Journal of Clinical Immunology最新文献

{"title":"A Novel Case of IFNAR1 Deficiency Identified a Common Canonical Splice Site Variant in DOCK8 in Western Polynesia: The Importance of Validating Variants of Unknown Significance in Under-Represented Ancestries.","authors":"Aimee Huynh, Paul E Gray, Anna Sullivan, Joseph Mackie, Antoine Guerin, Geetha Rao, Karrnan Pathmanandavel, Erika Della Mina, Georgina Hollway, Matthew Hobbs, Karen Enthoven, Patrick O'Young, Sam McManus, Luke H Wainwright, Megan Higgins, Fallon Noon, Melanie Wong, Paul Bastard, Qian Zhang, Jean-Laurent Casanova, Kuang-Chih Hsiao, Alberto Pinzon-Charry, Cindy S Ma, Stuart G Tangye","doi":"10.1007/s10875-024-01774-x","DOIUrl":"10.1007/s10875-024-01774-x","url":null,"abstract":"<p><p>Advanced genomic technologies such as whole exome or whole genome sequencing have improved diagnoses and disease outcomes for individuals with genetic diseases. Yet, variants of unknown significance (VUS) require rigorous validation to establish disease causality or modification, or to exclude them from further analysis. Here, we describe a young individual of Polynesian ancestry who in the first 13 mo of life presented with SARS-CoV-2 pneumonia, severe enterovirus meningitis and adenovirus gastroenteritis, and severe adverse reaction to MMR vaccination. Genomic analysis identified a previously reported pathogenic homozygous variant in IFNAR1 (c.1156G > T, p.Glu386* LOF), which is common in Western Polynesia. Moreover, a new and putatively deleterious canonical splice site variant in DOCK8 was also found in homozygosity (c.3234 + 2T > C). This DOCK8 variant is common in Polynesians and other under-represented ancestries in large genomic databases. Despite in silico bioinformatic predictions, extensive in vitro and ex vivo analysis revealed the DOCK8 variant likely be neutral. Thus, our study reports a novel case of IFNAR1 deficiency, but also highlights the importance of functional validation of VUS, including those predicted to be deleterious, and the pressing need to expand our knowledge of the genomic architecture and landscape of under-represented populations and ancestries.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"44 8","pages":"170"},"PeriodicalIF":7.2,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11298505/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141889394","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inheritance of STING mosaicism in two half-siblings.","authors":"Alix de Becdelièvre, Laurye-Anne Eveillard, Beata Wolska-Kuśnierz, Marie-Louise Frémond","doi":"10.1007/s10875-024-01768-9","DOIUrl":"10.1007/s10875-024-01768-9","url":null,"abstract":"","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"44 7","pages":"168"},"PeriodicalIF":7.2,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7616363/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141792621","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exclusive Characteristics of the p.E555K Dominant-Negative Variant in Autosomal Dominant E47 Deficiency.","authors":"Takanori Utsumi, Miyuki Tsumura, Masato Yashiro, Zenichiro Kato, Kosuke Noma, Fumiaki Sakura, Reiko Kagawa, Yoko Mizoguchi, Shuhei Karakawa, Hidenori Ohnishi, Charlotte Cunningham-Rundles, Peter D Arkwright, Masao Kobayashi, Hirokazu Kanegane, Dusan Bogunovic, Bertrand Boisson, Jean-Laurent Casanova, Takaki Asano, Satoshi Okada","doi":"10.1007/s10875-024-01758-x","DOIUrl":"10.1007/s10875-024-01758-x","url":null,"abstract":"<p><strong>Purpose: </strong>Transcription factor 3 (TCF3) encodes 2 transcription factors generated by alternative splicing, E12 and E47, which contribute to early lymphocyte differentiation. In humans, autosomal dominant (AD) E47 transcription factor deficiency is an inborn error of immunity characterized by B-cell deficiency and agammaglobulinemia. Only the recurrent de novo p.E555K pathogenic variant has been associated with this disease and acts via a dominant-negative (DN) mechanism. In this study, we describe the first Asian patient with agammaglobulinemia caused by the TCF3 p.E555K variant and provide insights into the structure and function of this variant.</p><p><strong>Methods: </strong>TCF3 variant was identified by inborn errors of immunity-related gene panel sequencing. The variant E555K was characterized by alanine scanning of the E47 basic region and comprehensive mutational analysis focused on position 555.</p><p><strong>Results: </strong>The patient was a 25-year-old male with B-cell deficiency, agammaglobulinemia, and mild facial dysmorphic features. We confirmed the diagnosis of AD E47 transcription factor deficiency by identifying a heterozygous missense variant, c.1663 G>A; p.E555K, in TCF3. Alanine scanning of the E47 basic region revealed the structural importance of position 555. Comprehensive mutational analysis focused on position 555 showed that only the glutamate-to-lysine substitution had a strong DN effect. 3D modeling demonstrated that this variant not only abolished hydrogen bonds involved in protein‒DNA interactions, but also inverted the charge on the surface of the E47 protein.</p><p><strong>Conclusions: </strong>Our study reveals the causative mutation hotspot in the TCF3 DN variant and highlights the weak negative selection associated with the TCF3 gene.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"44 7","pages":"167"},"PeriodicalIF":7.2,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11286708/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141788236","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic Testing in Patients with Autoimmune Lymphoproliferative Syndrome: Experience of 802 Patients at Cincinnati Children's Hospital Medical Center.","authors":"Xinxiu Xu, James Denton, Yaning Wu, Jie Liu, Qiaoning Guan, D Brian Dawson, Jack Bleesing, Wenying Zhang","doi":"10.1007/s10875-024-01772-z","DOIUrl":"10.1007/s10875-024-01772-z","url":null,"abstract":"<p><p>Autoimmune lymphoproliferative syndrome (ALPS) is a rare genetic disorder featuring chronic lymphadenopathy, splenomegaly, cytopenias, and increased lymphoma risk. Differentiating ALPS from immunodeficiencies with overlapping symptoms is challenging. This study evaluated the performance and the diagnostic yield of a 15-gene NGS panel for ALPS at Cincinnati Children's Hospital Medical Center. Samples from 802 patients submitted for ALPS NGS panel were studied between May 2014 and January 2023. A total of 62 patients (7.7%) had a definite diagnosis: 52/62 cases (84%) showed 37 unique pathogenic/likely pathogenic germline FAS variants supporting ALPS diagnosis (6.5%, 52/802). The ALPS diagnostic yield increased to 30% in patients who additionally fulfilled abnormal ALPS immunology findings criteria. 17/37 (46%) diagnostic FAS variants were novel variants reported for the first time in ALPS. 10/802 cases (1.2%) showed diagnostic findings in five genes (ADA2, CTLA4, KRAS, MAGT1, NRAS) which are related to autoimmune lymphoproliferative immunodeficiency (ALPID). Family studies enabled the reclassification of variants of unknown significance (VUS) and also the identification of at-risk family members of FAS-positive patients, which helped in the follow-up diagnosis and treatment. Alongside family studies, complete clinical phenotypes and abnormal ALPS immunology and Fas-mediated apoptosis results helped clarify uncertain genetic findings. This study describes the largest cohort of genetic testing for suspected ALPS in North America and highlights the effectiveness of the ALPS NGS panel in distinguishing ALPS from non-ALPS immunodeficiencies. More comprehensive assessment from exome or genome sequencing could be considered for undefined ALPS-U patients or non-ALPS immunodeficiencies after weighing cost, completeness, and timeliness of different genetic testing options.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"44 7","pages":"166"},"PeriodicalIF":7.2,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11282156/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141766192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discordant Phenotypes of Nephritis in Patients with X-linked Agammaglobulinemia.","authors":"Toru Kanamori, Tomohiro Udagawa, Takayuki Fujii, Hiroyoshi Matsukura, Yuka Iwaya, Motoshi Sonoda, Keisuke Sugimoto, Masahiro Takeguchi, Atsunori Yoshino, I-Feng Wang, Daw-Yang Hwang, Harry W Schroeder, Masaki Shimizu, Hans D Ochs, Tomohiro Morio, Hirokazu Kanegane","doi":"10.1007/s10875-024-01766-x","DOIUrl":"10.1007/s10875-024-01766-x","url":null,"abstract":"<p><strong>Purpose: </strong>To define the clinical and histological characteristics of nephritis in patients with X-linked agammaglobulinemia (XLA) and their immunological profiles.</p><p><strong>Methods: </strong>The clinical, immunological, and histological findings of nine patients with XLA and nephritis were retrospectively analyzed.</p><p><strong>Results: </strong>Based on kidney histological findings, patients with XLA and nephritis could be divided into two groups, viz., chronic glomerulonephritis (CGN) and tubulointerstitial nephritis (TIN). The two groups showed different immunological profiles. Patients in the CGN group exhibited an atypical immunological profile of XLA, with pathogenic leaky B cells producing immunoglobulins that may play a role in forming immune complexes and causing immune-mediated glomerulonephritis. In contrast, patients in the TIN group exhibited a typical immunological profile of XLA, suggesting that antibody-independent/other BTK-dependent mechanisms, or immunoglobulin replacement therapy (IgRT)-related immune/nonimmune-mediated nephrotoxicity causes TIN.</p><p><strong>Conclusion: </strong>Nephritis occurring in patients with XLA could have links between their renal pathology and immunological status. Careful observation is recommended to detect kidney pathology in patients with XLA on IgRT.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"44 7","pages":"164"},"PeriodicalIF":7.2,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141759028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic Characteristics of a Large Pediatric Cohort of Patients with Inborn Errors of Immunity: Single-Center Experience.","authors":"Natalia Kuzmenko, Maxim Alexenko, Anna Mukhina, Yulia Rodina, Mariia Fadeeva, Dmitrii Pershin, Amina Kieva, Elena Raykina, Miсhael Maschan, Galina Novichkova, Anna Shcherbina","doi":"10.1007/s10875-024-01767-w","DOIUrl":"10.1007/s10875-024-01767-w","url":null,"abstract":"<p><p>More than 450 genetic defects result in inborn errors of immunity (IEI). Their individual prevalence in specific cohorts is influenced by national characteristics and other factors. We present results of genetic testing conducted in 1809 Russian children with IEI. Genetic defects confirming IEI were found in 1112 out of 1809 (61.5%) probands. These defects included variants in 118 single genes (87.9% of patients) and aberrations in 6 chromosomes (11.8%). Notably, three patients harbored pathogenic variants in more than one IEI gene. Large deletions constituted 5% of all defects. Out of the 799 original variants, 350 (44%) have not been described previously. Rare genetic defects (10 or fewer patients per gene) were identified in 20% of the patients. Among 967 probands with germline variants, defects were inherited in an autosomal dominant manner in 29%, X-linked in 34%, and autosomal recessive in 37%. Four females with non-random X-inactivation exhibited symptoms of X-linked diseases (BTK, WAS, CYBB, IKBKG gene defects). Despite a relatively low rate of consanguinity in Russia, 47.9% of autosomal recessive gene defects were found in a homozygous state. Notably, 28% of these cases carried \"Slavic\" mutation of the NBN gene or known hot-spot mutations in other genes. The diversity of IEI genetic forms and the high frequency of newly described variants underscore the genetic heterogeneity within the Russian IEI group. The new variants identified in this extensive cohort will enrich genetic databases.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"44 7","pages":"165"},"PeriodicalIF":7.2,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141759029","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Autoantibodies Neutralizing GM-CSF in HIV-Negative Colombian Patients Infected with Cryptococcus gattii and C. neoformans.","authors":"Carlos A Arango-Franco, Julian Rojas, Carolina Firacative, Mélanie Migaud, Clara Inés Agudelo, José Luis Franco, Jean-Laurent Casanova, Anne Puel, Jairo Lizarazo, Elizabeth Castañeda, Andrés A Arias","doi":"10.1007/s10875-024-01757-y","DOIUrl":"10.1007/s10875-024-01757-y","url":null,"abstract":"<p><strong>Background: </strong>Cryptococcosis is a life-threatening disease caused by Cryptococcus neoformans or C. gattii. Neutralizing autoantibodies (auto-Abs) against granulocyte-macrophage colony-stimulating factor (GM-CSF) in otherwise healthy adults with cryptococcal meningitis have been described since 2013. We searched for neutralizing auto-Abs in sera collected from Colombian patients with non-HIV-associated cryptococcosis in a retrospective national cohort from 1997 to 2016.</p><p><strong>Methods: </strong>We reviewed clinical and laboratory records and assessed the presence of neutralizing auto-Abs against GM-CSF in 30 HIV negative adults with cryptococcosis (13 caused by C. gattii and 17 caused by C. neoformans).</p><p><strong>Results: </strong>We detected neutralizing auto-Abs against GM-CSF in the sera of 10 out of 13 (77%) patients infected with C. gattii and one out of 17 (6%) patients infected with C. neoformans.</p><p><strong>Conclusions: </strong>We report eleven Colombian patients diagnosed with cryptococcosis who had auto-Abs that neutralize GM-CSF. Among these patients, ten were infected with C. gattii and only one with C. neoformans.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"44 7","pages":"163"},"PeriodicalIF":7.2,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11249431/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141616579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Omenn Syndrome can Occur during Enzyme Therapy for Adenosine Deaminase Deficiency.","authors":"Elizabeth M Forbes, Peter B McNaughton","doi":"10.1007/s10875-024-01764-z","DOIUrl":"10.1007/s10875-024-01764-z","url":null,"abstract":"","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"44 7","pages":"162"},"PeriodicalIF":7.2,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141616580","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<ArticleTitle xmlns:ns0=\"http://www.w3.org/1998/Math/MathML\">Prevalence of Anti-Interferon <ns0:math><ns0:mi>α</ns0:mi></ns0:math> Auto-Antibodies in Patients with Antibody Deficiency.","authors":"Douglas L Fink, Orest Idilli, Adrian Shields, Alex Richter, Siobhan O Burns","doi":"10.1007/s10875-024-01761-2","DOIUrl":"10.1007/s10875-024-01761-2","url":null,"abstract":"","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"44 7","pages":"161"},"PeriodicalIF":7.2,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141579839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical, Immunological, and Genetic Features in Patients with NFKB1 and NFKB2 Mutations: a Systematic Review.","authors":"Nazanin Fathi, Matineh Nirouei, Zahra Salimian Rizi, Saba Fekrvand, Hassan Abolhassani, Fereshte Salami, Arsh Haj Mohamad Ebrahim Ketabforoush, Gholamreza Azizi, Amene Saghazadeh, Marzie Esmaeili, Amir Almasi-Hashiani, Nima Rezaei","doi":"10.1007/s10875-024-01763-0","DOIUrl":"10.1007/s10875-024-01763-0","url":null,"abstract":"<p><strong>Background: </strong>Inborn errors of immunity (IEIs) encompass various diseases with diverse clinical and immunological symptoms. Determining the genotype-phenotype of different variants in IEI entity precisely is challenging, as manifestations can be heterogeneous even in patients with the same mutated gene.</p><p><strong>Objective: </strong>In the present study, we conducted a systematic review of patients recorded with NFKB1 and NFKB2 mutations, two of the most frequent monogenic IEIs.</p><p><strong>Methods: </strong>The search for relevant literature was conducted in databases including Web of Science, PubMed, and Scopus. Information encompassing demographic, clinical, immunological, and genetic data was extracted from cases reported with mutations in NFKB1 and NFKB2. The comprehensive features of manifestations in patients were described, and a comparative analysis of primary characteristics was conducted between individuals with NFKB1 loss of function (LOF) and NFKB2 (p52-LOF/IκBδ-gain of function (GOF)) variants.</p><p><strong>Results: </strong>A total of 397 patients were included in this study, 257 had NFKB1 mutations and 140 had NFKB2 mutations. There were 175 LOF cases in NFKB1 and 122 p52^LOF/IκBδ^GOF cases in NFKB2 pivotal groups with confirmed functional implications. NFKB1LOF and p52^LOF/IκBδ^GOF predominant cases (81.8% and 62.5% respectively) initially presented with a CVID-like phenotype. Patients with NFKB1LOF variants often experienced hematologic autoimmune disorders, whereas p52^LOF/IκBδ^GOF patients were more susceptible to other autoimmune diseases. Viral infections were markedly higher in p52^LOF/IκBδ^GOF cases compared to NFKB1LOF (P-value < 0.001). NFKB2 (p52^LOF/IκBδ^GOF) patients exhibited a greater prevalence of ectodermal dysplasia and pituitary gland involvement than NFKB1LOF patients. Most NFKB1LOF and p52^LOF/IκBδ^GOF cases showed low CD19 + B cells, with p52^LOF/IκBδ^GOF having more cases of this type. Low memory B cells were more common in p52^LOF/IκBδ^GOF patients.</p><p><strong>Conclusions: </strong>Patients with NFKB2 mutations, particularly p52^LOF/IκBδ^GOF, are at higher risk of viral infections, pituitary gland involvement, and ectodermal dysplasia compared to patients with NFKB1LOF mutations. Genetic testing is essential to resolve the initial complexity and confusion surrounding clinical and immunological features. Emphasizing the significance of functional assays in determining the probability of correlations between mutations and immunological and clinical characteristics of patients is crucial.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"44 7","pages":"160"},"PeriodicalIF":7.2,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141579840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}