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Case Reports
. 2022 Jan;42(1):1-9.
doi: 10.1007/s10875-021-01151-y. Epub 2021 Oct 23.

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

Hassan Abolhassani  1   2 , Ahmad Vosughimotlagh  3 , Takaki Asano  4 , Nils Landegren  5   6 , Bertrand Boisson  4   7   8 , Samaneh Delavari  2 , Paul Bastard  7   8 , Maribel Aranda-Guillén  6 , Yating Wang  1 , Fanglei Zuo  1 , Fabian Sardh  5   6 , Harold Marcotte  9 , Likun Du  1 , Shen-Ying Zhang  4 , Qian Zhang  4 , Nima Rezaei  2 , Olle Kämpe  6   10 , Jean-Laurent Casanova  4   7   8   11 , Lennart Hammarström  1 , Qiang Pan-Hammarström  12
Affiliations
Case Reports

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

Hassan Abolhassani et al. J Clin Immunol. 2022 Jan.

Abstract

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.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Clinical and genetic evaluation of a patient with combined ATM and TLR7 deficiencies associated with critical COVID-19 disease. Panel a shows the pedigree of the index patient; panel b shows computed tomography (CT) scan of the lung with opacification and dense consolidation on air bronchograms; panel c shows cerebral abnormalities in magnetic resonance imaging (MRI); panel d shows confirmatory Sanger sequencing in the proband and his parents; Panel e depicts the protein expression and functional activity of the TLR7 variant in response to resquimod (R848) and imidazoquinoline CL264
Fig. 2
Fig. 2
Transient normalization of IgG and IgA levels in the index patient during the acute phase of SARS-CoV-2 infection
See this image and copyright information in PMC

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