RESUMEN
Background: Bloom Syndrome (BSyn) is an autosomal recessive disorder caused by biallelic germline variants in BLM, 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 in BLM (BLM variant 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 and BLM variant carriers. Methods: To determine whether de novo or somatic variation is increased in BSyn patients or carriers, we performed and analyzed exome sequencing on BSyn and control trios. Results: We 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 of de novo variants in BSyn probands compared to control probands. Conclusion: Our findings of increased CHIP in BSyn probands and carriers suggest that one or two germline pathogenic variants in BLM could 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.
RESUMEN
The primate premotor cortex is endowed with an "action observation/execution matching system", that is, the same premotor neurons discharge when actions are performed and when actions are observed. Hence, this system predicts a strong visual input to the motor system. Whether this input is dependent on visual experience or not has not been previously investigated. To address this issue we compared corticospinal excitability while subjects viewed frequently observed and less frequently observed hand actions of others and of themselves. Motor corticospinal excitability was larger when the action orientations were as they are frequently observed (Self-away, subject's own hand facing out from the subject, or Other-toward, an unknown hand facing toward the subject) compared with less frequently observed actions (Self-toward, subject's own hand facing "toward" the subject, or Other-away, an unknown hand facing out from the subject). This finding suggests that the modulation of motor corticospinal excitability during action observation and hence the "action observation/execution matching system" is largely dependent upon visual experience.
