Sonoko Sakata, Japan
Hiroshima University Graduate School of Biomedical and Health Sciences PediatricsPresenter of 1 Presentation
THE FIRST INTRONIC MUTATIONS WHICH CAUSED AUTOSOMAL RECESSIVE COMPLETE STAT1 DEFICIENCY
Abstract
Background and Aims
Autosomal recessive (AR) complete STAT1 deficiency is a rare primary immunodeficiency which causes life-threatening mycobacterial and viral infections. Prognosis of the patients are poor. Therefore, early diagnosis and appropriate therapeutic intervention are required.
Methods
Biallelic intronic STAT1 mutations were identified by whole exome sequencing (WES) and confirmed by immunoblot and flow cytometry.
Results
The patient is a 5-years-old Japanese boy who was born to nonconsanguineous parents. He received BCG vaccination at 9 months. Two months later, he developed disseminated BCG infections. Candidate gene approach for the suspicion of MSMD identified a heterozygous splice site mutation, 128+2 T>G, in STAT1 that was inherited from healthy father. Therefore, the antimycobacterial treatment was continued without confirming genetic etiology. After this episode, he repeated severe viral infections and developed vaccine induced varicella. He experienced M. malmoense positive multifocal osteomyelitis and mediastinal lymphadenitis without granuloma formation at the age of 4. Finally, an intronic mutation, 542-8A>G, in STAT1, which was inherited from healthy mother, was identified by WES at the age of 5. The STAT1 protein expression abolished in patient’s peripheral blood mononuclear cells. He is currently planned for hematopoietic stem cell transplantation.
Conclusions
The mutations identified in the current study were the first intronic mutations which caused AR complete STAT1 deficiency. Identification of intronic mutations by genomic study is sometimes challenging. Indeed, it took nearly four years to confirm molecular cause in the current study. The introduction of systemic gene expression analysis may help to improve diagnostic yield of undiagnosed patients.