DiGeorge syndrome (DGS) is a primary immunodeficiency characterized by various degrees of T-cell deficiency. In partial DGS (pDGS), other risk factors could predispose to recurrent infections, autoimmunity, and allergy. The aim of this study was to assess the effect of different factors in the development of infections, autoimmunity, and/or allergy in patients with pDGS. We studied 467 pDGS patients in follow-up at Great Ormond Street Hospital. Using a multivariate approach, we observed that palatal anomalies represent a risk factor for the development of recurrent otitis media with effusion. Gastroesophageal reflux/dysphagia and asthma/rhinitis represent a risk factor for the development of recurrent upper respiratory tract infections. Allergy and autoimmunity were associated with persistently low immunoglobulin M levels and lymphopenia, respectively. Patients with autoimmunity showed lower levels of CD3+, CD3+CD4+, and naïve CD4+CD45RA+CD27+ T lymphocytes compared with pDGS patients without autoimmunity. We also observed that the physiological age-related decline of the T-cell number was slower in pDGS patients compared with age-matched controls. The age-related recovery of the T-cell number depended on a homeostatic peripheral proliferation of T cells, as suggested by an accelerated decline of the naïve T lymphocytes in pDGS as well as a more skewed T-cell repertoire in older pDGS patients. These evidences suggest that premature CD4+ T-cell aging and lymphopenia induced spontaneous peripheral T-cell proliferation might contribute to the pathogenesis of autoimmunity in patients with pDGS. Infections in these patients represent, in most of the cases, a complication of anatomical or gastroenterological anomalies rather than a feature of the underlying immunodeficiency.

The Wiskott–Aldrich syndrome (WAS) is due to mutations of the WAS gene encoding for the cytoskeletal WAS protein, leading to abnormal downstream signaling from the T cell and B cell antigen receptors (TCR and BCR). We hypothesized that the impaired signaling through the TCR and BCR in WAS would subsequently lead to aberrations in the immune repertoire of WAS patients. Using next generation sequencing (NGS), the T cell receptor β and B cell immunoglobulin heavy chain (IGH) repertoires of eight patients with WAS and six controls were sequenced. Clonal expansions were identified within memory CD4+ cells as well as in total, naïve and memory CD8+ cells from WAS patients. In the B cell compartment, WAS patient IGH repertoires were also clonally expanded and showed skewed usage of IGHV and IGHJ genes, and increased usage of IGHG constant genes, compared with controls. To our knowledge, this is the first study that demonstrates significant abnormalities of the immune repertoire in WAS patients using NGS.

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Autoimmune lymphoproliferative syndrome (ALPS) is a rare immunodeficiency caused by mutations in genes affecting the extrinsic apoptotic pathway (FAS, FASL, CASP10). This study evaluated the clinical manifestations, laboratory findings and molecular genetic results of 215 patients referred as possible ALPS. Double negative T-cell (DNT) percentage and in vitro apoptosis functional tests were evaluated by FACS; interleukin 10 and 18 (IL-10, -18) and soluble FAS ligand (sFASL) were measured by ELISA. Genetic analysis was performed by next generation sequencing. Clinical background data were collected from patients' records. Patients were categorised into definite, suspected and unlikely ALPS, and laboratory parameters were compared among these groups. From 215 patients, 38 met the criteria for definite ALPS and 17 for suspected ALPS. The definite and suspected ALPS patient population showed higher DNT than unlikely ALPS and had higher rates of lymphoproliferation. Definite ALPS patients had a significantly more abnormal in vitro apoptosis function with lower annexin than patients with suspected ALPS (P=0.002) and patients not meeting the ALPS criteria (P<0.001). The combination of elevated DNT and an abnormal in vitro apoptosis functional test was the most useful to identify all types of ALPS patients; the combination of abnormal in vitro apoptosis functional test and elevated sFASL was a predictive marker for ALPS-FAS group identification. Lymphoproliferation, apoptosis functional test and DNT are the most sensitive markers; elevated IL-10 and IL-18 are additional indicators for ALPS. The combination of elevated sFASL and an abnormal apoptosis function was the most valuable prognosticator for patients with FAS mutations.

Primary ciliary dyskinesia (PCD) is a rare genetic disorder of motile cilia dysfunction generally inherited as an autosomal recessive disease. Genetic testing is increasingly considered an early step in the PCD diagnostic workflow. We used targeted panel next‐generation sequencing (NGS) for genetic screening of 33 Egyptian families with clinically highly suspected PCD. All variants prioritized were Sanger confirmed in the affected individuals and correctly segregated within the family. Targeted NGS yielded a high diagnostic output (70%) with biallelic mutations identified in known PCD genes. Mutations were identified in 13 genes overall, with CCDC40 and CCDC39 the most frequently mutated genes among Egyptian patients. Most identified mutations were predicted null effect variants (79%) and not reported before (85%). This study reveals that the genetic landscape of PCD among Egyptians is highly heterogeneous, indicating that a targeted NGS approach covering multiple genes will provide a superior diagnostic yield compared to Sanger sequencing for genetic diagnosis. The high diagnostic output achieved here highlights the potential of placing genetic testing early within the diagnostic workflow for PCD, in particular in developing countries where other diagnostic tests can be less available.

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Background and aims The African Society for Immunodeficiency (ASID), looked to form concise region-friendly guidelines for the clinical diagnosis and management of Inborn Errors of Immunity (IEI). The main objective was to develop these guidelines to accommodate for the locally prevalent endemic diseases and the disparity of resources within the continent. Furthermore, the society aimed to publish these guidelines to increase awareness among African physicians, and facilitate patient capture, diagnosis and initial management. Methods The African Society for Immunodeficiency convened an African IEI guidelines taskforce, which developed an initial standard operating procedure. This document entailed the main list of IEI in need of urgent guidelines formulation, validation and review processes. The first group of diseases chosen to start the formulation of the guidelines were diseases of immune dysregulation. Simultaneously, this was associated with assigning a local African IEI guidelines working party, consisting of mainly locally established experts and young doctors. Results Two pilot studies were produced for the project targeting the clinical diagnosis and management of autoimmune lymphoproliferative syndrome and Immune Dysregulation with Colitis, respectively. These guidelines will ensure better patient capture, diagnosis, and management especially given local endemic diseases and lack of resources. Moreover, it shall increase local inter-centre or regional collaboration with pioneers and experts within the field inside as well as outside the African continent.