X-Linked Tlr7 Deficiency Underlies Critical Covid-19 Pneumonia in a Male Patient With Ataxia-Telangiectasia Publisher Pubmed



Abolhassani H^{1, 2} ; Vosughimotlagh A³ ; Asano T⁴ ; Landegren N^{5, 6} ; Boisson B^{4, 7, 8} ; Delavari S² ; Bastard P^{7, 8} ; Arandaguillen M⁶ ; Wang Y¹ ; Zuo F¹ ; Sardh F^{5, 6} ; Marcotte H⁹ ; Du L¹ ; Zhang SY⁴ Show All Authors
Source: Journal of Clinical Immunology Published:2022

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. © 2021, The Author(s).