Increased Frequency of Clonal Hematopoiesis of Indeterminate Potential in Bloom Syndrome Probands and Carriers

Abstract

ABSTRACTBackgroundBloom Syndrome (BSyn) is an autosomal recessive disorder caused by biallelic germline variants inBLM,which functions to maintain genomic stability. BSyn patients have poor growth, immune defects, insulin resistance, and a significantly increased risk of malignancies, most commonly hematologic. The malignancy risk in carriers of pathogenic variants inBLM(BLMvariant carriers) remains understudied. Clonal hematopoiesis of indeterminate potential (CHIP) is defined by presence of somatic mutations in leukemia-related genes in blood of individuals without leukemia and is associated with increased risk of leukemia. We hypothesize that somatic mutations driving clonal expansion may be an underlying mechanism leading to increased cancer risk in BSyn patients andBLMvariant carriers.MethodsTo determine whetherde novoor somatic variation is increased in BSyn patients or carriers, we performed and analyzed exome sequencing on BSyn and control trios.ResultsWe discovered that both BSyn patients and carriers had increased numbers of low-frequency, putative somatic variants in CHIP genes compared to controls. Furthermore, BLM variant carriers had increased numbers of somatic variants in DNA methylation genes compared to controls. There was no statistical difference in the numbers ofde novovariants in BSyn probands compared to control probands.ConclusionOur findings of increased CHIP in BSyn probands and carriers suggest that one or two germline pathogenic variants inBLMcould be sufficient to increase the risk of clonal hematopoiesis. These findings warrant further studies in larger cohorts to determine the significance of CHIP as a potential biomarker of aging, cancer, cardiovascular disease, morbidity and mortality.