title: Novel compound heterozygous DNA ligase IV mutations in an adolescent with a slowly-progressing radiosensitive-severe combined immunodeficiency.
abstract: We herein describe a case of a 17-year-old boy with intractable common warts, short stature, microcephaly and slowly-progressing pancytopenia. Simultaneous quantification of T-cell receptor recombination excision circles (TREC) and immunoglobulin κ-deleting recombination excision circles (KREC) suggested very poor generation of both T-cells and B-cells. By whole exome sequencing, novel compound heterozygous mutations were identified in the patient's DNA ligase IV (LIG4) gene. The diagnosis of LIG4 syndrome was confirmed by delayed DNA double-strand break repair kinetics in γ-irradiated fibroblasts from the patient and their restoration by an introduction of wild-type LIG4. Although the patient received allogeneic hematopoietic stem cell transplantation from his haploidentical mother, he unfortunately expired due to an insufficiently reconstructed immune system. An earlier definitive diagnosis using TREC/KREC quantification and whole exome sequencing would thereby allow earlier intervention, which would be essential for improving long-term survival in similar cases with slowly-progressing LIG4 syndrome masked in adolescents.
authors.affiliation: Department of Hematology and Oncology, Kinan Hospital, Wakayama, Japan.
authors.forename: Shinobu
authors.initials: S
authors.lastname: Tamura
authors.affiliation: Department of Hematology and Oncology, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Higuchi
authors.affiliation: Department of Hematology and Oncology, Kinan Hospital, Wakayama, Japan.
authors.forename: Masaharu
authors.initials: M
authors.lastname: Tamaki
authors.affiliation: Sarashi Clinic, Wakayama, Japan.
authors.forename: Chizuko
authors.initials: C
authors.lastname: Inoue
authors.affiliation: Department of Dermatology, University of the Ryukyus, Okinawa, Japan.
authors.forename: Ryoko
authors.initials: R
authors.lastname: Awazawa
authors.affiliation: Department of Pediatrics, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Mitsuki
authors.affiliation: Nagasaki University Research Centre for Genomic Instability and Carcinogenesis, Nagasaki University, Nagasaki, Japan; Department of Genome Repair, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Nakazawa
authors.affiliation: Department of Human Genetics, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mishima
authors.affiliation: Department of Dermatology, University of the Ryukyus, Okinawa, Japan.
authors.forename: Kenzo
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: Department of Hematology and Oncology, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Kondo
authors.affiliation: Department of Pediatrics, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Imai
authors.affiliation: Department of Pediatrics, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Morio
authors.affiliation: Department of Technology Development, Kazusa DNA Research Institute, Kisarazu, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Ohara
authors.affiliation: Nagasaki University Research Centre for Genomic Instability and Carcinogenesis, Nagasaki University, Nagasaki, Japan; Department of Genome Repair, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
authors.forename: Tomoo
authors.initials: T
authors.lastname: Ogi
authors.affiliation: Department of Dermatology, Wakayama Medical University, Wakayama, Japan.
authors.forename: Fukumi
authors.initials: F
authors.lastname: Furukawa
authors.affiliation: Department of Hematology and Oncology, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Inoue
authors.affiliation: Department of Human Genetics, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan.
authors.forename: Koh-ichiro
authors.initials: K
authors.lastname: Yoshiura
authors.affiliation: Department of Dermatology, Wakayama Medical University, Wakayama, Japan. Electronic address: nkanazaw@wakayama-med.ac.jp.
authors.forename: Nobuo
authors.initials: N
authors.lastname: Kanazawa
mesh_terms: D000293:Adolescent; D019465:Craniofacial Abnormalities / Q000235:genetics*; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000235:genetics*; D006130:Growth Disorders / Q000235:genetics*; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics*; D008297:Male; D008831:Microcephaly / Q000235:genetics*; D010198:Pancytopenia / Q000235:genetics*; D016511:Severe Combined Immunodeficiency / Q000235:genetics*
chemical_list: C000607893:LIG4 protein, human; D011088:DNA Ligases; D000072481:DNA Ligase ATP
keywords: DNA ligase IV; Hematopoietic stem cell transplantation; LIG4 syndrome; Severe combined immunodeficiency; TREC/KREC; Whole exome sequencing