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J Allergy Clin Immunol Pract. 2024 Nov 21:S2213-2198(24)01175-9. doi: 10.1016/j.jaip.2024.11.011. Online ahead of print.

ABSTRACT

BACKGROUND: Inequities in genetic testing have been documented in a range of diseases, and no-charge genetic testing programs have been proposed as a means to enhance access. However, no studies have examined disparities in genetic testing for inborn errors of immunity (IEI) and the impact of no-charge programs on testing equity.

OBJECTIVE: To examine, socioeconomic, geographic, and racial disparities in the uptake of genetic testing for IEI in the US, and the impact of a no-charge sponsored program on testing equity.

METHODS: Retrospective cohort analysis of: (1) a national claims database capturing individuals with IEI (n=18,603), and (2) data from a clinical genetic testing laboratory capturing IEI patients participating in a no-charge sponsored program (n=6,681) and a non-sponsored program (n=29,579) for IEI genetic testing.

RESULTS: Among IEI patients captured in the claims database, those residing in areas of greater deprivation (OR 0.95, 95% CI 0.92-0.98), rural areas (OR 0.82, 95% CI 0.71-0.96), and non-White neighborhoods (OR 0.89, 95% CI 0.81-0.98) were less likely to undergo genetic testing. Participants of the sponsored IEI genetic testing program lived in areas of greater deprivation, compared with the non-sponsored program (median: 46 vs 42, p<0.001). However, minoritized racial groups were underrepresented in both the sponsored and non-sponsored programs, relative to disease burden.

CONCLUSION: We found significant disparities in genetic testing for IEI. Although eliminating financial barrier to testing reduced socioeconomic disparities in genetic testing for IEI, racial disparities persisted. Further research is needed to address barriers to testing among underserved populations.

PMID:39579980 | DOI:10.1016/j.jaip.2024.11.011

J Clin Immunol. 2024 Nov 23;45(1):46. doi: 10.1007/s10875-024-01831-5.

ABSTRACT

PURPOSE: CTLA4 deficiency is an inborn error of immunity (IEI) due to heterozygosity for germline loss-of-function variants of the CTLA4 gene located on chromosome 2q33.2. CTLA4 deficiency underlies pleiotropic immune and lymphoproliferation-mediated features with incomplete penetrance. It has been identified in hundreds of patients but copy number variants (CNVs) have been reported in only 12 kindreds, including nine which displayed large 2q33.1-2q33.2 deletions encompassing CTLA4.

METHODS: We conducted a nationwide study in France to identify patients with 2q33 deletions encompassing CTLA4. We investigated the clinical and immunological phenotypes and genotypes of these patients.

RESULTS: We identified 12 patients across six unrelated kindreds with clinical immunodeficiency. Neurological features were recorded in three patients, including one with syndromic neurodevelopmental disorder. Single-nucleotide polymorphism (SNP) or comparative genomic hybridization (CGH) array analysis, and targeted high-throughput sequencing revealed five different heterozygous 2q33 deletions of 26 kilobases to 7.12 megabases in size and encompassing one to 41 genes. We identified a contiguous gene syndrome (CGS) due to associated KLF7 deficiency in a kindred with a neurodevelopmental phenotype.

CONCLUSION: Deletions within the 2q33 region encompassing CTLA4 are rare and not extensively explored, and are probably underdiagnosed in cytogenetic practice. A literature review identified 14 different CGS loci including at least one gene responsible for an IEI. The deletions involved in IEIs should be systematically delimited, to facilitate screening for CGS.

PMID:39578275 | DOI:10.1007/s10875-024-01831-5

J Intern Med. 2024 Nov 23. doi: 10.1111/joim.20034. Online ahead of print.

ABSTRACT

BACKGROUND: Primary ciliary dyskinesia (PCD) is a rare, genetically heterogeneous disease. Due to difficulty accessing diagnostic services and a lack of awareness of the syndrome, clinicians often fail to recognize the classic phenotype, leading to missed diagnoses.

METHODS: Relevant medical records were accessed through The BIG DATA QUERY AND ANALYSIS SYSTEM of Peking Union Medical College Hospital from September 1, 2012 to March 31, 2024. The search strategy included the following key terms: (bronchiectasis OR atelectasis OR recurrent cough OR recurrent expectoration OR hemoptysis) AND (sinusitis OR nasal polyps OR otitis media OR neonatal pneumonia OR neonatal respiratory distress OR ectopic pregnancy OR infertility OR artificial insemination OR assisted reproduction OR hydrocephalus OR congenital heart disease OR organ laterality defect OR right-sided heart OR semen OR consanguineous marriage). Patients were filtered according to inclusion and exclusion criteria, and those with clinical suspicion of PCD were invited for screening, which included nasal nitric oxide and whole exome sequencing.

RESULTS: A total of 874 medical records were retrieved. After filtering based on inclusion and exclusion criteria, 65 patients with clinical suspicion of PCD were identified, 21 of whom accepted our invitation to complete PCD-related screening. Among them, four were diagnosed with PCD, one was diagnosed with cystic fibrosis, and one was diagnosed with immunodeficiency-21.

CONCLUSIONS: This is the first study to use an electronic medical record retrieval system to identify missed diagnoses PCD. We believe that the methods used in this study can be extended to other rare diseases in the future.

PMID:39578984 | DOI:10.1111/joim.20034

Sci Immunol. 2024 Nov 22;9(101):eadq8796. doi: 10.1126/sciimmunol.adq8796. Epub 2024 Nov 22.

ABSTRACT

Secondary lymphoid organs (SLOs) provide the confined microenvironment required for stromal cells to interact with immune cells to initiate adaptive immune responses resulting in B cell differentiation. Here, we studied three patients from two families with functional hyposplenism, absence of tonsils, and complete lymph node aplasia, leading to recurrent bacterial and viral infections. We identified biallelic loss-of-function mutations in LTBR, encoding the lymphotoxin beta receptor (LTβR), primarily expressed on stromal cells. Patients with LTβR deficiency had hypogammaglobulinemia, diminished memory B cells, regulatory and follicular T helper cells, and dysregulated expression of several tumor necrosis factor family members. B cell differentiation in an ex vivo coculture system was intact, implying that the observed B cell defects were not intrinsic in nature and instead resulted from LTβR-dependent stromal cell interaction signaling critical for SLO formation. Collectively, we define a human inborn error of immunity caused primarily by a stromal defect affecting the development and function of SLOs.

PMID:39576873 | DOI:10.1126/sciimmunol.adq8796

Front Immunol. 2024 Nov 7;15:1460990. doi: 10.3389/fimmu.2024.1460990. eCollection 2024.

ABSTRACT

BACKGROUND: WHIM syndrome is a rare, autosomal dominant inborn error of immunity characterized by warts, hypogammaglobulinemia, infection, and myelokathexis. It is caused mainly by heterozygous mutations at the C-terminus of the C-X-C chemokine receptor type 4 (CXCR4) gene.

METHODS: We described the detailed clinical, genetic, immunological and treatment characteristic of four WHIM patients from a single Chinese family.

RESULTS: Here, we report four patients from a family carrying a variant of CXCR4 (c.1016_1017dupCT), which introduces a frameshift at codon V340, resulting in an extension of 14 amino acids (p.V340L fs*27). We provide and in-depth analysis of their clinical, genetic, immunological and treatment characteristic, noting that these patients exhibited an atypical clinical phenotype when compared to reported CXCR4^R334X patients. Additionally, the frameshift variant CXCR4^V340fs led to impaired receptor downregulation in patients’ PBMCs, and in HEK293T cells transfected with the variant plasmids.

CONCLUSIONS: Our study provided detailed clinical features of four CXCR4^V340fs WHIM patients from one Chinese family who presented atypical phenotype and enrich the spectrum of WHIM syndrome.

PMID:39575248 | PMC:PMC11578956 | DOI:10.3389/fimmu.2024.1460990

Rev Med Inst Mex Seguro Soc. 2024 Nov 4;62(6):1-7. doi: 10.5281/zenodo.13306777.

ABSTRACT

Inborn errors of metabolism (IEM), also known as inherited metabolic disorders, are rare but associated with significant morbidity and mortality. The incidence is variable in all regions, worldwide it ranges from 1 in 569 to 2500 live births (LBI). The objective of this work was to carry out a narrative review to identify the guidelines that guide the detection of EIMs through official sources from various countries. A total of 13 documents were identified, including protocols, books, manuals, programs and 4 official websites for the detection of EIMs. In general, there is variability in the selection of EIMs that are detected, from 4 to 61 EIMs, primary congenital hypothyroidism and pheniceltonuria are the two EIMs that are included in most screening programs, spinal atrophy and severe combined immunodeficiency are detected less frequently, the incidence of each EIM is variable between countries and even between states of the same country, with congenital hypothyroidism being the most common. The guidelines for the selection of EIMs are determined by the internal policies of each country, the incidence and economic resources. There is no universal standard for the detection of EIMs, but they all pursue the same purpose: detection, diagnosis and timely treatment. In parallel, it allows us to estimate with greater precision the frequency of these disorders.

PMID:39570792 | DOI:10.5281/zenodo.13306777

J Exp Med. 2025 Jan 6;222(1):e20220979. doi: 10.1084/jem.20220979. Epub 2024 Nov 19.

ABSTRACT

The importance of calcium (Ca2+) as a second messenger in T cell signaling is exemplified by genetic deficiencies of STIM1 and ORAI1, which abolish store-operated Ca2+ entry (SOCE) resulting in combined immunodeficiency (CID). We report five unrelated patients with de novo missense variants in ITPR3, encoding a subunit of the inositol 1,4,5-trisphosphate receptor (IP3R), which forms a Ca2+ channel in the endoplasmic reticulum (ER) membrane responsible for the release of ER Ca2+ required to trigger SOCE, and for Ca2+ transfer to other organelles. The patients presented with CID, abnormal T cell Ca2+ homeostasis, incompletely penetrant ectodermal dysplasia, and multisystem disease. Their predominant T cell immunodeficiency is characterized by significant T cell lymphopenia, defects in late stages of thymic T cell development, and impaired function of peripheral T cells, including inadequate NF-κB- and NFAT-mediated, proliferative, and metabolic responses to activation. Pathogenicity is not due to haploinsufficiency, rather ITPR3 protein variants interfere with IP3R channel function leading to depletion of ER Ca2+ stores and blunted SOCE in T cells.

PMID:39560673 | DOI:10.1084/jem.20220979

bioRxiv [Preprint]. 2024 Oct 29:2024.10.27.620363. doi: 10.1101/2024.10.27.620363.

ABSTRACT

BACKGROUND: Copy number variation (CNV) is a class of genomic Structural Variation (SV) that underlie genomic disorders and can have profound implications for health. Short-read genome sequencing (sr-GS) enables CNV calling for genomic intervals of variable size and across multiple phenotypes. However, unresolved challenges include an overwhelming number of false-positive calls due to systematic biases from non-uniform read coverage and collapsed calls resulting from the abundance of paralogous segments and repetitive elements in the human genome.

METHODS: To address these interpretative challenges, we developed VizCNV. The VizCNV computational tool for inspecting CNV calls uses various data signal sources from sr-GS data, including read depth, phased B-allele frequency, as well as benchmarking signals from other SV calling methods. The interactive features and view modes are adept for analyzing both chromosomal abnormalities [e.g., aneuploidy, segmental aneusomy, and chromosome translocations], gene exonic CNV and non-coding gene regulatory regions. In addition, VizCNV includes a built-in filter schema for trio genomes, prioritizing the detection of impactful germline CNVs, such as de novo CNVs. Upon computational optimization by fine-tuning parameters to maximize sensitivity and specificity, VizCNV demonstrated approximately 83.8% recall and 77.2% precision on the 1000 Genome Project data with an average coverage read depth of 30x.

RESULTS: We applied VizCNV to 39 families with primary immunodeficiency disease without a molecular diagnosis. With implemented build-in filter, we identified two de novo CNVs and 90 inherited CNVs >10 kb per trio. Genotype-phenotype analyses revealed that a compound heterozygous combination of a paternal 12.8 kb deletion of exon 5 and a maternal missense variant allele of DOCK8 are likely the molecular cause of one proband.

CONCLUSIONS: VizCNV provides a robust platform for genome-wide relevant CNV discovery and visualization of such CNV using sr-GS data.

PMID:39553991 | PMC:PMC11565771 | DOI:10.1101/2024.10.27.620363

Eur J Immunol. 2024 Nov 16:e202451061. doi: 10.1002/eji.202451061. Online ahead of print.

ABSTRACT

Primary hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome caused by inborn errors of cytotoxicity. Patients with biallelic PRF1 null mutations (encoding perforin) usually develop excessive immune cell activation, hypercytokinemia, and life-threatening immunopathology in the first 6 months of life, often without an apparent infectious trigger. In contrast, perforin-deficient (PKO) mice only develop HLH after systemic infection with lymphocytic choriomeningitis virus (LCMV). We hypothesized that restricted microbe-immune cell interactions due to specific pathogen-free (SPF) housing might explain the need for this specific viral trigger in PKO mice. To investigate the influence of a “wild” microbiome in PKO mice, we fostered PKO newborns with Wildling microbiota (‘PKO-Wildlings’) and monitored them for signs of HLH. PKO-Wildlings survived long-term without spontaneous disease. Also, systemic infection with vaccinia virus did not reach the threshold of immune activation required to trigger HLH in PKO-Wildlings. Interestingly, after infection with LCMV, PKO-Wildlings developed an altered HLH pattern. This included lower IFN-γ serum levels along with improved IFN-γ-driven anemia, but more elevated levels of IL-17 and increased liver inflammation compared with PKO-SPF mice. Thus, wild microbiota alone is not sufficient to trigger HLH in PKO mice, but host-microbe interactions shape inflammatory cytokine patterns, thereby influencing manifestations of HLH immunopathology.

PMID:39548906 | DOI:10.1002/eji.202451061

Nat Commun. 2024 Nov 15;15(1):9921. doi: 10.1038/s41467-024-54228-8.

ABSTRACT

Primary antiphospholipid syndrome (PAPS) is a life-threatening clotting disorder mediated by pathogenic autoantibodies. Here we dissect the origin of self-reactive B cells in human PAPS using peripheral blood and bone marrow of patients with triple-positive PAPS via combined single-cell RNA sequencing, B cell receptors (BCR) repertoire profiling, CITEseq analysis and single cell immortalization. We find that antiphospholipid (aPL)-specific B cells are present in the naive compartment, polyreactive, and derived from the natural repertoire. Furthermore, B cells with aPL specificities are not eliminated in patients with PAPS, persist until the memory and long-lived plasma cell stages, likely after defective germinal center selection, while becoming less polyreactive. Lastly, compared with the non-PAPS cells, PAPS B cells exhibit distinct IFN and APRIL signature as well as dysregulated mTORC1 and MYC pathways. Our findings may thus elucidate the survival mechanisms of these autoreactive B cells and suggest potential therapeutic targets for the treatment of PAPS.

PMID:39548093 | DOI:10.1038/s41467-024-54228-8