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Methods Mol Biol. 2022;2453:169-190. doi: 10.1007/978-1-0716-2115-8_11.

ABSTRACT

Inborn errors of immunity (IEI) are genetic defects that can affect both the innate and the adaptive immune system. Patients with IEI usually present with recurrent infections, but many also suffer from immune dysregulation, autoimmunity, and malignancies.Inborn errors of the immune system can cause defects in the development and selection of the B-cell receptor (BCR ) repertoire. Patients with IEI can have a defect in one of the key processes of immune repertoire formation like V(D)J recombination, somatic hypermutation (SHM), class switch recombination (CSR), or (pre-)BCR signalling and proliferation. However, also other genetic defects can lead to quantitative and qualitative differences in the immune repertoire.In this chapter, we will give an overview of protocols that can be used to study the immune repertoire in patients with IEI, provide considerations to take into account before setting up experiments, and discuss analysis of the immune repertoire data using Antigen Receptor Galaxy (ARGalaxy).

PMID:35622327 | DOI:10.1007/978-1-0716-2115-8_11

Clin Immunol. 2022 May 22:109047. doi: 10.1016/j.clim.2022.109047. Online ahead of print.

ABSTRACT

BACKGROUND: Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract. Treatment for patients who have a monogenic cause of their IBD, often the youngest children, known as very early onset IBD (VEO-IBD), can be different from standard treatment for polygenic cases. Yet, ascertainment of these patients is difficult.

METHODS: We analyzed cases of VEO-IBD to understand the breadth of monogenic etiology and to identify clinical, laboratory, and flow cytometric correlates of this subpopulation.

RESULTS: Genetic causes of very early onset inflammatory bowel disease are highly diverse ranging from pure epithelial defects to classic T cell defects. Flow cytometry, other than testing for chronic granulomatous disease, has a low sensitivity for monogenic etiologies. Poor growth was a clinical feature associated with monogenic causality.

CONCLUSIONS: Genetic testing is, at this moment, the most robust method for the identification of monogenic cases of very early onset IBD.

PMID:35613698 | DOI:10.1016/j.clim.2022.109047

BMJ Case Rep. 2022 May 24;15(5):e248812. doi: 10.1136/bcr-2022-248812.

ABSTRACT

A patient, an adolescent male, presented to us with complaints of recurrent respiratory tract infections since childhood. Differentials considered were cystic fibrosis (CF), bronchial asthma with allergic bronchopulmonary aspergillosis (ABPA), primary ciliary dyskinesia (PCD) and primary immunodeficiency disorders. Sweat chloride test, total IgE and Aspergillus fumigatus specific serum IgE and IgG levels were normal ruling out CF and ABPA. Nasal nitric oxide (NO) screening test showed reduced NO levels, and high-speed video microscopy of nasal scrapings showed stiff beating cilia with reduced ciliary beat frequency confirming the diagnosis of PCD. Immunodeficiency workup showed reduced serum IgG, IgA and IgM, when repeated on two separate occasions when the patient was not harbouring any active infection, suggestive of pan-hypogammaglobulinaemia. Thus, a diagnosis of coexistent PCD and pan-hypogammaglobulinaemia was made. Detection of immunodeficiency disorders is important in patients with PCD as they may benefit from immunoglobulin replacement.

PMID:35609933 | DOI:10.1136/bcr-2022-248812

Orphanet J Rare Dis. 2022 May 23;17(1):210. doi: 10.1186/s13023-022-02365-y.

ABSTRACT

BACKGROUND: In order to facilitate the diagnostic process for adult patients suffering from a rare disease, the Undiagnosed Disease Program (UD-PrOZA) was founded in 2015 at the Ghent University Hospital in Belgium. In this study we report the five-year results of our multidisciplinary approach in rare disease diagnostics.

METHODS: Patients referred by a healthcare provider, in which an underlying rare disease is likely, qualify for a UD-PrOZA evaluation. UD-PrOZA uses a multidisciplinary clinical approach combined with state-of-the-art genomic technologies in close collaboration with research facilities to diagnose patients.

RESULTS: Between 2015 and 2020, 692 patients (94% adults) were referred of which 329 (48%) were accepted for evaluation. In 18% (60 of 329) of the cases a definite diagnosis was made. 88% (53 of 60) of the established diagnoses had a genetic origin. 65% (39 of 60) of the genetic diagnoses were made through whole exome sequencing (WES). The mean time interval between symptom-onset and diagnosis was 19 years. Key observations included novel genotype-phenotype correlations, new variants in known disease genes and the identification of three new disease genes. In 13% (7 of 53), identifying the molecular cause was associated with therapeutic recommendations and in 88% (53 of 60), gene specific genetic counseling was made possible. Actionable secondary findings were reported in 7% (12 of 177) of the patients in which WES was performed.

CONCLUSION: UD-PrOZA offers an innovative interdisciplinary platform to diagnose rare diseases in adults with previously unexplained medical problems and to facilitate translational research.

PMID:35606766 | DOI:10.1186/s13023-022-02365-y

Clin Endocrinol (Oxf). 2022 May 23. doi: 10.1111/cen.14782. Online ahead of print.

ABSTRACT

OBJECTIVE: Hematopoietic stem cell transplantation (HSCT) can be a curative treatment for malignant and nonmalignant diseases in children but is associated with significant late effects including growth failure. Growth hormone treatment (GHRx) is offered to improve growth, but limited data are available on its effect on adult height. We aim to evaluate the effectiveness of GHRx.

DESIGN: Single-center retrospective study.

PATIENTS: 34 patients who had received GHRx for ≥1 year were matched with two controls each, without GHRx, based on sex, indication for HSCT (malignancy, benign hematological disease or immunodeficiency), age at HSCT and conditioning with/without total body irradiation (TBI). All had reached adult height (AH).

MEASUREMENTS: The primary outcome measure was the difference between AH and predicted AH at start of GHRx or the equivalent age in controls (AH-PAH), calculated according to Bailey & Pinneau.

RESULTS: GHRx was started at age 12.0 ±2.6 years; median treatment duration was 3.8 years (range 1.7-9.2). AH-PAH SDS was significantly higher in GH treated boys (-0.5 ±0.7 SDS) than in controls (-1.5 ±1.0 SDS, p<0.001). Girls also had a higher AH-PAH after GHRx (+0.5 ±0.6 SDS) compared to controls (-0.2 SDS ±0.7, p<0.01). AH remained approximately 2 SDS below target height in treated and untreated individuals. Among GH-treated children, AH-PAH was higher in those who had received busulfan-based compared to TBI-based conditioning.

CONCLUSION: GHRx had a significant positive effect on AH compared to PAH, although AH remained far below target height. Higher AH-PAH was observed in girls and in those conditioned without TBI. This article is protected by copyright. All rights reserved.

PMID:35606687 | DOI:10.1111/cen.14782

J Clin Immunol. 2022 May 23. doi: 10.1007/s10875-022-01274-w. Online ahead of print.

ABSTRACT

The epidemiology of inborn errors of immunity (IEI) in the Republic of Ireland was first published in 2005 but has not been updated since. IEI prevalence data from Northern Ireland was last published in 2018. Using data from the United Kingdom Primary Immune Deficiency (UKPID) and European Society for Immunodeficiencies (ESID) registries, we reviewed all registered cases of IEI affecting adult patients ≥ 18 years of age from the two largest immunology specialist centres in Northern Ireland and the Republic of Ireland, respectively and calculated the combined minimum adult prevalence of IEI on the island of Ireland for the first time. We also recorded data pertaining to presenting symptoms of IEI, diagnostic delay, immunoglobulin data, and genetic testing, as well as briefly reporting data pertaining to secondary immunodeficiency in both countries. As of 1 May 2020, we identified a minimum adult IEI prevalence in Ireland of 8.85/100,000 population.

PMID:35604475 | DOI:10.1007/s10875-022-01274-w

Front Immunol. 2022 May 6;13:886117. doi: 10.3389/fimmu.2022.886117. eCollection 2022.

ABSTRACT

The transcription factor GATA2 plays a key role in the survival and self-renewal of hematopoietic stem and progenitor cells. Autosomal dominant variants in GATA2 cause a broad spectrum of heterogeneous phenotypes. Here, we present our experience with GATA2 deficiency in a retrospective multicenter analysis of computerized medical records of adult patients (age ≥18 years) treated between 2018 and 2022 at Shaare Zedek Medical Center in Jerusalem and Sheba Tel-Hashomer Medical Center in Ramat Gan, Israel. Two male and two female patients with GATA2 deficiency were identified. Three of the patients presented with symptoms in adult life and all patients were diagnosed as adults. Age at presentation was 10.5-36 years and age at diagnosis 24-47 years. Diagnosis was delayed in all patients by 1-24.5 years. The phenotypic diversity was notable. Patients presented with myelodysplastic syndrome (n=2), pulmonary alveolar proteinosis (n=1), and recurrent viral (n=1), bacterial (n=3), and mycobacterial (n=1) infections. Bone marrow biopsy revealed cytogenetic abnormalities in one patient (monosomy 7). Patients were diagnosed by exome sequencing (n=3) and Sanger sequencing of the coding exons in GATA2 (n=1). Novel heterozygous GATA2 variants (c.177C>A, p.Y59* and c.610dup, p.R204Pfs*78) were identified in two patients. Immune workup revealed B cell lymphopenia and monocytopenia in all tested patients. One patient died from overwhelming sepsis despite all patients being treated with antibiotics and anti-mycobacterials. Our cohort highlights the phenotypic diversity, late presentation, and delayed diagnosis of GATA2 deficiency. Increased awareness of this primary immune deficiency presenting in adult life is needed and should involve a high index of suspicion.

PMID:35603181 | PMC:PMC9120659 | DOI:10.3389/fimmu.2022.886117

J Allergy Clin Immunol Pract. 2022 May 19:S2213-2198(22)00490-1. doi: 10.1016/j.jaip.2022.05.004. Online ahead of print.

NO ABSTRACT

PMID:35598866 | DOI:10.1016/j.jaip.2022.05.004

J Pediatr. 2022 May 19:S0022-3476(22)00438-3. doi: 10.1016/j.jpeds.2022.05.028. Online ahead of print.

ABSTRACT

The optimal SARS-CoV-2 vaccine strategy for patients with a history of MIS-C is unclear. We performed an international survey (32 countries) and found substantial variations in vaccine policies. Respondents did not report relapses of MIS-C or other severe inflammatory side effects after SARS-CoV-2 vaccination in 273 patients with a history of MIS-C.

PMID:35598642 | DOI:10.1016/j.jpeds.2022.05.028

Brief Bioinform. 2022 May 23:bbac176. doi: 10.1093/bib/bbac176. Online ahead of print.

ABSTRACT

Distinguishing pathogenic variants from non-pathogenic ones remains a major challenge in clinical genetic testing of primary immunodeficiency (PID) patients. Most of the existing mutation pathogenicity prediction tools treat all mutations as homogeneous entities, ignoring the differences in characteristics of different genes, and use the same model for genes in different diseases. In this study, we developed a single nucleotide variant (SNV) pathogenicity prediction tool, Variant Impact Predictor for PIDs (VIPPID; https://mylab.shinyapps.io/VIPPID/), which was tailored for PIDs genes and used a specific model for each of the most prevalent PID known genes. It employed a Conditional Inference Forest model and utilized information of 85 features of SNVs and scores from 20 existing prediction tools. Evaluation of VIPPID showed that it had superior performance (area under the curve = 0.91) over non-specific conventional tools. In addition, we also showed that the gene-specific model outperformed the non-gene-specific models. Our study demonstrated that disease-specific and gene-specific models can improve SNV pathogenicity prediction performance. This observation supports the notion that each feature of mutations in the model can be potentially used, in a new algorithm, to investigate the characteristics and function of the encoded proteins.

PMID:35598327 | DOI:10.1093/bib/bbac176