4.6 Article

X-Linked TLR7 Deficiency Underlies Critical COVID-19 Pneumonia in a Male Patient with Ataxia-Telangiectasia

Journal

JOURNAL OF CLINICAL IMMUNOLOGY
Volume 42, Issue 1, Pages 1-9

Publisher

SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s10875-021-01151-y

Keywords

COVID-19; critical COVID-19; inborn errors of immunity; primary immunodeficiency; antibody deficiency; ataxia-telangiectasia; ATM; TLR7

Categories

Funding

  1. Karolinska Institute
  2. European Union's Horizon 2020 research and innovation program (ATAC) [101003650]
  3. Center for Innovative Medicine at Karolinska Institutet
  4. Swedish Research Council
  5. Swedish Cancer Society
  6. Knut and Alice Wallenberg Foundation (KAW)
  7. National Institutes of Health (NIH) [R01AI088364]
  8. National Center for Advancing Translational Sciences (NCATS)
  9. NIH Clinical and Translational Science Award (CTSA) program [UL1TR001866]
  10. Emergent Ventures
  11. Mercatus Center at George Mason University
  12. Fisher Center for Alzheimer's Research Foundation
  13. Meyer Foundation
  14. JPB Foundation
  15. French National Research Agency (ANR) under the Investments for the Future program [ANR-10-IAHU-01]
  16. ANR [ANR-14-CE14-0008-01, ANR-18-CE15-0020-02, ANR-20-CO11-0001]
  17. French Foundation for Medical Research (FRM) [EQU201903007798]
  18. FRM
  19. ANR GENCOVID project [ANR-20-COVI-0003]
  20. ANRS Nord-Sud [ANRS-COV05]
  21. Square Foundation
  22. Grandir-Fonds de solidarite pour l'enfance
  23. SCOR Corporate Foundation for Science
  24. Howard Hughes Medical Institute
  25. Rockefeller University
  26. St. Giles Foundation
  27. Fondation du Souffle
  28. Institut National de la Sante et de la Recherche Medicale (INSERM)
  29. University of Paris
  30. Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence [ANR-10-LABX-62-IBEID]
  31. Agence Nationale de la Recherche (ANR) [ANR-14-CE14-0008, ANR-20-COVI-0003, ANR-18-CE15-0020] Funding Source: Agence Nationale de la Recherche (ANR)

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This study identified a unique case of a patient with a preexisting inborn error of immunity (IEI) who developed critical COVID-19 pneumonia. Genetic analysis revealed homozygous deleterious mutations in the ATM gene and a hemizygous deleterious mutation in the TLR7 gene, underlying Ataxia-Telangiectasia (A-T) and critical COVID-19 in this patient. Among other A-T patients evaluated, SARS-CoV-2 infection resulted in mild symptoms or asymptomatic cases, highlighting the importance of genetic factors in COVID-19 severity.
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.

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