**1. Introduction**

Common variable immunodeficiency (CVID) is the most prevalent symptomatic primary immunodeficiency in the Caucasian population [1]. It comprises a heterogeneous group of diseases whose common characteristic is the inability to produce antibodies due to a defect in the development or function of B lymphocytes. The age of onset is very heterogeneous, ranging from childhood to the second and third decade of life [2]. Clinical and immunological manifestations vary between affected individuals, but the principal manifestations of CVID are increased susceptibility to recurrent infections, mainly of the respiratory tract, hypogammaglobulinemia, and low antibody response to vaccine antigens, which cannot be explained by previous exposures, treatments, or infections. In addition,

**Citation:** Díaz-Alberola, I.; Espuch-Oliver, A.; García-Aznar, J.M.; Ganoza-Gallardo, C.;

Aguilera-Franco, M.; Sampedro, A.; Jiménez, P.; López-Nevot, M.Á. Common Variable Immunodeficiency Associated with a De Novo *IKZF1* Variant and a Low Humoral Immune Response to the SARS-CoV-2 Vaccine. *J. Clin. Med.* **2022**, *11*, 2303. https:// doi.org/10.3390/jcm11092303

Academic Editor: Rita Consolini

Received: 30 March 2022 Accepted: 18 April 2022 Published: 20 April 2022

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**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

some patients also have autoimmune diseases, alteration in lymphocyte populations, or cancer [3].

Currently, its diagnosis is complicated by the lack of standardized diagnostic criteria due to its great clinical and analytical heterogeneity, low awareness on the part of clinicians, and the similarity of the disease with other immune disorders. Even so, several guidelines have emerged that help in the diagnosis of CVID, including the International Consensus Document (ICON) guidelines from 2015 [4] and the European Society for Immunodeficiencies (ESID) Registry Working Definitions for the Clinical Diagnosis of Inborn Errors of Immunity from 2019, with several updates [5]. In the laboratory, determinations of serum levels of immunoglobulin (Ig)G, IgA, and IgM antibodies, the study of lymphocyte populations, and B-cell immunophenotyping are useful in evaluating the patient's condition [2].

It is well known that CVID patients present suboptimal responses to vaccines, some of them being potentially dangerous and even contraindicated (such as live vaccines). In fact, the current ESID guideline for CVID includes a poor antibody response to vaccines as a criterion [5], although several studies show that the response to vaccines is not uniform in patients with mild hypogammaglobulinemia [6]. Very few studies exist on humoral and cellular responses to COVID-19 vaccines in patients with CVID [7–9]. This is due, on the one hand, to the fact that SARS-CoV-2 infection is very recent and, on the other hand, because the response to immunization depends on the type of vaccine, the patient's immune defect, and the type of antigen studied [7]. Looking at the humoral and cellular response to other vaccines not related to SARS-CoV-2 in patients with CVID, we find studies that suggest that these patients have a lower humoral response to the vaccines compared to the control group while maintaining a good cellular response [10,11].

Regarding the etiology, most cases of CVID are idiopathic, but to date, between 10 and 35% of CVID patients present monogenic defects, predominantly autosomal dominant with incomplete penetrance or with late onset of symptoms. The development of highthroughput sequencing technologies has allowed the identification of several mutations in genes encoding proteins essential for immune function that could be involved in the development of CVID. Thus, panels of primary immunodeficiency-associated genes have been created, allowing rapid screening of identified mutations using genetic techniques. Some of the CVID-associated genes include: *ICOS* (OMIM: #604558), *CD19* (OMIM: #107265), *CD81* (OMIM: #186845), *MS4A1* (OMIM: #112210), *CR2* (OMIM: #120650), *TNFSF12* (OMIM: #602695), *CTLA4* (OMIM: #123890), *LRBA* (OMIM: #606453) *TNFRSF13B* (OMIM: #60907), *TNFRSF13C* (OMIM#606269), *NFKB1* (OMIM: #164011), *NFKB2* (OMIM: #164012), *IL21* (OMIM: #605384), *IRF2BP2* (OMIM: #615332), *PIK3CD* (OMIM: #602839), *STAT3* (OMIM: #102582), and others [3]. Alteration in any of these genes can cause perturbations of specific immune pathways, resulting in "unique phenotypes" that can aid in the diagnosis of CVID [2]. In fact, in the 2019 update of the classification of primary immunodeficiencies (PID) by the expert committee of the International Union of Immunological Societies (IUIS), CVID is included within the group of PID with a predominance of antibody deficiencies. Furthermore, information regarding clinical, analytical, and molecular tests is provided and that could help clinicians in the diagnosis and management of these patients and their relatives [12].

Here, we report a case of a 46-year-old patient diagnosed with CVID in current treatment with intravenous immunoglobulins and clinically stable. Because of his negative family history of primary immunodeficiencies and in the context of the SARS-CoV-2 pandemic, we reassessed the patient immunologically, employing an NGS analysis to try to clarify the genetic cause of his disease, and analyzed his serological and cellular response to the COVID-19 vaccine. We identified a heterozygous R162Q variant of the *IKZF1* gene in our patient that was not present in his parents. This variant was previously described as pathogenic, associated with CVID type 13 following an autosomal dominant inheritance and high penetrance. Therefore, we present for the first time a case of CVID associated with a de novo heterozygous R162Q variant in the *IKZF1* gene in a patient with a low antibody immune response and a positive cellular response to the complete COVID-19 vaccination program.
