Kay Tanita1, Fumiaki Sakura2, Ryusuke Nambu3,4,5, Miyuki Tsumura2, Yusuke Imanaka2, Hidenori Ohnishi6, Zenichiro Kato6,7, Jie Pan4,5, Akihiro Hoshino1, Koji Suzuki8, Motoko Yasutomi8, Shuichiro Umetsu9, Chizuru Okada10, Masatoshi Takagi1, Kohsuke Imai11, Osamu Ohara12,13, Alexo M Muise4,5,14, Satoshi Okada2, Tomohiro Morio1, Hirokazu Kanegane15. 1. Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan. 2. Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan. 3. Division of Gastroenterology and Hepatology, Saitama Children's Medical Center, Saitama, Japan. 4. SickKids Inflammatory Bowel Disease Center, The Hospital for Sick Children, Toronto, ON, Canada. 5. Cell Biology Program, Research Institute, The Hospital for Sick Children, Toronto, ON, Canada. 6. Department of Pediatrics, Gifu University Graduate School of Medicine, Gifu, Japan. 7. Structural Medicine, United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu, Japan. 8. Department of Pediatrics, Faculty of Medical Sciences, University of Fukui, Fukui, Japan. 9. Department of Pediatric Hepatology and Gastroenterology, Saiseikai Yokohama-shi Tobu Hospital, Yokohama, Kanagawa, Japan. 10. Hiroshima Chuodori Children Clinic, Hiroshima, Japan. 11. Department of Community Pediatrics, Perinatal and Maternal Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan. 12. Department of Technology Development, Kazusa DNA Research Institute, Chiba, Japan. 13. Laboratory for Integrative Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. 14. Department of Pediatrics, Institute of Medical Science and Biochemistry, University of Toronto, the Hospital for Sick Children, Toronto, ON, Canada. 15. Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan. hkanegane.ped@tmd.ac.jp.
Abstract
PURPOSE: Germline loss-of-function variants in the signal transducer and activator of transcription 3 (STAT3) gene result in autosomal dominant hyper IgE syndrome, whereas somatic gain-of-function (GOF) variants in STAT3 are associated with some malignancies. In addition, germline GOF variants in STAT3 are linked to disorders involving autoimmunity and lymphoproliferation. In this study, we describe five Japanese families with germline GOF variants in STAT3, including three novel variants. We also present the clinical and immunological characteristics of these patients. METHODS: Eight patients from five families were enrolled in this study. We performed genetic and immunological analyses, and collected the associated clinical information. RESULTS: We identified five heterozygous variants in STAT3 using whole-exome sequencing and target gene sequencing. Two of these (E286G and T716M) were previously reported and three (K348E, E415G, and G618A) were novel. A STAT3 reporter assay revealed that all of the variants were GOF. However, the immunological and clinical characteristics among the patients were highly variable. CONCLUSION: Patients with STAT3 GOF variants exhibited clinical and immunological heterogeneity with incomplete penetrance.
PURPOSE: Germline loss-of-function variants in the signal transducer and activator of transcription 3 (STAT3) gene result in autosomal dominant hyper IgE syndrome, whereas somatic gain-of-function (GOF) variants in STAT3 are associated with some malignancies. In addition, germline GOF variants in STAT3 are linked to disorders involving autoimmunity and lymphoproliferation. In this study, we describe five Japanese families with germline GOF variants in STAT3, including three novel variants. We also present the clinical and immunological characteristics of these patients. METHODS: Eight patients from five families were enrolled in this study. We performed genetic and immunological analyses, and collected the associated clinical information. RESULTS: We identified five heterozygous variants in STAT3 using whole-exome sequencing and target gene sequencing. Two of these (E286G and T716M) were previously reported and three (K348E, E415G, and G618A) were novel. A STAT3 reporter assay revealed that all of the variants were GOF. However, the immunological and clinical characteristics among the patients were highly variable. CONCLUSION: Patients with STAT3 GOF variants exhibited clinical and immunological heterogeneity with incomplete penetrance.
Entities:
Keywords:
Signal transducer and activator of transcription 3; gain-of-function; heterogeneity; incomplete penetrance