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

TitleNovel Combined Immune Deficiency and Radiation Sensitivity Blended Phenotype in an Adult with Biallelic Variations in and .
Publication TypeJournal Article
Year of Publication2017
AuthorsChinn, IK, Sanders, RP, Stray-Pedersen, A, Coban-Akdemir, ZH, Kim, VHong-Diep, Dadi, H, Roifman, CM, Quigg, T, Lupski, JR, Orange, JS, I Hanson, C
JournalFront Immunol
Date Published2017

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 . Biallelic mutations in 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 variant of unknown significance. 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.

Alternate JournalFront Immunol
PubMed ID28603521
PubMed Central IDPMC5445153
Grant ListR01 AI067946 / AI / NIAID NIH HHS / United States
R01 AI120989 / AI / NIAID NIH HHS / United States
R01 NS058529 / NS / NINDS NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States