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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]

Missense variants in the RNF13 gene have been previously known to cause congenital microcephaly, epileptic encephalopathy, blindness, and failure to thrive through a gain‐of‐function disease mechanism. Here, we identify a nonsense variant, expected to result in protein truncation, in a similarly affected patient. We show that this nonsense variant, residing in the terminal exon, is likely to escape nonsense‐mediated decay while removing a critical region for protein function, thus resulting in a gain‐of‐function effect. We review the literature and disease databases and identify several other affected individuals with overlapping phenotypes carrying distinct truncating variants in the terminal exon upstream of the putative critical region. Furthermore, we analyze truncating variants from the general population, namely, the Genome Aggregation Database (gnomAD), and provide additional evidence supporting our hypothesis, and ruling out haploinsufficiency as an alternative disease mechanism. In summary, our case report, literature review, and analysis of disease and population databases strongly support the hypothesis that heterozygous gain‐of‐function variants in a critical region of RNF13 cause congenital microcephaly, epileptic encephalopathy, blindness, and failure to thrive. [ABSTRACT FROM AUTHOR]

Genetic variation in populations of Middle Eastern origin remains highly underrepresented in most comprehensive genomic databases. This underrepresentation hampers the functional annotation of the human genome and challenges accurate clinical variant interpretation. To highlight the importance of capturing genetic variation in the Middle East, we aggregated whole exome and genome sequencing data from 2116 individuals in the Middle East and established the Middle East Variation (MEV) database. Of the high-impact coding (missense and loss of function) variants in this database, 53% were absent from the most comprehensive Genome Aggregation Database (gnomAD), thus representing a unique Middle Eastern variation dataset which might directly impact clinical variant interpretation. We highlight 39 variants with minor allele frequency >1% in the MEV database that were previously reported as rare disease variants in ClinVar and the Human Gene Mutation Database (HGMD). Furthermore, the MEV database consisted of 281 putative homozygous loss of function (LoF) variants, or complete knockouts, of which 31.7% (89/281) were absent from gnomAD. This set represents either complete knockouts of 83 unique genes in reportedly healthy individuals, with implications regarding disease penetrance and expressivity, or might affect dispensable exons, thus refining the clinical annotation of those regions. Intriguingly, 24 of those genes have several clinically significant variants reported in ClinVar and/or HGMD. Our study shows that genetic variation in the Middle East improves functional annotation and clinical interpretation of the genome and emphasizes the need for expanding sequencing studies in the Middle East and other underrepresented populations. [ABSTRACT FROM AUTHOR]

The landscape and clinical utility of comprehensive genomic investigations for a wide range of pediatric rheumatic disorders have not been fully characterized in the Middle East. Here, 71 pediatric patients, of diverse Arab origins, were clinically and genetically assessed for a spectrum of rheumatology‐related diseases at the only dedicated tertiary children's hospital in the United Arab Emirates. Clinical genomic investigations included mainly (76%) next‐generation sequencing‐based gene panels and whole‐exome sequencing, along with rapid sequencing in the intensive care unit and urgent setting. The overall positive yield was 46.5%, whereas dual diagnoses were made in two cases (3%). Although the majority (21/33, 64%) of positive findings involved the MEFV gene, the remaining (12/33, 36%) alterations were attributed to 11 other genes/loci. Copy number variants (CNVs) contributed substantially (5/33, 15.2%) to the overall diagnostic yield. Sequencing‐based testing, specifically rapid sequencing, had a high positive rate and delivered timely results. Genetic findings guided clinical management plans and interventions in most cases (27/33, 81.8%). We highlight unique findings and provide additional evidence that heterozygous loss of function of the IFIH1 gene increases susceptibility to recurrent fevers. Our study provides new insights into the pathogenic variation landscape in pediatric rheumatic disorders. [ABSTRACT FROM AUTHOR]