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Front Immunol. 2017 May 26;8:576. doi: 10.3389/fimmu.2017.00576. eCollection 2017.

Novel Combined Immune Deficiency and Radiation Sensitivity Blended Phenotype in an Adult with Biallelic Variations in ZAP70 and RNF168.

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Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
Section of Immunology, Allergy, and Rheumatology, Texas Children's Hospital, Houston, TX, USA.
Center for Human Immunobiology, Texas Children's Hospital, Houston, TX, USA.
Texas Transplant Institute, Methodist Hospital, San Antonio, TX, USA.
Norwegian National Unit for Newborn Screening, Department of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway.
Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Baylor-Hopkins Center for Mendelian Genomics, Baylor College of Medicine, Houston, TX, USA.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Division of Immunology and Allergy, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
Canadian Centre for Primary Immunodeficiency, The Jeffrey Model Research Laboratory for the Diagnosis of Primary Immunodeficiency, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.


With the advent of high-throughput genomic sequencing techniques, novel genetic etiologies are being uncovered for previously unexplained Mendelian phenotypes, and the underlying genetic architecture of disease is being unraveled. Although most of these "mendelizing" disease traits represent phenotypes caused by single-gene defects, a percentage of patients have blended phenotypes caused by pathogenic variants in multiple genes. We describe an adult patient with susceptibility to bacterial, herpesviral, and fungal infections. Immunologic defects included CD8+ T cell lymphopenia, decreased T cell proliferative responses to mitogens, hypogammaglobulinemia, and radiation sensitivity. Whole-exome sequencing revealed compound heterozygous variants in ZAP70. Biallelic mutations in ZAP70 are known to produce a spectrum of immune deficiency that includes the T cell abnormalities observed in this patient. Analyses for variants in genes associated with radiation sensitivity identified the presence of a homozygous RNF168 variant of unknown significance. RNF168 deficiency causes radiosensitivity, immunodeficiency, dysmorphic features, and learning difficulties syndrome and may account for the radiation sensitivity. Thus, the patient was found to have a novel blended phenotype associated with multilocus genomic variation: i.e., separate and distinct genetic defects. These findings further illustrate the clinical utility of applying genomic testing in patients with primary immunodeficiency diseases.


RNF168; ZAP70; and learning difficulties syndrome; blended phenotype; dysmorphic features; immunodeficiency; primary immunodeficiency; radiosensitivity; whole-exome sequencing

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