Abstract
Common variable immunodeficiency (CVID) is the most common adult-onset primary antibody deficiency disease due to various causative genes. Several genes, which are known to be the cause of different diseases, have recently been reported as the cause of CVID in patients by performing whole exome sequencing (WES) analysis. Here, we found FANC gene mutations as a cause of adult-onset CVID in two patients. B cells were absent and CD4+ T cells were skewed toward CD45RO+ memory T cells. T-cell receptor excision circles (TRECs) and signal joint kappa-deleting recombination excision circles (sjKRECs) were undetectable in both patients. Both patients had no anemia, neutropenia, or thrombocytopenia. Using WES, we identified compound heterozygous mutations of FANCE in one patient and homozygous mutation of FANCA in another patient. The impaired function of FANC protein complex was confirmed by a monoubiquitination assay and by chromosome fragility test. We then performed several immunological evaluations including quantitative lymphocyte analysis and TRECs/sjKRECs analysis for 32 individuals with Fanconi anemia (FA). In total, 22 FA patients (68.8%) were found to have immunological abnormalities, suggesting that such immunological findings may be common in FA patients. These data indicate that FANC mutations are involved in impaired lymphogenesis probably by the accumulation of DNA replication stress, leading to CVID. It is important to diagnose FA because it drastically changes clinical management. We propose that FANC mutations can cause isolated immunodeficiency in addition to bone marrow failure and malignancy.
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Acknowledgments
This work was supported by grants from the Ministry of Defense; the Ministry of Education, Culture, Sports, Science, and Technology (nos. 26293250 and 15 K15396); the Ministry of Health, Labor, and Welfare (no. 14427260); the Kawano Masanori Memorial Public Interest Incorporated Foundation for Promotion of Pediatrics; the Practical Research for Rare/Intractable Diseases from Japan Agency for Medical Research and Development, AMED; The Japan Foundation for Pediatric Research; and Drs. M. and W. Hirose, Dr. H. Matsuda, and Dr. H. Seto. We thank Dr. Yuki Tsujita, Dr. Yumiko Ogura, and Dr. Hirokazu Kawaguchi for medical support. We would also like to thank Ms. Kaori Tomita, Ms. Kimiko Gasa, and Dr. Naomi Terada for their skillful technical assistance.
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Contributions: Y.S., N.M., K.I., A.A., M.Y., and H.Y. treated the patients and designed the clinical laboratory tests; K.S. and N.M. performed flow cytometric analysis; K.H. performed TRECs and sjKRECs analyses; M. Takagi established skin fibroblast of patient 2; M.Y. performed the chromosome fragility tests; A.H. and M. Takata performed monoubiquitination assay and validation of FANC mutations; K.Y., Y.O., Y.S., K.C., H.T., S.M., H.M., S.K., and S.O. performed WES of patient 1; O.O. performed WES of patient 2; K.I., T.M., and S.N. designed the overall study, supervised the experiments, and performed analyses and interpretation of the data.
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Sekinaka, Y., Mitsuiki, N., Imai, K. et al. Common Variable Immunodeficiency Caused by FANC Mutations. J Clin Immunol 37, 434–444 (2017). https://doi.org/10.1007/s10875-017-0396-4
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DOI: https://doi.org/10.1007/s10875-017-0396-4