Clinical exome sequencing data from patients with inborn errors of immunity: Cohort level diagnostic yield and the benefit of systematic reanalysis.

While next generation sequencing has expanded the scientific understanding of Inborn Errors of Immunity (IEI), the clinical use and re-use of exome sequencing is still emerging. We revisited clinical exome data from 1300 IEI patients using an updated in silico IEI gene panel. Variants were classified and curated through expert review. The molecular diagnostic yield after standard exome analysis was 11.8 %. Through systematic reanalysis, we identified variants of interest in 5.2 % of undiagnosed patients, with 76.7 % being (candidate) disease-causing, providing a (candidate) diagnosis in 15.2 % of our cohort. We find a 1.7 percentage point increase in conclusive molecular diagnoses. We find a high degree of actionability in patients with a genetic diagnosis (76.4 %). Despite the modest absolute diagnostic gain, these data support the benefit of iterative exome reanalysis in IEI patients, conveying the notion that our current understanding of genes and variants involved in IEI is by far not saturated.

Clinical Presentation and Management of Multisystem Inflammatory Syndrome in Children With COVID-19: A Systematic Review.

Multisystem inflammatory syndrome in children (MIS-C) is a relatively new syndrome associated with coronavirus disease 2019 (COVID-19) that is characterized by a severe clinical course compared to pediatric COVID-19. This review aimed to compile the available evidence on the clinical presentation and management of MIS-C in children with COVID-19. During this systematic review, a comprehensive search was performed in the following databases: PubMed, Embase, Medline, Google Scholar, Cochrane, and Scopus, using predetermined search terms, such as Medical Subject Headings (MeSH) and keywords to find relevant studies on the MIS-C. Relevant data were extracted, and the quality of the studies was evaluated using suitable methods. The collected findings were synthesized and discussed in the study. The World Health Organization's (WHO) definition of MIS-C was the most favored due to its precision and inclusiveness. MIS-C primarily affected children aged 6-12 years, with male predominance. MIS-C involves a range of systems, including gastrointestinal, cardiovascular, hematologic, mucocutaneous, and respiratory. Radiographic findings revealed cardiovascular abnormalities, solid visceral organ involvement, and bowel abnormalities, reflecting a systemic inflammatory process. Laboratory investigations unveiled elevated inflammatory markers, neutrophil activation, release of extracellular traps in vessels, elevated procalcitonin, hyponatremia, hypoalbuminemia, low hemoglobin, and thrombocytopenia. The inflammatory markers and autoantibody profiles are essential in differentiating MIS-C from COVID-19. The preferred treatment primarily involves immunomodulatory therapies like intravenous immunoglobulin (IVIG), glucocorticoids, and interleukin-6 or 1RA inhibitors or a combination of those. In severe cases, extracorporeal membrane oxygenation (ECMO) and mechanical ventilation are necessary, leading to reduced mortality and quick recovery. This review found that the average hospital stay was seven days, and most discharged children fully recovered within seven days. MIS-C is a life-threatening post-COVID-19 condition and involves multiple systems due to systemic inflammation, with elevated inflammation markers. Recognition of multisystem involvement is crucial, and prompt identification and multidisciplinary treatment are vital for optimal outcomes.

Multiple Family Members With Delayed Cord Separtion and Combined Immunodeficiency With Novel Mutation in IKBKB.

Background: Inhibitor of kappa kinase 2 (IKK2) deficiency is a recently described combined immunodeficiency. It undermines the nuclear factor-kappa B (NF-κB) activation pathway. Methods: The clinical and immunological data of four patients diagnosed with combined immunodeficiency (CID) from two related Saudi families were collected. Autozygosity mapping of all available members and whole exome sequencing of the index case were performed to define the genetic etiology. Results: The patients had early onset (2-4 months of age) severe infections caused by viruses, bacteria, mycobacteria, and fungi. They all had hypogammaglobulinemia and low absolute lymphocyte count. Their lymphocytes failed to respond to PHA mitogen stimulation. A novel homozygous non-sense mutation in the IKBKB gene, c.850C>T (p. Arg284*) was identified in the index patient and segregated with the disease in the rest of the family. He underwent hematopoietic stem cell transplantation (HSCT) from a fully matched sibling with no conditioning. The other three patients succumbed to their disease. Interestingly, all patients had delayed umbilical cord separation. Conclusion: IKK2 deficiency causes CID with high mortality. Immune reconstitution with HSCT should be considered as early as possible. Delayed umbilical cord separation in CID patients may be a clue to IKK2 deficiency.

Exome sequencing in routine diagnostics: a generic test for 254 patients with primary immunodeficiencies.

BACKGROUND: Diagnosis of primary immunodeficiencies (PIDs) is complex and cumbersome yet important for the clinical management of the disease. Exome sequencing may provide a genetic diagnosis in a significant number of patients in a single genetic test. METHODS: In May 2013, we implemented exome sequencing in routine diagnostics for patients suffering from PIDs. This study reports the clinical utility and diagnostic yield for a heterogeneous group of 254 consecutively referred PID patients from 249 families. For the majority of patients, the clinical diagnosis was based on clinical criteria including rare and/or unusual severe bacterial, viral, or fungal infections, sometimes accompanied by autoimmune manifestations. Functional immune defects were interpreted in the context of aberrant immune cell populations, aberrant antibody levels, or combinations of these factors. RESULTS: For 62 patients (24%), exome sequencing identified pathogenic variants in well-established PID genes. An exome-wide analysis diagnosed 10 additional patients (4%), providing diagnoses for 72 patients (28%) from 68 families altogether. The genetic diagnosis directly indicated novel treatment options for 25 patients that received a diagnosis (34%). CONCLUSION: Exome sequencing as a first-tier test for PIDs granted a diagnosis for 28% of patients. Importantly, molecularly defined diagnoses indicated altered therapeutic options in 34% of cases. In addition, exome sequencing harbors advantages over gene panels as a truly generic test for all genetic diseases, including in silico extension of existing gene lists and re-analysis of existing data.

Biallelic RIPK1 mutations in humans cause severe immunodeficiency, arthritis, and intestinal inflammation.

RIPK1 (receptor-interacting serine/threonine kinase 1) is a master regulator of signaling pathways leading to inflammation and cell death and is of medical interest as a drug target. We report four patients from three unrelated families with complete RIPK1 deficiency caused by rare homozygous mutations. The patients suffered from recurrent infections, early-onset inflammatory bowel disease, and progressive polyarthritis. They had immunodeficiency with lymphopenia and altered production of various cytokines revealed by whole-blood assays. In vitro, RIPK1-deficient cells showed impaired mitogen-activated protein kinase activation and cytokine secretion and were prone to necroptosis. Hematopoietic stem cell transplantation reversed cytokine production defects and resolved clinical symptoms in one patient. Thus, RIPK1 plays a critical role in the human immune system.