2021 Oct 23;1-9.
 doi: 10.1007/s10875-021-01151-y. Online ahead of print.

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

Hassan Abolhassani12Ahmad Vosughimotlagh3Takaki Asano4Nils Landegren56Bertrand Boisson478Samaneh Delavari2Paul Bastard78Maribel Aranda-Guillén6Yating Wang1Fanglei Zuo1Fabian Sardh56Harold Marcotte9Likun Du1Shen-Ying Zhang4Qian Zhang4Nima Rezaei2Olle Kämpe610Jean-Laurent Casanova47811Lennart Hammarström1Qiang Pan-Hammarströmqiang.pan-hammarstrom@ki.se." href="https://pubmed.ncbi.nlm.nih.gov/34686943/#affiliation-12" ref="linksrc=author_aff" style="box-sizing: inherit; background-color: rgb(241, 241, 241); color: rgb(50, 58, 69); text-decoration: none; font-size: inherit; display: inline-block; line-height: 1; padding: 0.1rem 0.3rem; border-radius: 2px; transition: color 0.3s ease 0s; margin-right: 0px;">12


  • 1Department of Biosciences and Nutrition, Karolinska Institutet, 14183, Huddinge, Sweden.
  • 2Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.
  • 3Department of Pediatrics, North Khorasan University of Medical Sciences, Bojnurd, Iran.
  • 4St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.
  • 5Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
  • 6Centre for Molecular Medicine, Department of Medicine (Solna), Karolinska Institute, Stockholm, Sweden.
  • 7Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France.
  • 8University of Paris, Imagine Institute, Paris, France.
  • 9Department of Laboratory Medicine, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden.
  • 10Department of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital, Stockholm, Sweden.
  • 11Howard Hughes Medical Institute, New York, NY, USA.
  • 12Department of Biosciences and Nutrition, Karolinska Institutet, 14183, Huddinge, Sweden. qiang.pan-hammarstrom@ki.se.
Free PMC article


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.

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