A number sign (#) is used with this entry because of evidence that immunodeficiency-95 (IMD95) is caused by homozygous loss-of-function mutation in the IFIH1 gene (606951) on chromosome 2q24. Heterozygous mutation in the IFIH1 gene may confer susceptibility to the disease; environmental factors are believed to play a large role in the phenotypic variability.

Immunodeficiency-95 (IMD95) is an autosomal recessive disorder characterized predominantly by the onset of recurrent and severe viral respiratory infections in infancy or early childhood. Affected individuals often require hospitalization or respiratory support for these infections, which include human rhinovirus (HRV) and RSV. Immunologic workup is usually normal, although some mild abnormalities may be observed. The disorder results from a loss of ability of the innate immune system to sense viral genetic information, which causes a lack of interferon (IFN) production, poor response to viral and immunologic stimulation, and failure to control viral replication (summary by Lamborn et al., 2017, Asgari et al., 2017, Cananzi et al., 2021).

Lamborn et al. (2017) reported a 5-year-old girl of Karenni descent from Burma with a history of intrauterine growth retardation who developed a severe upper respiratory infection at 40 days of age. PCR analysis was positive for HRV (human rhinovirus) and influenza B. The infection was complicated by respiratory failure requiring mechanical ventilation and ECMO. She subsequently had multiple recurrent viral respiratory infections often needing hospitalization, urinary tract infections, acute gastroenteritis, and bacterial infections of her feeding tube. Immunologic workup initially showed lymphopenia and low serum Ig levels, but these normalized between 3 and 4 years. She mounted functional antibodies to vaccination. In addition to IMD95, the patient also had onset of type I diabetes mellitus at age 2 years, short stature with poor growth, hypotonia, muscle weakness, and delayed motor and language development. Brain imaging showed enlarged ventricles, decreased periventricular white matter volume, and deep structural abnormalities. Microarray analysis identified a heterozygous 4-kb deletion on chromosome 2 encompassing the TM4SF20 gene (615404.0001), which is associated with language delay, white matter abnormalities, and developmental delay (SLI5; 615432). The authors concluded that this patient had several genetic problems and manifested at least 2 monogenetic disorders: IMD95 and SLI5.

Zaki et al. (2017) reported a 6-year-old Egyptian girl, born of consanguineous parents, with early-onset recurrent viral and bacterial respiratory tract infections and high fever often requiring hospitalization. She also had persistent EBV infection. Apart from elevated IgG3 and decreased IgG4, immunologic evaluation was normal. In addition to IMD95, the patient had PHGDH deficiency (601815) confirmed by genetic analysis. Features of that disease included microcephaly (-8.5 SD), lack of developmental progress, severe seizures, spasticity, and congenital cataracts.

Asgari et al. (2017) reported a 16-month-old girl who presented with respiratory failure due to RSV infection requiring invasive ventilation. The disease was complicated by a pulmonary superinfection with Staphylococcus aureus. She had a full recovery and did not develop any other severe infections up to age 3 years. Immunologic workup and response to vaccination were normal.

Cananzi et al. (2021) reported a girl (patient 1), born of consanguineous Moroccan parents, with a complex immunologic disorder. Soon after birth, she had neonatal sepsis followed by CMV infection and multiple recurrent infections in the first year of life. At 4 months, she had moderate to severe interstitial pneumonia due to parainfluenza virus type 3, which required prolonged hospitalization and oxygen therapy. She later developed central venous catheter-related bacterial sepsis. Immunologic workup showed increased memory CD4+ T cells and activated T cells. In addition, the patient developed persistent vomiting and diarrhea at 20 days of life that progressed to inflammatory diarrhea associated with nonspecific colitis and immune-mediated enteropathy. There was a good response of the gastrointestinal symptoms to steroids and sirolimus. This phenotype was consistent with very early-onset inflammatory bowel disease (VEOIBD).

The transmission pattern of IMD95 in the family reported by Lamborn et al. (2017) was consistent with autosomal recessive inheritance.

In a 5-year-old girl from Burma with IMD95, Lamborn et al. (2017), identified a homozygous missense mutation in the IFIH1 gene (K365E; 606951.0011). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was found at a low frequency in the ExAC database (0.06%) only in the heterozygous state and mainly in Asian populations. Both unaffected parents and an unaffected brother were heterozygous for the mutation. Patient cells showed normal protein levels, but the mutant protein was unable to bind to the poly(I:C) ligand, suggesting improper assembly and impaired downstream signaling. In vitro functional expression studies using a luciferase reporter assay demonstrated that the K365E mutant had minimal IFNB1 (147640) and NFKB (see 164011) promoter activity after stimulation with poly(I:C) compared to wildtype. Cotransfection of the mutant with wildtype showed no dominant-negative effects; the findings were consistent with a loss of function. Increased human rhinovirus (HRV) replication was observed in patient primary respiratory nasal epithelial cells compared to controls. However, patient nasal epithelial cells did not show increased viral replication of influenza or RSV. Similarly, silencing of IFIH1 in a respiratory epithelial cell line resulted in increased HRV transcripts, increased production of infectious virus, and decreased levels of IFN-regulated transcripts after HRV infection compared to controls, consistent with impaired viral recognition and antiviral responses. Transduction with wildtype, but not mutant, IFIH1 improved control of HRV replication. Similar to patient cells, silencing of IFIH1 did not increase replication of influenza or RSV in vitro. Overall, these findings indicated that IFIH1 has a nonredundant role in immunity against respiratory infections specifically caused by HRV. Although the patient had a history of influenza, RSV, and bacterial infections, Lamborn et al. (2017) postulated that these were secondary complications of lung injury due to early recurrent HRV infection. Genetic analysis also identified 14 other homozygous missense mutations, 2 compound heterozygous missense mutations, and 3 de novo missense mutations, but the IFIH1 mutation was computationally predicted and functional demonstrated to be deleterious.

In a 6-year-old girl, born of consanguineous Egyptian parents, with IMD95, Zaki et al. (2017) identified a homozygous nonsense mutation in the IFIH1 gene (K889X; 606951.0012). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present in the heterozygous state in the unaffected parents and sib. Western blot analysis of patient fibroblasts showed significantly decreased IFIH1 protein levels compared to controls, suggesting that the mutant transcript undergoes nonsense-mediated mRNA decay and results in a loss of function. In addition to IMD95, manifest as recurrent severe viral respiratory infections and persistent EBV infection, the patient also had a severe neurodevelopmental disorder with seizures and microcephaly associated with a homozygous missense mutation in the PHGDH gene (V425M; 606879.0002).

In 3-year-old girl (patient 1), born of consanguineous Moroccan parents, with IMD95, Cananzi et al. (2021) identified a homozygous frameshift mutation in the IFIH1 gene (606951.0013). It was predicted to result in nonsense-mediated mRNA decay or produce a truncated protein lacking important functional domains. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present in the heterozygous state in each unaffected parent. In vitro functional studies using a luciferase reporter assay showed that mutant IFIH1 failed to activate the IFNB1 (147640) promoter following stimulation, consistent with a loss-of-function effect.

In a girl (PRI_022) with IMD95, Asgari et al. (2017) identified a homozygous splice site mutation in the IFIH1 gene (606951.0014). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present at a low frequency in the gnomAD database (0.64%), including 7 homozygotes. Western blot analysis of patient cells showed that the mutant protein was expressed upon in vitro RSV infection. In vitro functional expression studies in HEK293T cells transfected with the mutation showed that the mutant protein was unstable, failed to lead to IFNB1 (147640) production, and had no detectable ATPase activity compared to wildtype, consistent with a loss-of-function effect. There was also evidence for a dominant-negative effect on the wildtype protein. Additional in vitro studies showed that RSV and HRV replication levels were increased in cells transduced with the mutation, indicating a central role for IFIH1 in innate immune recognition of RSV and HRV and in controlling these infections. Three additional children with severe early-onset viral HRC or RSV respiratory infections were heterozygous for the splice site variant and 4 further children were heterozygous for other loss-of-function variants in the IFIH1 gene, suggesting that heterozygosity may confer susceptibility to the disease. However, carrier parents were unaffected. The patients were part of a cohort of 120 children with severe manifestations of common viral respiratory infections who underwent exome sequencing.

Using mice deficient in MDA5, Kato et al. (2006) showed that MDA5 and RIGI (609631) recognize different types of double-stranded RNAs: MDA5 recognizes PIC and RIGI detects in vitro transcribed double-stranded RNAs. RNA viruses are also differentially recognized by RIGI and MDA5. Kato et al. (2006) found that RIGI is essential for the production of interferons in response to RNA viruses including paramyxoviruses, influenza virus, and Japanese encephalitis virus, whereas MDA5 is critical for picornavirus detection. Furthermore, Rig1-null and Mda5-null mice are highly susceptible to infection with these respective RNA viruses compared to control mice. Kato et al. (2006) concluded that, taken together, their data show that RIGI and MDA5 distinguish different RNA viruses and are critical for host antiviral responses.