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CTLA-4 Insufficiency due to a Novel CTLA-4 Deletion, Identified through Copy Number Variation Analysis
BACKGROUND: The diagnostic yield of next-generation sequencing (NGS) technologies in the diagnosis of monogenic inborn errors of immunity (IEI) remains limited, rarely exceeding 30%. Monoallelic pathogenic germline variants in cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) result in variable i...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
S. Karger AG
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9808738/ https://www.ncbi.nlm.nih.gov/pubmed/36273440 http://dx.doi.org/10.1159/000527051 |
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author | Olfe, Lisa von Hardenberg, Sandra Hofmann, Winfried Auber, Bernd Baumann, Ulrich Beier, Rita Adriawan, Ignatius Ryan Atschekzei, Faranaz Witte, Torsten Sogkas, Georgios |
author_facet | Olfe, Lisa von Hardenberg, Sandra Hofmann, Winfried Auber, Bernd Baumann, Ulrich Beier, Rita Adriawan, Ignatius Ryan Atschekzei, Faranaz Witte, Torsten Sogkas, Georgios |
author_sort | Olfe, Lisa |
collection | PubMed |
description | BACKGROUND: The diagnostic yield of next-generation sequencing (NGS) technologies in the diagnosis of monogenic inborn errors of immunity (IEI) remains limited, rarely exceeding 30%. Monoallelic pathogenic germline variants in cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) result in variable immunodeficiency and immune dysregulation. The genetic diagnosis of CTLA-4 insufficiency can affect follow-up procedures and may lead to consideration of treatment with CTLA-4-Ig. OBJECTIVES: The aim of the study was to identify the genetic cause of familial immunodeficiency and immune dysregulation in cases where single nucleotide variant analysis of short-read NGS data yielded no diagnostic result. METHODS: Analysis of copy number variants (CNVs) was applied on short-read NGS data. RESULTS: We identified a novel monoallelic deletion-insertion variant in CTLA-4 (c.445_568-544delinsTTTGCGATTG) resulting in familial autoimmunity. This is the second larger scale variant in CTLA-4, which despite consistently reduced expression of CTLA-4 displayed variable expressivity, ranging from typical juvenile idiopathic arthritis to common variable immunodeficiency-like immunodeficiency. CONCLUSIONS: Our report suggests the significance of integration of CNV analysis in routine evaluation of NGS, which may increase its diagnostic yield in IEI. |
format | Online Article Text |
id | pubmed-9808738 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | S. Karger AG |
record_format | MEDLINE/PubMed |
spelling | pubmed-98087382023-01-04 CTLA-4 Insufficiency due to a Novel CTLA-4 Deletion, Identified through Copy Number Variation Analysis Olfe, Lisa von Hardenberg, Sandra Hofmann, Winfried Auber, Bernd Baumann, Ulrich Beier, Rita Adriawan, Ignatius Ryan Atschekzei, Faranaz Witte, Torsten Sogkas, Georgios Int Arch Allergy Immunol Experimental Immunology − Brief Report BACKGROUND: The diagnostic yield of next-generation sequencing (NGS) technologies in the diagnosis of monogenic inborn errors of immunity (IEI) remains limited, rarely exceeding 30%. Monoallelic pathogenic germline variants in cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) result in variable immunodeficiency and immune dysregulation. The genetic diagnosis of CTLA-4 insufficiency can affect follow-up procedures and may lead to consideration of treatment with CTLA-4-Ig. OBJECTIVES: The aim of the study was to identify the genetic cause of familial immunodeficiency and immune dysregulation in cases where single nucleotide variant analysis of short-read NGS data yielded no diagnostic result. METHODS: Analysis of copy number variants (CNVs) was applied on short-read NGS data. RESULTS: We identified a novel monoallelic deletion-insertion variant in CTLA-4 (c.445_568-544delinsTTTGCGATTG) resulting in familial autoimmunity. This is the second larger scale variant in CTLA-4, which despite consistently reduced expression of CTLA-4 displayed variable expressivity, ranging from typical juvenile idiopathic arthritis to common variable immunodeficiency-like immunodeficiency. CONCLUSIONS: Our report suggests the significance of integration of CNV analysis in routine evaluation of NGS, which may increase its diagnostic yield in IEI. S. Karger AG 2022-10-21 /pmc/articles/PMC9808738/ /pubmed/36273440 http://dx.doi.org/10.1159/000527051 Text en Copyright © 2022 by The Author(s). Published by S. Karger AG, Basel https://creativecommons.org/licenses/by-nc/4.0/This article is licensed under the Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC). Usage and distribution for commercial purposes requires written permission. |
spellingShingle | Experimental Immunology − Brief Report Olfe, Lisa von Hardenberg, Sandra Hofmann, Winfried Auber, Bernd Baumann, Ulrich Beier, Rita Adriawan, Ignatius Ryan Atschekzei, Faranaz Witte, Torsten Sogkas, Georgios CTLA-4 Insufficiency due to a Novel CTLA-4 Deletion, Identified through Copy Number Variation Analysis |
title | CTLA-4 Insufficiency due to a Novel CTLA-4 Deletion, Identified through Copy Number Variation Analysis |
title_full | CTLA-4 Insufficiency due to a Novel CTLA-4 Deletion, Identified through Copy Number Variation Analysis |
title_fullStr | CTLA-4 Insufficiency due to a Novel CTLA-4 Deletion, Identified through Copy Number Variation Analysis |
title_full_unstemmed | CTLA-4 Insufficiency due to a Novel CTLA-4 Deletion, Identified through Copy Number Variation Analysis |
title_short | CTLA-4 Insufficiency due to a Novel CTLA-4 Deletion, Identified through Copy Number Variation Analysis |
title_sort | ctla-4 insufficiency due to a novel ctla-4 deletion, identified through copy number variation analysis |
topic | Experimental Immunology − Brief Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9808738/ https://www.ncbi.nlm.nih.gov/pubmed/36273440 http://dx.doi.org/10.1159/000527051 |
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