The Ever-Increasing Array of Novel Inborn Errors of Immunity: an Interim Update by the IUIS Committee

Tangye, Stuart G.; Al‐Herz, Waleed; Bousfiha, Aziz; Cunningham‐Rundles, Charlotte; Franco, José Luis; Holland, Steven M.; Klein, Christoph; Morio, Tomohiro; Oksenhendler, Éric; Pïcard, Capucine; Puel, Anne; Puck, Jennifer M.; Seppänen, Mikko; Somech, Raz; Su, Helen C.; Sullivan, Kathleen E.; Torgerson, Troy R.; Meyts, Isabelle

doi:10.1007/s10875-021-00980-1

Cited by 191 publications

(182 citation statements)

References 72 publications

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“…Extended author information available on the last page of the article 450 monogenic diseases (mainly with autosomal recessive inheritance) have been identified in patients with IEI [2][3][4], resulting in better management and treatment of these patients [5,6]. The majority of IEI patients are susceptible to recurrent severe infections causing significant morbidity and mortality.…”

Section: Introductionmentioning

confidence: 99%

Consensus Middle East and North Africa Registry on Inborn Errors of Immunity

et al. 2021

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Background Inborn errors of immunity (IEIs) are a heterogeneous group of genetic defects of immunity, which cause high rates of morbidity and mortality mainly among children due to infectious and non-infectious complications. The IEI burden has been critically underestimated in countries from middle- and low-income regions and the majority of patients with IEI in these regions lack a molecular diagnosis. Methods We analyzed the clinical, immunologic, and genetic data of IEI patients from 22 countries in the Middle East and North Africa (MENA) region. The data was collected from national registries and diverse databases such as the Asian Pacific Society for Immunodeficiencies (APSID) registry, African Society for Immunodeficiencies (ASID) registry, Jeffrey Modell Foundation (JMF) registry, J Project centers, and International Consortium on Immune Deficiency (ICID) centers. Results We identified 17,120 patients with IEI, among which females represented 39.4%. Parental consanguinity was present in 60.5% of cases and 27.3% of the patients were from families with a confirmed previous family history of IEI. The median age of patients at the onset of disease was 36 months and the median delay in diagnosis was 41 months. The rate of registered IEI patients ranges between 0.02 and 7.58 per 100,000 population, and the lowest rates were in countries with the highest rates of disability-adjusted life years (DALY) and death rates for children. Predominantly antibody deficiencies were the most frequent IEI entities diagnosed in 41.2% of the cohort. Among 5871 patients genetically evaluated, the diagnostic yield was 83% with the majority (65.2%) having autosomal recessive defects. The mortality rate was the highest in patients with non-syndromic combined immunodeficiency (51.7%, median age: 3.5 years) and particularly in patients with mutations in specific genes associated with this phenotype (RFXANK, RAG1, and IL2RG). Conclusions This comprehensive registry highlights the importance of a detailed investigation of IEI patients in the MENA region. The high yield of genetic diagnosis of IEI in this region has important implications for prevention, prognosis, treatment, and resource allocation.

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Section: Introductionmentioning

confidence: 99%

Consensus Middle East and North Africa Registry on Inborn Errors of Immunity

et al. 2021

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“…One intuitively attractive hypothesis is that an intrinsic immune deficiency might increase risk both, of infection, and more severe consequences of infection. Pathogenic variants in over 450 genes have been reported to cause single-gene inborn errors of immunity (IEIs) (4,5), and it is tempting to speculate that the IEI population would be at particular risk. Individuals with variants in almost all the categories of IEIs in the 2019 International Union of Immunological Societies (IUIS) classification of IEIs (4) have been reported to have SARS-CoV-2 infection, including those with phenocopies of disease (where the disorder is caused by somatic variants or autoantibodies to immunologically relevant proteins, and mimics the phenotype of a genetic defect).…”

Section: Identifying Risk Predictors Remains a Pressing Needmentioning

confidence: 99%

Do monogenic inborn errors of immunity cause susceptibility to severe COVID-19?

Cotsapas¹,

Saarela²,

Farmer³

et al. 2021

Journal of Clinical Investigation

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The SARS-CoV-2 virus, which causes COVID-19, has been associated globally with substantial morbidity and mortality. Numerous reports over the past year have described the clinical and immunological profiles of COVID-19 patients, and while some trends have emerged for risk stratification, they do not provide a complete picture. Therefore, efforts are ongoing to identify genetic susceptibility factors of severe disease. In this issue of the JCI, Povysil et al. performed a large, multi-country study, sequencing genomes from patients with mild and severe COVID-19, along with population controls. Contrary to previous reports, the authors observed no enrichment of predicted loss-of-function variants in genes in the type I interferon pathway, which might predispose to severe disease. These studies suggest that more evidence is needed to substantiate

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“…Thus, the group of primary immunodeficiencies, which is vast and heterogeneous, is now merged with that of inborn errors of innate immunity (IEIs). In 2021, there have been more than 450 single-gene innate errors of immunity underlying phenotypes encompassing as diverse manifestations as infections, malignancies, allergy, autoimmunity [ 148 ]. These phenotypes may be exclusive, but are most often overlapping, with immune deficiency being combined with, for example, autoimmune manifestations or lymphoproliferation [ 149 ].…”

Section: Clinical Casesmentioning

confidence: 99%

Challenging Mimickers in the Diagnosis of Sarcoidosis: A Case Study

et al. 2021

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Sarcoidosis is a systemic granulomatous disease of unknown cause characterized by a wide variety of presentations. Its diagnosis is based on three major criteria: a clinical presentation compatible with sarcoidosis, the presence of non-necrotizing granulomatous inflammation in one or more tissue samples, and the exclusion of alternative causes of granulomatous disease. Many conditions may mimic a sarcoid-like granulomatous reaction. These conditions include infections, neoplasms, immunodeficiencies, and drug-induced diseases. Moreover, patients with sarcoidosis are at risk of developing opportunistic infections or lymphoma. Reliably confirming the diagnosis of sarcoidosis and better identifying new events are major clinical problems in daily practice. To address such issues, we present seven emblematic cases, seen in our department, over a ten-year period along with a literature review about case reports of conditions misdiagnosed as sarcoidosis.

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The Ever-Increasing Array of Novel Inborn Errors of Immunity: an Interim Update by the IUIS Committee

Cited by 191 publications

References 72 publications

Consensus Middle East and North Africa Registry on Inborn Errors of Immunity

Consensus Middle East and North Africa Registry on Inborn Errors of Immunity

Do monogenic inborn errors of immunity cause susceptibility to severe COVID-19?

Challenging Mimickers in the Diagnosis of Sarcoidosis: A Case Study

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