Recurrent and Prolonged Infections in a Child with a Homozygous IFIH1 Nonsense Mutation

Abstract

In an Egyptian girl born to consanguineous parents, whole-exome sequencing (WES) identified a homozygous mutation in PHGDH, c.1273G>A (p.Val425Met), indicating 3-phosphoglycerate dehydrogenase deficiency. This diagnosis was compatible with the patient’s microcephaly, severe psychomotor retardation, seizures and cataracts. However, she additionally suffered from recurrent (at least monthly) episodes of prolonged and severe chest infections requiring hospitalization, suggesting a secondary, predisposing and potentially Mendelian, condition. A local reactivation of an EBV infection in the respiratory tract was detected after a recent chest infection, likely representing an opportunistic infection based on a compromised immune system. Further inspection of WES data revealed a homozygous nonsense mutation, c.2665A>T (p.Lys889∗), in IFIH1, encoding MDA5. MDA5 detects long viral double-stranded RNA that is generated during replication of picorna viruses, and thereby activates the type I interferon signaling pathway. The results of Western blot analysis of protein from cultured fibroblasts of the patient indicates absence of wild type MDA5/IFIH1, compatible with NMD. We propose that, analogous to the severe course of primary influenza infection due to biallelic deficiency of a downstream effector, IRF7, homozygous loss of IFIH1 defines a novel Mendelian immunodeficiency disorder that increases susceptibility to severe viral infections. This is contrasted to heterozygous gain-of-function IFIH1 mutations in autoimmune diseases. Our findings highlight the potential of comprehensive genomic investigations in patients from consanguineous families to identify monogenic predispositions to severe infections.

Human genetics of life-threatening influenza pneumonitis

“…No further rhinovirus infections or IAV infections have been reported in this patient to date (Asgari et al 2017). The third patient suffered from recurrent severe upper and lower respiratory tract/chest infections requiring frequent hospitalization and intensive care, although the viral pathogen was not identified from her nasal swabs (Zaki et al 2017). Thus, one of the three individuals with homozygous LOF MDA5 deficiency has suffered from severe influenza infections.…”

“…Two of the 11 individuals (including parents of the index patients) carrying heterozygous LOF IFIH1 mutations reported by Asgari et al suffered from severe rhinovirus infections and 5 suffered from severe RSV infections (Asgari et al 2017). However, the heterozygous parents and siblings of the three reported homozygous patients are clinically healthy (Asgari et al 2017;Lamborn et al 2017;Zaki et al 2017). The probability of being loss-of-function intolerant (pLI) for IFIH1 is 0 (o/e = 1.25), which suggests that heterozygous LOF mutations of this gene would be tolerated in the general population.…”

“…However, there is indirect evidence to suggest that MDA5 contributes to host defense against influenza. In total, three patients with homozygous LOF IFIH1 mutations have been reported since 2017 (Asgari et al 2017;Lamborn et al 2017;Zaki et al 2017). The first suffered from recurrent severe rhinovirus infections, revealing the first genetic cause of the common cold (Lamborn et al 2017).…”

Differential metabolism -associated gene expression of duck pancreatic cells in response to two subtype s of duck hepatitis A virus type 1

“…Finally, 3-phosphoserine is converted to Lserine by PSP [24]. L-serine is an important precursor involved in various processes, such as synthesis of proteins and phospholipids as well as the synthesis of tetrahydrofolate metabolites and speci c amino acids, namely glycine, cysteine and D-serine [25,26]. Previous studies have shown that L-serine supplementation can attenuate alcoholic fatty liver formation in mice and rats [27].…”

Recent advances in understanding inherited deficiencies in immunity to infections

“…In the induction of protection against these viruses, MDA5 senses long fragments of cytosolic dsDNA, leading to the production of type I IFNs and pro-inflammatory IL-1 family of cytokines 78,79 . Several LOF mutations in IFH1, encoding MDA5, have been reported in patients suffering from severe respiratory viral infections [80][81][82] (Table 1). These mutations impaired downstream IFN signaling and led to defective control of HRV replication in vitro 80,81 .…”