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X-Linked TLR7 Deficiency Underlies Critical COVID-19 Pneumonia in a Male Patient with Ataxia-Telangiectasia
Karolinska Inst, Dept Biosci & Nutr, S-14183 Huddinge, Sweden.;Univ Tehran Med Sci, Res Ctr Immunodeficiencies, Pediat Ctr Excellence, Childrens Med Ctr, Tehran, Iran.ORCID iD: 0000-0002-4838-0407
North Khorasan Univ Med Sci, Dept Pediat, Bojnurd, Iran.
Rockefeller Univ, Rockefeller Branch, St Giles Lab Human Genet Infect Dis, 1230 York Ave, New York, NY 10021 USA.ORCID iD: 0000-0003-1424-2433
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism. Karolinska Inst, Ctr Mol Med, Dept Med Solna, Stockholm, Sweden.ORCID iD: 0000-0002-6163-9540
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2022 (English)In: Journal of Clinical Immunology, ISSN 0271-9142, E-ISSN 1573-2592, Vol. 42, no 1, p. 1-9Article in journal (Refereed) Published
Abstract [en]

Background Coronavirus disease 2019 (COVID-19) exhibits a wide spectrum of clinical manifestations, ranging from asymptomatic to critical conditions. Understanding the mechanism underlying life-threatening COVID-19 is instrumental for disease prevention and treatment in individuals with a high risk.

Objectives We aimed to identify the genetic cause for critical COVID-19 pneumonia in a patient with a preexisting inborn error of immunity (IEI).

Methods Serum levels of specific antibodies against the virus and autoantibodies against type I interferons (IFNs) were measured. Whole exome sequencing was performed, and the impacts of candidate gene variants were investigated. We also evaluated 247 ataxia-telangiectasia (A-T) patients in the Iranian IEI registry.

Results We report a 7-year-old Iranian boy with a preexisting hyper IgM syndrome who developed critical COVID-19 pneumonia. IgM only specific COVID-19 immune response was detected but no autoantibodies against type I IFN were observed. A homozygous deleterious mutation in the ATM gene was identified, which together with his antibody deficiency, radiosensitivity, and neurological signs, established a diagnosis of A-T. Among the 247 A-T patients evaluated, 36 had SARS-CoV-2 infection, but all had mild symptoms or were asymptomatic except the index patient. A hemizygous deleterious mutation in the TLR7 gene was subsequently identified in the patient.

Conclusions We report a unique IEI patient with combined ATM and TLR7 deficiencies. The two genetic defects underlie A-T and critical COVID-19 in this patient, respectively.

Place, publisher, year, edition, pages
2022. Vol. 42, no 1, p. 1-9
Keywords [en]
COVID-19, critical COVID-19, inborn errors of immunity, primary immunodeficiency, antibody deficiency, ataxia-telangiectasia, ATM, TLR7
National Category
Immunology in the medical area Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
URN: urn:nbn:se:uu:diva-470070DOI: 10.1007/s10875-021-01151-yISI: 000710443300001PubMedID: 34686943OAI: oai:DiVA.org:uu-470070DiVA, id: diva2:1648364
Funder
EU, Horizon 2020, 101003650Swedish Research CouncilSwedish Cancer SocietyKnut and Alice Wallenberg FoundationAvailable from: 2022-03-30 Created: 2022-03-30 Last updated: 2022-08-22Bibliographically approved

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Landegren, NilsSardh, Fabian

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Abolhassani, HassanAsano, TakakiLandegren, NilsSardh, Fabian
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AutoimmunityScience for Life Laboratory, SciLifeLabDepartment of Medical Biochemistry and MicrobiologyClinical diabetology and metabolism
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Immunology in the medical areaPublic Health, Global Health, Social Medicine and Epidemiology

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