Page 199 - Haematologica Vol. 110 - January 2025

LETTER TO THE EDITOR
of de novo variants and somatic variants. Our findings reveal an increased frequency of low frequency, putatively somatic variants in CHIP genes in BSyn probands and BLM carriers, compared to sex- and age-matched controls.
An oral presentation at the American Society of Hematology 2023 meeting identified BLM as one of 18 clonal hematopoi- esis genes associated with hematopoietic malignancy in the heterozygous state,12 consistent with our CHIP findings. These variants were predominantly synonymous variants in BSyn probands and splice variants in BLM carriers. In contrast to prior studies on clonal hematopoiesis, which have identified somatic variants most frequently in DNMT3A, ASXL1, and TET2,9 we identified mainly synonymous and benign splice variants primarily in NOTCH1 and CUX1.
The absence of significant differences in mean somatic and germline variants between BSyn probands and BLM carriers suggests other factors besides BLM mutations, such as envi- ronmental exposures or other genetic modifiers, may influence mutation patterns. Limitations of our study include small sample size, use of two different exome enrichment methods, and use of exome sequencing to detect ultra-low-frequency clones. Future studies using deep-amplicon sequencing of longitudinal samples could validate these findings.
Our study contributes to the growing literature on increased somatic mutation rate and cancer risk in carriers for genes important in maintaining genomic integrity. These findings may pave the way for early biomarkers in cancer detection and general health assessment in rare disease patients and carriers. Larger-scale studies with BSyn cohorts are imperative to unravel the mechanisms underpinning BLM PV and their contribution to CHIP and cancer risk.
Authors
Isabella Lin,1,2,3 Angela Wei,1,2,3,4 Tsumugi A. Gebo,5,6 Paul C. Boutros,1,4,5,6,7,8 Maeve Flanagan,9 Nicole Kucine,9 Christopher Cunniff,9 Valerie A. Arboleda1,2,3,4,5,8# and Vivian Y. Chang5,6,10,11#
1Department of Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, CA; 2Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA; 3Department of Computational Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA; 4Interdepartmental BioInformatics Program, UCLA, Los Angeles, CA; 5 Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA; 6Institute for Precision Health, University of California Los Angeles, Los Angeles, CA; 7Department of Urology, University of California Los Angeles, Los Angeles, CA; 8Molecular Biology
References
1. Cunniff C, Bassetti JA, Ellis NA. Bloom’s syndrome: clinical spectrum, molecular pathogenesis, and cancer predisposition. Mol Syndromol. 2017;8(1):4-23.
Institute, University of California, Los Angeles, CA; 9Department of Pediatrics, Weill Cornell Medicine, New York, NY; 10Division of Pediatric Hematology/ Oncology, UCLA, Los Angeles, CA and 11Children’s Discovery and Innovation Institute, UCLA, Los Angeles, CA, USA
#VAA and VYC contributed equally as senior authors.
Correspondence:
V.Y. CHANG - vchang@mednet.ucla.edu
https://doi.org/10.3324/haematol.2024.285239
Received: March 20, 2024. Accepted: July 18, 2024. Early view: July 25, 2024.
©2025 Ferrata Storti Foundation Published under a CC BY-NC license
Disclosures
PCB sits on the scientific advisory boards of Sage Bionetworks, Intersect Diagnostics Inc. and BioSymetrics Inc. The other authors have no conflicts of interest to disclose.
Contributions
VC, VA, IL and AW designed and conceptualized the study, analyzed the generated data, and wrote the paper. PB and TAG performed mapping and variant calling of WES data and IL performed VarSeq trio exome analysis. MF, NK, CC coordinated sample collection and DNA extraction. All authors contributed to the final editing of the manuscript.
Acknowledgments
We thank the UCLA Technology for Genomics and Bioinformatics for their sequencing expertise, and Dr. Jeff Gornbein from the UCLA Statistics Department for his expertise and aid in statistical analyses. We would like to acknowledge the families and patients who participated in this study and donated their time and efforts to make this possible.
Funding
This work was supported by the following funding sources awarded to VAA: NIH DP5OD024579 and the ASXL Research Related Endowment Pilot Grant (2020-2022), IL: NIH T32 GM008042 and VYC: NIH 1K08HL138305. CC and NK received support from The New York Community Trust.
Data-sharing statement
Data available on request to corresponding author.
2. Landrum MJ, Lee JM, Riley GR, et al. ClinVar: public archive of relationships among sequence variation and human phenotype. Nucleic Acids Res. 2014;42(database issue):D980-9855.
Haematologica | 110 January 2025
191