title: Diagnostic challenge of Diamond-Blackfan anemia in mothers and children by whole-exome sequencing.
abstract: Diamond-Blackfan anemia (DBA) is a pure red cell aplasia that arises from defective ribosomal proteins (RPs). Patients with this rare ribosomopathy present with neonatal anemia and occasional dysmorphism. Clinical heterogeneity and clusters of causative RP genes hamper the diagnosis and perinatal management. We report three mother-and-child pairs of anemia who were finally diagnosed by whole-exome sequencing. Each pair showed distinct disease severity and response to anemia treatment. Only one mother had the diagnostic dysmorphism, including short stature, webbed neck, and thenar hypoplasia. This mother had a frame-shift mutation of RPL11 (exon 3, c.58_59del). Her infant showed transient neonatal anemia, but had no mutations of RP genes. The other mother-child pairs had a missense mutation of RPS19 (exon 4, c.185G>A), and a splicing error of RPS7 (exon 3, c.76-1G>T), respectively. Other than the reported mutations, there were no variants in genes significantly associated with anemia. Our results suggested that whole-exome sequencing (WES) is effective for achieving a prompt and correct diagnosis of human ribosomopathy.
authors.affiliation: Department of Pediatrics, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-kogushi, Ube, Yamaguchi, 755-8505, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Ichimura
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto-shi, Kyoto, 606-8501, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Department of Pediatrics, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.|Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Okuno
authors.affiliation: Third Department of Internal Medicine, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-kogushi, Ube, Yamaguchi, 755-8505, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Yujiri
authors.affiliation: Department of Pediatrics, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan.
authors.forename: Kozo
authors.initials: K
authors.lastname: Nagai
authors.affiliation: Department of Pediatrics, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Nishi
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Shiraishi
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto-shi, Kyoto, 606-8501, Japan.
authors.forename: Hiroo
authors.initials: H
authors.lastname: Ueno
authors.affiliation: Department of Pediatrics, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori, 036-8562, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Toki
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Chiba
authors.affiliation: Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: Department of Pediatrics, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Muramatsu
authors.affiliation: Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Hara
authors.affiliation: Department of Transfusion Medicine and Cell Processing, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kanno
authors.affiliation: Department of Pediatrics, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Kojima
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan.|Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyano
authors.affiliation: Department of Pediatrics, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori, 036-8562, Japan.
authors.forename: Etsuro
authors.initials: E
authors.lastname: Ito
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto-shi, Kyoto, 606-8501, Japan.
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
authors.affiliation: Department of Pediatrics, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-kogushi, Ube, Yamaguchi, 755-8505, Japan. ohgas@pediatr.med.kyushu-u.ac.jp.|Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. ohgas@pediatr.med.kyushu-u.ac.jp.
authors.forename: Shouichi
authors.initials: S
authors.lastname: Ohga
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics; D000328:Adult; D029503:Anemia, Diamond-Blackfan / Q000175:diagnosis* / Q000235:genetics; D002675:Child, Preschool; D059472:Exome / Q000235:genetics*; D019066:Facies; D005190:Family; D005260:Female; D006801:Humans; D008297:Male; D009133:Muscular Atrophy / Q000235:genetics; D010375:Pedigree; D012269:Ribosomal Proteins / Q000235:genetics; D017422:Sequence Analysis, DNA
chemical_list: D012269:Ribosomal Proteins; C027624:ribosomal protein L11; C040343:ribosomal protein S19; C037442:ribosomal protein S7
keywords: Diamond–Blackfan anemia; Inherited bone marrow failure syndrome; Ribosomal protein; Whole-exome sequencing