrew J, Tokita Mari J, Lewis Katie L, Paul Alexander J, Schmitz Elizabeth G, Saucier Nermina, Yan Jia, Kamen Michael, Seifert Bryce A, NIAID Centralized Sequencing Program,, Klion Amy D, Khoury Paneez, Delmonte Ottavia M, Notarangelo Luigi D, Freeman Alexandra F, Zerbe Christa S, Uzel Gulbu, Metcalfe Dean D, Komarow Hirsh D, Carter Melody C, McDermott David H, Murphy Philip M, Olivier Kenneth N, Fuss Ivan, Strober Warren, Rao V Koneti, Bergerson Jenna R E, Almeida de Jesus Adriana, Goldbach-Mansky Raphaela, Al-Herz Waleed, Holland Steven M, Cooper Megan A, Similuk Morgan N, Walkiewicz Magdalena A
Аннотация
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, 9 (31%) 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.