International archives of allergy and immunology · 2022
CTLA-4 Insufficiency due to a Novel CTLA-4 Deletion, Identified through Copy Number Variation Analysis.
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Olfe Lisa, von Hardenberg Sandra, Hofmann Winfried, Auber Bernd, Baumann Ulrich, Beier Rita, Adriawan Ignatius Ryan, Atschekzei Faranaz, Witte Torsten, Sogkas Georgios
Аннотация
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.
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.