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Novel Combined Immune Deficiency and Radiation Sensitivity Blended Phenotype in an Adult with Biallelic Variations in ZAP70 and RNF168
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 phenoty...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5445153/ https://www.ncbi.nlm.nih.gov/pubmed/28603521 http://dx.doi.org/10.3389/fimmu.2017.00576 |
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author | Chinn, Ivan K. Sanders, Robert P. Stray-Pedersen, Asbjørg Coban-Akdemir, Zeynep H. Kim, Vy Hong-Diep Dadi, Harjit Roifman, Chaim M. Quigg, Troy Lupski, James R. Orange, Jordan S. Hanson, I. Celine |
author_facet | Chinn, Ivan K. Sanders, Robert P. Stray-Pedersen, Asbjørg Coban-Akdemir, Zeynep H. Kim, Vy Hong-Diep Dadi, Harjit Roifman, Chaim M. Quigg, Troy Lupski, James R. Orange, Jordan S. Hanson, I. Celine |
author_sort | Chinn, Ivan K. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5445153 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-54451532017-06-09 Novel Combined Immune Deficiency and Radiation Sensitivity Blended Phenotype in an Adult with Biallelic Variations in ZAP70 and RNF168 Chinn, Ivan K. Sanders, Robert P. Stray-Pedersen, Asbjørg Coban-Akdemir, Zeynep H. Kim, Vy Hong-Diep Dadi, Harjit Roifman, Chaim M. Quigg, Troy Lupski, James R. Orange, Jordan S. Hanson, I. Celine Front Immunol Immunology 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. Frontiers Media S.A. 2017-05-26 /pmc/articles/PMC5445153/ /pubmed/28603521 http://dx.doi.org/10.3389/fimmu.2017.00576 Text en Copyright © 2017 Chinn, Sanders, Stray-Pedersen, Coban-Akdemir, Kim, Dadi, Roifman, Quigg, Lupski, Orange and Hanson. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Chinn, Ivan K. Sanders, Robert P. Stray-Pedersen, Asbjørg Coban-Akdemir, Zeynep H. Kim, Vy Hong-Diep Dadi, Harjit Roifman, Chaim M. Quigg, Troy Lupski, James R. Orange, Jordan S. Hanson, I. Celine Novel Combined Immune Deficiency and Radiation Sensitivity Blended Phenotype in an Adult with Biallelic Variations in ZAP70 and RNF168 |
title | Novel Combined Immune Deficiency and Radiation Sensitivity Blended Phenotype in an Adult with Biallelic Variations in ZAP70 and RNF168 |
title_full | Novel Combined Immune Deficiency and Radiation Sensitivity Blended Phenotype in an Adult with Biallelic Variations in ZAP70 and RNF168 |
title_fullStr | Novel Combined Immune Deficiency and Radiation Sensitivity Blended Phenotype in an Adult with Biallelic Variations in ZAP70 and RNF168 |
title_full_unstemmed | Novel Combined Immune Deficiency and Radiation Sensitivity Blended Phenotype in an Adult with Biallelic Variations in ZAP70 and RNF168 |
title_short | Novel Combined Immune Deficiency and Radiation Sensitivity Blended Phenotype in an Adult with Biallelic Variations in ZAP70 and RNF168 |
title_sort | novel combined immune deficiency and radiation sensitivity blended phenotype in an adult with biallelic variations in zap70 and rnf168 |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5445153/ https://www.ncbi.nlm.nih.gov/pubmed/28603521 http://dx.doi.org/10.3389/fimmu.2017.00576 |
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