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

Author:

Abolhassani Hassan,Vosughimotlagh Ahmad,Asano Takaki,Landegren Nils,Boisson Bertrand,Delavari Samaneh,Bastard Paul,Aranda-Guillén Maribel,Wang Yating,Zuo Fanglei,Sardh Fabian,Marcotte Harold,Du Likun,Zhang Shen-Ying,Zhang Qian,Rezaei Nima,Kämpe Olle,Casanova Jean-Laurent,Hammarström Lennart,Pan-Hammarström QiangORCID

Abstract

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.

Funder

European Union’s Horizon 2020

Foundation for the National Institutes of Health

Karolinska Institute

Publisher

Springer Science and Business Media LLC

Subject

Immunology,Immunology and Allergy

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