scholarly journals Prevalence of Pathogenic and Potentially Pathogenic Inborn Error of Immunity Associated Variants in Children with Severe Sepsis

2022 ◽  
Author(s):  
Kate F. Kernan ◽  
Lina Ghaloul-Gonzalez ◽  
Jerry Vockley ◽  
Janette Lamb ◽  
Deborah Hollingshead ◽  
...  
Keyword(s):  
Severe Sepsis ◽  
Rare Variants ◽  
Phenotypic Effect ◽  
Inborn Errors ◽  
Inborn Errors Of Immunity ◽  
Mutation Database ◽  
Inflammatory Phenotype ◽  
Life Threatening ◽  
American Children ◽  
Pediatric Sepsis

Abstract   Purpose Our understanding of inborn errors of immunity is increasing; however, their contribution to pediatric sepsis is unknown. Methods We used whole-exome sequencing (WES) to characterize variants in genes related to monogenic immunologic disorders in 330 children admitted to intensive care for severe sepsis. We defined candidate variants as rare variants classified as pathogenic or potentially pathogenic in QIAGEN’s Human Gene Mutation Database or novel null variants in a disease-consistent inheritance pattern. We investigated variant correlation with infection and inflammatory phenotype. Results More than one in two children overall and three of four African American children had immunodeficiency-associated variants. Children with variants had increased odds of isolating a blood or urinary pathogen (blood: OR 2.82, 95% CI: 1.12–7.10, p = 0.023, urine: OR: 8.23, 95% CI: 1.06–64.11, p = 0.016) and demonstrating increased inflammation with hyperferritinemia (ferritin $$\ge 500$$ ≥ 500 ng/mL, OR: 2.16, 95% CI: 1.28–3.66, p = 0.004), lymphopenia (lymphocyte count < 1000/µL, OR: 1.66, 95% CI: 1.06 – 2.60, p = 0.027), thrombocytopenia (platelet count < 150,000/µL, OR: 1.76, 95% CI: 1.12–2.76, p = 0.013), and CRP greater than 10 mg/dl (OR: 1.71, 95% CI: 1.10–2.68, p = 0.017). They also had increased odds of requiring extracorporeal membrane oxygenation (ECMO, OR: 4.19, 95% CI: 1.21–14.5, p = 0.019). Conclusion Herein, we describe the genetic findings in this severe pediatric sepsis cohort and their microbiologic and immunologic significance, providing evidence for the phenotypic effect of these variants and rationale for screening children with life-threatening infections for potential inborn errors of immunity.

scholarly journals Prevalence of Pathogenic and Potentially Pathogenic Inborn Error of Immunity Associated Variants in Children with Severe Sepsis

2021 ◽  
Author(s):  
Kate F. Kernan ◽  
Lina Ghaloul-Gonzalez ◽  
Jerry Vockley ◽  
Janette Lamb ◽  
Debborah Hollingshead ◽  
...  
Keyword(s):  
Severe Sepsis ◽  
Rare Variants ◽  
Genetic Mutation ◽  
Phenotypic Effect ◽  
Inborn Errors ◽  
Inborn Errors Of Immunity ◽  
Mutation Database ◽  
Inflammatory Phenotype ◽  
American Children ◽  
Pediatric Sepsis

Abstract Purpose: Our understanding of inborn errors of immunity is increasing however, their contribution to pediatric sepsis is unknown. Methods: We used whole exome sequencing to characterize variants in genes related to monogenic immunologic disorders in 330 children admitted to intensive care for severe sepsis. We defined candidate variants as rare variants classified as pathogenic or potentially pathogenic in Qiagen’s Human Genetic Mutation Database or novel null variants in a disease-consistent inheritance pattern. We investigated variant correlation with infection and inflammatory phenotype. Results: More than one in two children overall and three of four African American children had immunodeficiency-associated variants. Children with variants had increased odds of isolating a blood or urinary pathogen (blood: OR 2.82, 95% CI: 1.12 – 7.10, p = 0.023, urine: OR: 8.23, 95% CI: 1.06 – 64.11, p = 0.016) and demonstrating increased inflammation with hyperferritinemia (ferritin ng/mL, OR: 2.16, 95% CI: 1.28 – 3.66, p = 0.004), lymphopenia (lymphocyte count <1000/µL, OR: 1.66, 95% CI: 1.06 – 2.60, p = 0.027), thrombocytopenia (platelet count < 150,000/µL, OR: 1.76, 95% CI: 1.12 – 2.76, p = 0.013) and CRP greater than 10mg/dL (OR: 1.71, 95%CI: 1.10 – 2.68, p = 0.017). They also had increased odds of requiring extracorporeal membrane oxygenation (ECMO, OR: 4.19, 95%CI: 1.21 – 14.5, p = 0.019).Conclusion: Herein, we describe the genetic findings in this severe pediatric sepsis cohort and their microbiologic and immunologic significance, providing evidence for phenotypic effect of these variants and rationale for screening children with life-threatening infection for potential inborn errors of immunity.

scholarly journals Prevalence of Pathogenic and Potentially Pathogenic Inborn Error of Immunity Associated Variants in Children with Severe Sepsis

2021 ◽  
Author(s):  
Kate F. Kernan ◽  
Lina Ghaloul-Gonzalez ◽  
Jerry Vockley ◽  
Janette Lamb ◽  
Deborah Hollingshead ◽  
...  
Keyword(s):  
Severe Sepsis ◽  
Rare Variants ◽  
Genetic Mutation ◽  
P Value ◽  
Inborn Errors ◽  
Inborn Errors Of Immunity ◽  
Mutation Database ◽  
Life Threatening ◽  
American Children ◽  
Pediatric Sepsis

Abstract Purpose: Our understanding of the inborn errors of immunity that cause immunodeficiencies is increasing however, their contribution to pediatric sepsis is unknown. Methods: We used whole exome sequencing to characterize variants previously reported in monogenic immunologic disorders in 330 children admitted to intensive care for severe sepsis. Candidate variants were restricted to novel null variants or rare variants classified as pathogenic or potentially pathogenic in Qiagen’s Human Genetic Mutation Database in a disease consistent inheritance pattern. Results: One in two children overall and two of three African American children had immunodeficiency-associated variants. Children with candidate variants had increased odds of isolating a blood or urinary pathogen (blood: OR 2.05, 95% CI 1.16 - 3.65, p- value = 0.014, urine: OR: 2.35, 95% CI 1.02 – 5.41, p- value = 0.04) and laboratory evidence of increased immune activation with increased odds of hyperferritinemia (ferritin ≥ 500 ng/ml, OR: 1.92, 95% CI: 1.16 – 3.20, p- value = 0.013) and lymphopenia (minimum lymphocyte count <1000/µL, OR: 1.62, 95% CI: 1.03 – 2.55, p- value = 0.038). Conclusion: Herein, we describe the genetic findings in this pediatric sepsis cohort and their microbiologic and immunologic significance providing rationale for screening children with life-threatening infection for potential inborn errors of immunity.

scholarly journals Correction to: Life-Threatening Infections Due to Live-Attenuated Vaccines: Early Manifestations of Inborn Errors of Immunity

2019 ◽  
Vol 39 (5) ◽  
pp. 527-527 ◽  
Author(s):  
Laura Pöyhönen ◽  
Jacinta Bustamante ◽  
Jean-Laurent Casanova ◽  
Emmanuelle Jouanguy ◽  
Qian Zhang
Keyword(s):  
Inborn Errors ◽  
Live Attenuated Vaccines ◽  
Inborn Errors Of Immunity ◽  
Life Threatening

scholarly journals Targeted NGS Yields Plentiful Ultra-Rare Variants in Inborn Errors of Immunity Patients

Genes ◽  
2021 ◽  
Vol 12 (9) ◽  
pp. 1299
Author(s):  
Alice Grossi ◽  
Maurizio Miano ◽  
Marina Lanciotti ◽  
Francesca Fioredda ◽  
Daniela Guardo ◽  
...  
Keyword(s):  
Rare Variants ◽  
Causative Gene ◽  
Inborn Errors ◽  
Variants Of Unknown Significance ◽  
Inborn Errors Of Immunity ◽  
Complex Patients ◽  
Unknown Significance ◽  
Gene Panels ◽  
Clinical Pictures ◽  
Next Generation Sequencing Ngs

Inborn errors of immunity (IEI) include a large group of inherited diseases sharing either poor, dysregulated, or absent and/or acquired function in one or more components of the immune system. Next-generation sequencing (NGS) has driven a rapid increase in the recognition of such defects, though the wide heterogeneity of genetically diverse but phenotypically overlapping diseases has often prevented the molecular characterization of the most complex patients. Two hundred and seventy-two patients were submitted to three successive NGS-based gene panels composed of 58, 146, and 312 genes. Along with pathogenic and likely pathogenic causative gene variants, accounting for the corresponding disorders (37/272 patients, 13.6%), a number of either rare (probably) damaging variants in genes unrelated to patients’ phenotype, variants of unknown significance (VUS) in genes consistent with their clinics, or apparently inconsistent benign, likely benign, or VUS variants were also detected. Finally, a remarkable amount of yet unreported variants of unknown significance were also found, often recurring in our dataset. The NGS approach demonstrated an expected IEI diagnostic rate. However, defining the appropriate list of genes for these panels may not be straightforward, and the application of unbiased approaches should be taken into consideration, especially when patients show atypical clinical pictures.

scholarly journals Life-Threatening Infections Due to Live-Attenuated Vaccines: Early Manifestations of Inborn Errors of Immunity

2019 ◽  
Vol 39 (4) ◽  
pp. 376-390 ◽  
Author(s):  
Laura Pöyhönen ◽  
Jacinta Bustamante ◽  
Jean-Laurent Casanova ◽  
Emmanuelle Jouanguy ◽  
Qian Zhang
Keyword(s):  
Inborn Errors ◽  
Live Attenuated Vaccines ◽  
Inborn Errors Of Immunity ◽  
Life Threatening

scholarly journals Inborn errors of type I IFN immunity in patients with life-threatening COVID-19

Science ◽  
2020 ◽  
Vol 370 (6515) ◽  
pp. eabd4570 ◽  
Author(s):  
Qian Zhang ◽  
Paul Bastard ◽  
Zhiyong Liu ◽  
Jérémie Le Pen ◽  
Marcela Moncada-Velez ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Rare Variants ◽  
Human Fibroblasts ◽  
Severe Infection ◽  
Type I ◽  
Type I Ifn ◽  
Loss Of Function ◽  
Inborn Errors ◽  
Life Threatening ◽  
Dependent Type

Clinical outcome upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ranges from silent infection to lethal coronavirus disease 2019 (COVID-19). We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern Toll-like receptor 3 (TLR3)– and interferon regulatory factor 7 (IRF7)–dependent type I interferon (IFN) immunity to influenza virus in 659 patients with life-threatening COVID-19 pneumonia relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally defined LOF variants underlying autosomal-recessive or autosomal-dominant deficiencies in 23 patients (3.5%) 17 to 77 years of age. We show that human fibroblasts with mutations affecting this circuit are vulnerable to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection.

scholarly journals 1441: PATHOGENIC AND POTENTIALLY PATHOGENIC INBORN ERRORS OF IMMUNITY VARIANTS IN PEDIATRIC SEVERE SEPSIS

2021 ◽  
Vol 50 (1) ◽  
pp. 723-723
Author(s):  
Kate Kernan ◽  
Lina Ghaloul-Gonzalez ◽  
Jerry Vockley ◽  
Janette Lamb ◽  
Deborah Hollingshead ◽  
...  
Keyword(s):  
Severe Sepsis ◽  
Inborn Errors ◽  
Inborn Errors Of Immunity

scholarly journals Severe infectious diseases of childhood as monogenic inborn errors of immunity

2015 ◽  
Vol 112 (51) ◽  
pp. E7128-E7137 ◽  
Author(s):  
Jean-Laurent Casanova
Keyword(s):  
Infectious Diseases ◽  
Human Genetics ◽  
Single Gene ◽  
Incomplete Penetrance ◽  
Healthy Children ◽  
Genetic Theory ◽  
Inborn Errors ◽  
Inborn Errors Of Immunity ◽  
Life Threatening ◽  
Genetically Determined

This paper reviews the developments that have occurred in the field of human genetics of infectious diseases from the second half of the 20th century onward. In particular, it stresses and explains the importance of the recently described monogenic inborn errors of immunity underlying resistance or susceptibility to specific infections. The monogenic component of the genetic theory provides a plausible explanation for the occurrence of severe infectious diseases during primary infection. Over the last 20 y, increasing numbers of life-threatening infectious diseases striking otherwise healthy children, adolescents, and even young adults have been attributed to single-gene inborn errors of immunity. These studies were inspired by seminal but neglected findings in plant and animal infections. Infectious diseases typically manifest as sporadic traits because human genotypes often display incomplete penetrance (most genetically predisposed individuals remain healthy) and variable expressivity (different infections can be allelic at the same locus). Infectious diseases of childhood, once thought to be archetypal environmental diseases, actually may be among the most genetically determined conditions of mankind. This nascent and testable notion has interesting medical and biological implications.

Life-threatening infectious diseases of childhood: single-gene inborn errors of immunity?

2010 ◽  
Vol 1214 (1) ◽  
pp. 18-33 ◽  
Author(s):  
Alexandre Alcaïs ◽  
Lluis Quintana-Murci ◽  
David S. Thaler ◽  
Erwin Schurr ◽  
Laurent Abel ◽  
...  
Keyword(s):  
Infectious Diseases ◽  
Single Gene ◽  
Inborn Errors ◽  
Inborn Errors Of Immunity ◽  
Life Threatening

Acute hepatic porphyrias for the neurologist: current concepts and perspectives

2021 ◽  
Author(s):  
Paulo Victor Sgobbi de Souza ◽  
Bruno de Mattos Lombardi Badia ◽  
Igor Braga Farias ◽  
Eduardo Augusto Gonçalves ◽  
Wladimir Bocca Vieira de Rezende Pinto ◽  
...  
Keyword(s):  
Central Nervous System Involvement ◽  
Therapeutic Interventions ◽  
Inborn Errors ◽  
Intravenous Glucose ◽  
Inherited Metabolic Disorders ◽  
Life Threatening ◽  
Acute Porphyrias ◽  
Diagnostic Work ◽  
Atypical Presentations ◽  
Interfering Rna

ABSTRACT Background: Acute hepatic porphyrias represent an expanding group of complex inherited metabolic disorders due to inborn errors of metabolism involving heme biosynthesis. Objective: We aimed to review the main clinical and therapeutic aspects associated with acute hepatic porphyrias. Methods: The authors provided a wide non-systematic review of current concepts and recently acquired knowledge about acute hepatic porphyrias. Results: Acute neurovisceral attacks are the most common and life-threatening presentation of this group and are often considered the main clinical manifestation by clinicians during differential diagnosis and the start of proper diagnostic work-up for acute porphyrias. However, atypical presentations with central nervous system involvement, neuropsychiatric disturbances, and some subtypes with photosensitivity usually make the definite diagnosis difficult and late. Early therapeutic interventions are essential during emergency treatment and intercritical periods to avoid recurrent severe presentations. The availability of new disease-modifying therapeutic proposals based on small interfering RNA (siRNA)-based therapies, complementary to the classic intravenous glucose infusion and hemin-based treatments, emphasizes the importance of early diagnosis and genetic counseling of patients. Conclusions: This review article highlights the main biochemical, pathophysiological, clinical, and therapeutic aspects of acute hepatic porphyrias in clinical practice.

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