Rare and Common Germline and Somatic Variants Shape Immune Cytopenia Risk and Enable Risk Stratification
- 1CHU Sainte-Justine Azrieli Research Center, Montreal, Quebec, Canada; Faculty of Medicine, Universite de Montreal, Montreal, Quebec, Canada
Abstract
The genetic risk factors of immune cytopenias are unclear. Immune cytopenias have been reported in various genetic contexts: 1) inherited error of immunity genes, mainly due to rare germline variants, 2) systemic lupus erythematosus, associated with common germline variants, 3) hematological malignancies, and 4) clonal hematopoiesis, the latter two due to somatic variants. However, the respective contribution and interaction of these variants remain to be investigated. Here, we used two large biobanks with whole genome sequencing data to systematically investigate the genetic contribution to immune cytopenia. We found that the four types of genetic variants independently contribute to immune cytopenia risk. We notably found that carriers of variants in some autosomal recessive genes of inherited error of immunity had an increased risk of immune cytopenia. Additionally, common variant- mediated risk of systemic lupus erythematosus also increased the risk of immune cytopenia. Overall, a third to a half of patients with immune cytopenia carried at least one of the four genetic risk variants investigated. Combining the four variants allowed stratifying the risk of immune cytopenia in both general and high-risk population. In general population, the 10- year incidence of immune cytopenia in the lowest and highest risk groups was 0.8{per thousand} and 15{per thousand}, respectively. In sum, this work identified that different genetic risk factors can lead to immune cytopenia. A large proportion of individuals with immune cytopenia carried an underlying genetic risk factor. Finally, combining these genetic risk factors enabled risk stratification.
Related
- Germline removal reprograms somatic genome maintenance towards faster, energy-efficient, high-fidelity DNA defence and repair
- Somatic Structural Variant Discovery from Tumor Specific Strings Computed Against a Draft Composite Germline Reference
- Cytotoxic T-cell lymphoma with muscle involvement and germline variants in inborn error of immunity-related genes: clinical and genetic insights from a case series
- Targeted Germline Sequencing Identifies Ultra-Rare DDR Variants in High-Risk Prostate Cancer : Short title: Germline DDR Variants in High-Risk Prostate Cancer.
- A common germline 3′ UTR variant controls DDIT4 translation efficiency and stress responses in cancer cells
BibTeX
@misc{faria2026rare,
title = {{Rare and Common Germline and Somatic Variants Shape Immune Cytopenia Risk and Enable Risk Stratification}},
author = {S. D. S. Faria and J. Bineau and R. Moisan and M.-A. Legault and E. Lecluze and T. Pincez},
howpublished = {medRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.26.26361484},
url = {https://www.medrxiv.org/content/10.64898/2026.08.26.26361484v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Rare and Common Germline and Somatic Variants Shape Immune Cytopenia Risk and Enable Risk Stratification
AU - S. D. S. Faria
AU - J. Bineau
AU - R. Moisan
AU - M.-A. Legault
AU - E. Lecluze
AU - T. Pincez
PY - 2026
DA - 2026/08/26
PB - medRxiv
DO - 10.64898/2026.08.26.26361484
UR - https://www.medrxiv.org/content/10.64898/2026.08.26.26361484v1
AB - The genetic risk factors of immune cytopenias are unclear. Immune cytopenias have been reported in various genetic contexts: 1) inherited error of immunity genes, mainly due to rare germline variants, 2) systemic lupus erythematosus, associated with common germline variants, 3) hematological malignancies, and 4) clonal hematopoiesis, the latter two due to somatic variants. However, the respective contribution and interaction of these variants remain to be investigated. Here, we used two large biobanks with whole genome sequencing data to systematically investigate the genetic contribution to immune cytopenia. We found that the four types of genetic variants independently contribute to immune cytopenia risk. We notably found that carriers of variants in some autosomal recessive genes of inherited error of immunity had an increased risk of immune cytopenia. Additionally, common variant- mediated risk of systemic lupus erythematosus also increased the risk of immune cytopenia. Overall, a third to a half of patients with immune cytopenia carried at least one of the four genetic risk variants investigated. Combining the four variants allowed stratifying the risk of immune cytopenia in both general and high-risk population. In general population, the 10- year incidence of immune cytopenia in the lowest and highest risk groups was 0.8{per thousand} and 15{per thousand}, respectively. In sum, this work identified that different genetic risk factors can lead to immune cytopenia. A large proportion of individuals with immune cytopenia carried an underlying genetic risk factor. Finally, combining these genetic risk factors enabled risk stratification.
ER -