Translational and clinical immunologyAbnormal hematopoiesis and autoimmunity in human subjects with germline IKZF1 mutations
Section snippets
Study approval
Informed consent was obtained from patients or their parents. The study was conducted in accordance with the Helsinki Declaration and approved by the ethics boards of the University of Toyama and Tokyo Medical and Dental University.
Genetic analysis
For whole-exome sequencing (WES), exome capture was carried out with a SureSelect Human All Exon V5 Kit (Agilent Technologies, Santa Clara, Calif), and massively parallel sequencing was performed with a HiSeq 2000 platform (Illumina, San Diego, Calif) with 100-bp
Identification of heterozygous mutations in IKZF1
Initially, we identified heterozygous IKZF1 mutations in 3 families from a dysgammaglobulinemia cohort (Table I, Fig 1, and see the Supplemental Note in this article's Online Repository at www.jacionline.org). A 7-year-old boy (A.1) had ITP and dysgammaglobulinemia with low B-cell counts at 5 years of age. Patient B.1, a 16-year-old girl, had recurrent sinopulmonary bacterial infections since 2 months of age and was treated with intravenous immunoglobulin. She also had a history of Pneumocystis
Discussion
Here we described 9 patients from 6 families with heterozygous IKZF1 mutations. We identified 5 missense mutations and 1 splice site mutation in the IKZF1. Two missense mutations (p.R162Q and p.Y210C) were previously reported,7, 9 but 4 mutations (p.C147R, p.N159S, p.R162W, and c.589+1G>A) were novel. Interestingly, the p.R162L mutation was described by Kuehn et al,9 and p.R162 might be recurrently mutated in IKZF1. All but 1 patient presented with dysgammaglobulinemia accompanied by a
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Supported by the Research on Measures for Intractable Disease Project (to S.K.) and grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (to T.M. and H.K.) and the Ministry of Health, Labour, and Welfare of Japan (to S.N.).
Disclosure of potential conflict of interest: K. Imai has received a grant from the Ministry of Health, Labour, and Welfare (H23-012). S. Ogawa has received grants from Grant-in-Aid for Scientific Research (KAKENHI 15H05909) and the Ministry of Health, Labor and Welfare. T. Morio has received a grant from CSL-Behring. H. Kanegane has received a grant from the Japan Society for the Promotion of Science (JP26461570). The rest of the authors declare that they have no relevant conflicts of interest.
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These authors contributed equally to this work.