A number sign (#) is used with this entry because of evidence that COVID-19-related immunodeficiency-74 (IMD74) is caused by hemizygous mutation in the TLR7 gene (300365) on chromosome Xp22.

Immunodeficiency-74 (IMD74) is an X-linked recessive specific immunologic disorder characterized by the development of severe respiratory insufficiency in response to infection with the COVID-19 coronavirus, also known as SARS-CoV-2 ssRNA coronavirus. Affected individuals usually require mechanical ventilation in the ICU in order to survive. Laboratory studies show activation of the immune response and may show perturbation of some values, such as increased D-dimers and fibrinogen. In vitro functional studies of patient immune cells show impaired signaling through the TLR7 pathway, resulting in defective type I and type II interferon (IFN) responses. The patients reported to date did not have a history of immunodeficiency or chronic disease (summary by van Der Made et al., 2020).

Van der Made et al. (2020) reported 2 pairs of adult brothers from 2 unrelated families (family 1 of Dutch ancestry and family 2 of African ancestry) who developed severe respiratory insufficiency associated with proven COVID-19 (SARS-CoV-2) infection. The patients, who ranged in age from 21 to 32 years, had no significant medical history, except for nonallergic rhinitis in 1 and a history of malaria infection in another. None had a history of notable recurrent infections or chronic disease. Symptoms at disease onset included cough, fever, dyspnea, myalgia, and nausea with vomiting. Chest imaging showed bilateral pulmonary consolidations or ground-glass opacities with dense infiltrates. All required mechanical ventilatory support in the ICU; the time from symptom onset to ICU admission ranged from 6 to 11 days, and time spent in the ICU ranged from 10 to 16 days. One patient died at age 29 years after developing a concurrent bacterial superinfection, whereas the others survived. One of the 3 survivors had readmission due to secondary right-sided pneumothorax. Laboratory studies showed appropriately increased white blood cell count and increased levels of the inflammatory marker C-reactive protein. Two patients tested had elevated D-dimers and ferritin, and one of these patients also had increased fibrinogen.

Zhang et al. (2022) identified 7 boys from 5 families with IMD74 from an international cohort of 112 children less than 16 years of age who were hospitalized for COVID-19 pneumonia, accounting for 6% of children and 9% of boys in the study. None of the affected patients had a previous adverse reaction to the MMR vaccination, and only 1 had failure to thrive and a previous history of infections, including recurrent fever, upper respiratory infections, and osteomyelitis of the hip, and had been diagnosed with hyper-IgM syndrome with treatment with IVIg. Pneumonia was moderate in 1, severe in 3, and critical in 3; all survived. Sequencing of other family members identified 2 persons with the same TLR7 variant genotype, a 52-year-old maternal uncle who had critical COVID-19 pneumonia and an 8-year-old brother who had asymptomatic SARS-CoV-2 infection. This second case suggested incomplete penetrance.

The transmission pattern of IMD74 in the families reported by van der Made et al. (2020) was consistent with X-linked recessive inheritance.

In 4 affected men from 2 unrelated families with IMD74, van der Made et al. (2020) identified hemizygous mutations in the TLR7 gene: a frameshift (300365.0001) and a missense (V795F; 300365.0002) mutation. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were not present in the gnomAD database. In family 1, the mutation was inherited from the unaffected mother; studies of the unaffected mother in family 2 were not performed. In vitro functional studies showed that peripheral blood cells from the 3 patients tested did not show enhanced expression of TLR7 in response to the agonist imiquimod, in contrast to controls. Patient cells showed defective agonist-induced upregulation of type I IFN-related genes in the TLR7 pathway, such as IRF7 (605047), IFNB1 (147640), and ISG15 (147571), consistent with a loss-of-function effect. Mononuclear cells derived from both index patients also showed impaired gamma-interferon (IFNG; 147570) production in response to TLR7 stimulation, indicating defects in the type II IFN signaling pathway. However, the IFNG response to stimulation with C. albicans was intact, showing a normal capacity to produce IFNG. The authors hypothesized that TLR7 deficiency could lead to impaired viral clearance, thereby increasing the direct cytopathic viral effects and ensuing hyperinflammatory response. The findings supported a role for TLR7 as a recognizer of ssRNA viruses such as SARS-CoV-2 and possibly MERS-CoV and SARS-CoV, and also demonstrated that the TLR7-signaling pathway is a critical inducer of type I and type II IFN responses to SARS-CoV-2 in humans.

Using whole-exome or whole-genome sequencing in an international cohort of 112 children less than 16 years of age who were hospitalized for COVID-19 pneumonia, Zhang et al. (2022) identified 7 boys (P5-P11) from 5 families who were hemizygous for variants in TLR7, consistent with IMD74. None of these variants were found in a control population of 1,224 children and adults with benign SARS-CoV-2 without pneumonia. X-linked TLR7 deficiency was seen in 6% of children and 9% of boys with COVID-19 pneumonia. The 5 variants were all missense (I174R, N75H, D244Y, H781L, and L372M) and were shown to cause loss of function. The TLR7 variant was inherited from an unaffected mother in 4 families and was de novo in the fifth family. Sequencing of other family members identified 2 persons with the same TLR7 variant genotype, a 52-year-old maternal uncle who had critical COVID-19 pneumonia and an 8-year-old brother who had asymptomatic SARS-CoV-2 infection. This second case suggested incomplete penetrance.