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The IFIH1 gene, encoding melanoma differentiation‐associated protein 5 (MDA5), is an indispensable innate immune regulator involved in the early detection of viral infections. Previous studies described MDA5 dysregulation in weakened immunological responses, and increased susceptibility to microbial infections and autoimmune disorders. Monoallelic gain‐of‐function of the IFIH1 gene has been associated with multisystem disorders, namely Aicardi–Goutieres and Singleton–Merten syndromes, while biallelic loss causes immunodeficiency. In this study, nine patients suffering from recurrent infections, inflammatory diseases, severe COVID‐19 or multisystem inflammatory syndrome in children (MIS‐C) were identified with putative loss‐of‐function IFIH1 variants by whole‐exome sequencing. All patients revealed signs of lymphopaenia and an increase in inflammatory markers, including CRP, amyloid A, ferritin and IL‐6. One patient with a pathogenic homozygous variant c.2807+1G>A was the most severe case showing immunodeficiency and glomerulonephritis. The c.1641+1G>C variant was identified in the heterozygous state in patients suffering from periodic fever, COVID‐19 or MIS‐C, while the c.2016delA variant was identified in two patients with inflammatory bowel disease or MIS‐C. There was a significant association between IFIH1 monoallelic loss of function and susceptibility to infections in males. Expression analysis showed that PBMCs of one patient with a c.2016delA variant had a significant decrease in ISG15, IFNA and IFNG transcript levels, compared to normal PBMCs, upon stimulation with Poly(I:C), suggesting that MDA5 receptor truncation disrupts the immune response. Our findings accentuate the implication of rare monogenic IFIH1 loss‐of‐function variants in altering the immune response, and severely predisposing patients to inflammatory and infectious diseases, including SARS‐CoV‐2‐related disorders. [ABSTRACT FROM AUTHOR]

Background: Exome- or genome-based panels-also known as slices or virtual panels-are now a popular approach that involves comprehensive genomic sequencing while restricting analysis to subsets of genes based on patients' phenotypes. This flexible strategy enables frequent gene updates based on novel disease associations as well as reflexing to analyzing other genes up to the whole exome or genome. With recent improvements addressing limitations associated with virtual panels, the advantages of this approach, relative to static custom-based panels, remain to be systematically characterized., Methods: Here we perform slice testing on 1014 patients (50.5% females; average age 17 years) referred from multiple pediatric clinics within a single center in the Middle East (83% Arab population)., Results: Initial analysis uncovered molecular diagnoses for 235 patients for a diagnostic yield of 23% (235/1014). "On the fly" focused analysis in most negative cases (N = 779) identified clinically significant variants correlating with patients' presentations in genes outside the originally ordered panel for another 35 patients (3.5% or 35/1024) increasing the overall diagnostic yield to 27%. The pathogenic variants underlying the additional cases (13% of all positive cases) were excluded from the original "panel" gene list, mainly as result of issues related to panel selection, novel gene-disease associations, phenotype spectrum broadening, or gene lists variability. The additional findings led to changes in clinical management in most patients (94%)., Conclusions: Our findings support slice testing as an efficient and flexible platform that facilitates updates to gene lists to achieve high clinical sensitivity and utility., (© Association for Diagnostics & Laboratory Medicine 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)