Pathogenic mutations identified by a multimodality approach in 117 Japanese Fanconi anemia patients
Minako Mori,
Asuka Hira,
Kenichi Yoshida,
Hideki Muramatsu,
Yusuke Okuno,
Yuichi Shiraishi,
Michiko Anmae,
Jun Yasuda,
Shu Tadaka,
Kengo Kinoshita,
Tomoo Osumi,
Yasushi Noguchi,
Souichi Adachi,
Ryoji Kobayashi,
Hiroshi Kawabata,
Kohsuke Imai,
Tomohiro Morio,
Kazuo Tamura,
Akifumi Takaori-Kondo,
Masayuki Yamamoto,
Satoru Miyano,
Seiji Kojima,
Etsuro Ito,
Seishi Ogawa,
Keitaro Matsuo,
Hiromasa Yabe,
Miharu Yabe,
Minoru Takata
Affiliations
Minako Mori
Laboratory of DNA Damage Signaling, Department of Late Effects Studies, Radiation Biology Center, Graduate School of Biostudies, Kyoto University, Kyoto, Japan;Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Asuka Hira
Laboratory of DNA Damage Signaling, Department of Late Effects Studies, Radiation Biology Center, Graduate School of Biostudies, Kyoto University, Kyoto, Japan
Kenichi Yoshida
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Hideki Muramatsu
Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
Yusuke Okuno
Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
Yuichi Shiraishi
Laboratory of DNA Information Analysis, Human Genome Center, The Institute of Medical Science, University of Tokyo, Tokyo Japan
Michiko Anmae
Medical Genetics Laboratory, Graduate School of Science and Engineering, Kindai University, Osaka, Japan
Jun Yasuda
Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
Shu Tadaka
Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
Kengo Kinoshita
Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan;Department of Applied Information Sciences, Graduate School of Information Sciences, Tohoku University, Sendai, Japan;Institute of Development, Aging, and Cancer, Tohoku University, Sendai, Japan
Tomoo Osumi
Children’s Cancer Center, National Center for Child Health and Development, Tokyo, Japan
Yasushi Noguchi
Department of Pediatrics, Japanese Red Cross Narita Hospital, Chiba, Japan
Souichi Adachi
Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan
Ryoji Kobayashi
Department of Pediatrics and Adolescence, Sapporo Hokuyu Hospital, Sapporo, Japan
Hiroshi Kawabata
Department of Hematology and Immunology, Kanazawa Medical University, Uchinada-machi, Japan
Kohsuke Imai
Department of Community Pediatrics, Perinatal and Maternal Medicine, Tokyo Medical and Dental University, Tokyo, Japan
Tomohiro Morio
Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan
Kazuo Tamura
Medical Genetics Laboratory, Graduate School of Science and Engineering, Kindai University, Osaka, Japan
Akifumi Takaori-Kondo
Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Masayuki Yamamoto
Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan;Department of Medical Biochemistry, Graduate School of Medicine, Tohoku University, Sendai, Japan
Satoru Miyano
Laboratory of DNA Information Analysis, Human Genome Center, The Institute of Medical Science, University of Tokyo, Tokyo Japan
Seiji Kojima
Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
Etsuro Ito
Department of Pediatrics, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
Seishi Ogawa
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan;Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska Institute, Stockholm, Sweden
Keitaro Matsuo
Division of Molecular and Clinical Epidemiology, Aichi Cancer Center Research Institute, Nagoya, Japan
Hiromasa Yabe
Department of Innovative Medical Science, Tokai University School of Medicine, Isehara, Kanagawa, Japan
Miharu Yabe
Department of Innovative Medical Science, Tokai University School of Medicine, Isehara, Kanagawa, Japan
Minoru Takata
Laboratory of DNA Damage Signaling, Department of Late Effects Studies, Radiation Biology Center, Graduate School of Biostudies, Kyoto University, Kyoto, Japan
Fanconi anemia is a rare recessive disease characterized by multiple congenital abnormalities, progressive bone marrow failure, and a predisposition to malignancies. It results from mutations in one of the 22 known FANC genes. The number of Japanese Fanconi anemia patients with a defined genetic diagnosis was relatively limited. In this study, we reveal the genetic subtyping and the characteristics of mutated FANC genes in Japan and clarify the genotype-phenotype correlations. We studied 117 Japanese patients and successfully subtyped 97% of the cases. FANCA and FANCG pathogenic variants accounted for the disease in 58% and 25% of Fanconi anemia patients, respectively. We identified one FANCA and two FANCG hot spot mutations, which are found at low percentages (0.04-0.1%) in the whole-genome reference panel of 3,554 Japanese individuals (Tohoku Medical Megabank). FANCB was the third most common complementation group and only one FANCC case was identified in our series. Based on the data from the Tohoku Medical Megabank, we estimate that approximately 2.6% of Japanese are carriers of disease-causing FANC gene variants, excluding missense mutations. This is the largest series of subtyped Japanese Fanconi anemia patients to date and the results will be useful for future clinical management.
