Novel compound heterozygous DNA ligase IV mutations in an adolescent with a slowly-progressing radiosensitive-severe combined immunodeficiency

Shinobu Tamura; Kohei Higuchi; Masaharu Tamaki; Chizuko Inoue; Ryoko Awazawa; Noriko Mitsuki; Yuka Nakazawa; Hiroyuki Mishima; Kenzo Takahashi; Osamu Kondo; Kohsuke Imai; Tomohiro Morio; Osamu Ohara; Tomoo Ogi; Fukumi Furukawa; Masami Inoue; Koh-ichiro Yoshiura; Nobuo Kanazawa

doi:10.1016/j.clim.2015.07.004

Novel compound heterozygous DNA ligase IV mutations in an adolescent with a slowly-progressing radiosensitive-severe combined immunodeficiency

Clin Immunol. 2015 Oct;160(2):255-60. doi: 10.1016/j.clim.2015.07.004. Epub 2015 Jul 11.

Authors

Shinobu Tamura¹, Kohei Higuchi², Masaharu Tamaki¹, Chizuko Inoue³, Ryoko Awazawa⁴, Noriko Mitsuki⁵, Yuka Nakazawa⁶, Hiroyuki Mishima⁷, Kenzo Takahashi⁴, Osamu Kondo², Kohsuke Imai⁵, Tomohiro Morio⁵, Osamu Ohara⁸, Tomoo Ogi⁶, Fukumi Furukawa⁹, Masami Inoue², Koh-ichiro Yoshiura⁷, Nobuo Kanazawa¹⁰

Affiliations

¹ Department of Hematology and Oncology, Kinan Hospital, Wakayama, Japan.
² Department of Hematology and Oncology, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan.
³ Sarashi Clinic, Wakayama, Japan.
⁴ Department of Dermatology, University of the Ryukyus, Okinawa, Japan.
⁵ Department of Pediatrics, Tokyo Medical and Dental University, Tokyo, Japan.
⁶ 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.
⁷ Department of Human Genetics, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan.
⁸ Department of Technology Development, Kazusa DNA Research Institute, Kisarazu, Japan.
⁹ Department of Dermatology, Wakayama Medical University, Wakayama, Japan.
¹⁰ Department of Dermatology, Wakayama Medical University, Wakayama, Japan. Electronic address: nkanazaw@wakayama-med.ac.jp.

PMID: 26172957
DOI: 10.1016/j.clim.2015.07.004

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.

Keywords: DNA ligase IV; Hematopoietic stem cell transplantation; LIG4 syndrome; Severe combined immunodeficiency; TREC/KREC; Whole exome sequencing.

Publication types

Case Reports
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Craniofacial Abnormalities / genetics*
DNA Ligase ATP
DNA Ligases / genetics*
Growth Disorders / genetics*
Humans
Immunologic Deficiency Syndromes / genetics*
Male
Microcephaly / genetics*
Pancytopenia / genetics*
Severe Combined Immunodeficiency / genetics*

Substances

LIG4 protein, human
DNA Ligases
DNA Ligase ATP

Supplementary concepts

LIG4 Syndrome
Severe combined immunodeficiency with sensitivity to ionizing radiation