CTLA-4 Insufficiency due to a Novel <b><i>CTLA</i></b>-<b><i>4</i></b> Deletion, Identified through Copy Number Variation Analysis

Abstract

<b><i>Background:</i></b> 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 (<i>CTLA</i>-<i>4</i>) 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. <b><i>Objectives:</i></b> 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. <b><i>Methods:</i></b> Analysis of copy number variants (CNVs) was applied on short-read NGS data. <b><i>Results:</i></b> We identified a novel monoallelic deletion-insertion variant in <i>CTLA</i>-<i>4</i> (c.445_568-544delinsTTTGCGATTG) resulting in familial autoimmunity. This is the second larger scale variant in <i>CTLA-4</i>, which despite consistently reduced expression of CTLA-4 displayed variable expressivity, ranging from typical juvenile idiopathic arthritis to common variable immunodeficiency-like immunodeficiency. <b><i>Conclusions:</i></b> Our report suggests the significance of integration of CNV analysis in routine evaluation of NGS, which may increase its diagnostic yield in IEI.