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

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

doi:10.1007/s10875-021-01151-y

Abstract

BackgroundCoronavirus 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.ObjectivesWe aimed to identify the genetic cause for critical COVID-19 pneumonia in a patient with a preexisting inborn error of immunity (IEI).MethodsSerum 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.ResultsWe 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.ConclusionsWe 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.

Highlights

IntroductionThe coronavirus disease 2019 (COVID-19) pandemic, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has already affected more than 240
The coronavirus disease 2019 (COVID-19) pandemic, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has already affected more than 240Article Summary Line A-T patients usually present with mild or asymptomatic COVID-19 unless having additional genetic defects
Screening of COVID-19 were conducted on all registered inborn error of immunity (IEI) patients as previously described during the pandemic using reverse transcriptase-polymerase chain reactions (RT-PCR) and high-resolution computed tomography (HRCT) as well as other basic laboratory tests [12]

Summary

Introduction

The coronavirus disease 2019 (COVID-19) pandemic, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has already affected more than 240. Article Summary Line A-T patients usually present with mild or asymptomatic COVID-19 unless having additional genetic defects. The combined TLR7-ATM deficient case reported here illustrates that two genetic defects can underlie two different immunodeficiency phenotypes. Extended author information available on the last page of the article million people around the world [1] This zoonotic enveloped virus is mainly transmitted by inhalation and infected people are usually asymptomatic, or have mild upper respiratory disease, and more rarely non-hypoxemic (intermediate) pneumonia. Objectives We aimed to identify the genetic cause for critical COVID-19 pneumonia in a patient with a preexisting inborn error of immunity (IEI). The two genetic defects underlie A-T and critical COVID-19 in this patient, respectively

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