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

- An adolescent case with intractable warts and progressing pancytopenia was presented.
- A severe combined immunodeficiency was revealed by quantification of TREC and KREC.
- Novel compound heterozygous LIG4 mutations were identified by whole exome sequencing.
- Diagnosis was confirmed by the analysis of DNA double-strand break repair kinetics.
- Hematopoietic stem cell transplantation from haploidentical mother was unsuccessful.

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.