**1. Introduction**

The 22q11.2 genomic region is prone to meiotic errors due to the presence of several large blocks of low-copy repeats (LCRs) [1,2]. 22q11.2 deletion is causative of DiGeorge syndrome (DGS) and other clinical conditions, previously described separately, such as velocardiofacial syndrome (MIM #192430), conotruncal anomaly face syndrome (MIM #217095) (or Takao syndrome), (CTAFS), Opitz G/BBB syndrome (MIM #145410), and Cayler cardiofacial syndromes. All these conditions are now collected under the definition of "22q11.2 deletion syndrome" (22q11.2DS) according to the common genetic etiology [3]. 22q11.2DS has an estimated incidence of 1:4000 live births, with approximately 80–90% of cases presenting with de novo inheritance [2]. The 22q11.2 typical deleted region is approximately 3 Mb in size and harbors more than 40 protein-coding genes, seven microRNAs (miRNAs), and ten non-coding RNAs (according to build GRCh37). Different sets of genes are involved, such as *TBX1*, *HIRA*, and *COMT* [3], showing the great phenotypic variability that makes this pathology a classic example of a syndrome with variable expressivity and incomplete penetrance. The clinical phenotype is mainly characterized by congenital

**Citation:** Alberio, A.M.Q.; Legitimo, A.; Bertini, V.; Baroncelli, G.I.; Costagliola, G.; Valetto, A.; Consolini, R. Clinical, Immunological, and Genetic Findings in a Cohort of Patients with the DiGeorge Phenotype without 22q11.2 Deletion. *J. Clin. Med.* **2022**, *11*, 2025. https:// doi.org/10.3390/jcm11072025

Academic Editor: Takao Fujisawa

Received: 26 February 2022 Accepted: 31 March 2022 Published: 5 April 2022

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heart disease (CHD), palatal and craniofacial abnormalities, hypoparathyroidism, immune deficiencies or autoimmune diseases (related to thymic a/hypoplasia), and neurocognitive impairment [4,5]. The severity of symptoms is also variable, ranging from quite severe to near-normal life conditions [6]. After the introduction of array comparative genomic hybridization (CGH) technology, further copy number variations (CNVs) have been identified, which are associated with clinical pictures resembling 22q11.2DS [7–10]. However, in 6% to 17% of patients, the identification of a genetic cause remains unknown, with serious consequences for their therapeutic management.

In this paper, we describe the clinical picture, the immunological abnormalities, and the genomic alterations of a cohort of patients with highly evocative DGS phenotype without 22q11.2 deletion. This may contribute to the diagnosis of patients presenting with primary immunodeficiency and developmental defects of unknown etiology.
