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Haematologica 2019 Volume 104(10):1962-1973
Bone Marrow Failure
Pathogenic mutations identified by a multimodality approach in 117 Japanese Fanconi anemia patients
Minako Mori,1,2 Asuka Hira,1 Kenichi Yoshida,3 Hideki Muramatsu,4 Yusuke Okuno,4 Yuichi Shiraishi,5 Michiko Anmae,6 Jun Yasuda,7
Shu Tadaka,7 Kengo Kinoshita,7,8,9 Tomoo Osumi,10 Yasushi Noguchi,11 Souichi Adachi,12 Ryoji Kobayashi,13 Hiroshi Kawabata,14 Kohsuke Imai,15 Tomohiro Morio,16 Kazuo Tamura,6 Akifumi Takaori-Kondo,2
Masayuki Yamamoto, Satoru Miyano, Seiji Kojima, Etsuro Ito,
3,19 20 Seishi Ogawa, Keitaro Matsuo,
Hiromasa Yabe,
21
Miharu Yabe
21
and
Minoru Takata1
7,17 5 4 18
1Laboratory of DNA Damage Signaling, Department of Late Effects Studies, Radiation Biology Center, Graduate School of Biostudies, Kyoto University, Kyoto, Japan; 2Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan; 3Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan; 4Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan; 5Laboratory of DNA Information Analysis, Human Genome Center, The Institute of Medical Science, University of Tokyo, Tokyo Japan; 6Medical Genetics Laboratory, Graduate School of Science and Engineering, Kindai University, Osaka, Japan; 7Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan; 8Department of Applied Information Sciences, Graduate School of Information Sciences, Tohoku University, Sendai, Japan; 9Institute of Development, Aging, and Cancer, Tohoku University, Sendai, Japan; 10Children’s Cancer Center, National Center for Child Health and Development, Tokyo, Japan; 11Department of Pediatrics, Japanese Red Cross Narita Hospital, Chiba, Japan; 12Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan; 13Department of Pediatrics and Adolescence, Sapporo Hokuyu Hospital, Sapporo, Japan; 14Department of Hematology and Immunology, Kanazawa Medical University, Uchinada-machi, Japan; 15Department of Community Pediatrics, Perinatal and Maternal Medicine, Tokyo Medical and Dental University, Tokyo, Japan; 16Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan; 17Department of Medical Biochemistry, Graduate School of Medicine, Tohoku University, Sendai, Japan; 18Department of Pediatrics, Hirosaki University Graduate School of Medicine, Hirosaki, Japan; 19Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska Institute, Stockholm, Sweden; 20Division of Molecular and Clinical Epidemiology, Aichi Cancer Center Research Institute, Nagoya, Japan and 21Department of Innovative Medical Science, Tokai University School of Medicine, Isehara, Kanagawa, Japan
ABSTRACT
Fanconi anemia is a rare recessive disease characterized by multiple con- genital abnormalities, progressive bone marrow failure, and a predis- position 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 comple- mentation 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 sub- typed Japanese Fanconi anemia patients to date and the results will be use- ful for future clinical management.
Correspondence:
MINORU TAKATA
mtakata@house.rbc.kyoto-u.ac.jp
MIHARU YABE
miharu@is.icc.u-tokai.ac.jp
Received: September 20, 2018. Accepted: February 15, 2019. Pre-published: February 21, 2019.
doi:10.3324/haematol.2018.207241
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