Asgari, SamiraSchlapbach, Luregn JAnchisi, StéphanieHammer, ChristianBartha, IstvanJunier, ThomasMottet-Osman, GenevièvePosfay-Barbe, Klara MLongchamp, DavidStocker, MartinCordey, SamuelKaiser, LaurentRiedel, ThomasKenna, TonyLong, DeborahSchibler, AndreasTelenti, AmalioTapparel, CarolineMcLaren, Paul JGarcin, DominiqueFellay, Jacques2017-08-212017-08-212017-08-21201710.1073/pnas.1704259114https://infoscience.epfl.ch/handle/20.500.14299/139778WOS:000406653300065Viral respiratory infections are usually mild and self-limiting; still they exceptionally result in life-threatening infections in previously healthy children. To investigate a potential genetic cause, we recruited 120 previously healthy children requiring support in intensive care because of a severe illness caused by a respiratory virus. Using exome and transcriptome sequencing, we identified and characterized three rare loss-of-function variants in IFIH1, which encodes an RIG-I-like receptor involved in the sensing of viral RNA. Functional testing of the variants IFIH1 alleles demonstrated that the resulting proteins are unable to induce IFN-β, are intrinsically less stable than wild-type IFIH1, and lack ATPase activity. In vitro assays showed that IFIH1 effectively restricts replication of human respiratory syncytial virus and rhinoviruses. We conclude that IFIH1 deficiency causes a primary immunodeficiency manifested in extreme susceptibility to common respiratory RNA viruses.respiratory syncytial virusrhinovirusIFIH1RIG-I-like receptor familysevere pediatric infectious diseasetext::journal::journal article::research article