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Rare predicted loss...
Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19
- Article/chapterEnglish2022
Publisher, publication year, extent ...
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Cold Spring Harbor Laboratory,2022
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LIBRIS-ID:oai:prod.swepub.kib.ki.se:236324795
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http://kipublications.ki.se/Default.aspx?queryparsed=id:236324795URI
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https://doi.org/10.1101/2022.10.22.22281221DOI
Supplementary language notes
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Language:English
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Summary in:English
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Subject category:vet swepub-contenttype
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Subject category:art swepub-publicationtype
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BackgroundWe previously reported inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity in 1-5% of unvaccinated patients with life-threatening COVID-19, and auto-antibodies against type I IFN in another 15-20% of cases.MethodsWe report here a genome-wide rare variant burden association analysis in 3,269 unvaccinated patients with life-threatening COVID-19 (1,301 previously reported and 1,968 new patients), and 1,373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. A quarter of the patients tested had antibodies against type I IFN (234 of 928) and were excluded from the analysis.ResultsNo gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants wasTLR7, with an OR of 27.68 (95%CI:1.5-528.7,P=1.1×10−4), in analyses restricted to biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR=3.70 [95%CI:1.3-8.2],P=2.1×10−4). Adding the recently reportedTYK2COVID-19 locus strengthened this enrichment, particularly under a recessive model (OR=19.65 [95%CI:2.1-2635.4];P=3.4×10−3). When these 14 loci andTLR7were considered, all individuals hemizygous (n=20) or homozygous (n=5) for pLOF or bLOF variants were patients (OR=39.19 [95%CI:5.2-5037.0],P=4.7×10−7), who also showed an enrichment in heterozygous variants (OR=2.36 [95%CI:1.0-5.9],P=0.02). Finally, the patients with pLOF or bLOF variants at these 15 loci were significantly younger (mean age [SD]=43.3 [20.3] years) than the other patients (56.0 [17.3] years;P=1.68×10−5).ConclusionsRare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old.
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Talouarn, E
(author)
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Marchal, A
(author)
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Manry, J
(author)
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Seeleuthner, Y
(author)
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Zhang, Y
(author)
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Bolze, A
(author)
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Chaldebas, M
(author)
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Milisavljevic, B
(author)
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Zhang, P
(author)
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Gervais, A
(author)
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Bastard, P
(author)
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Asano, T
(author)
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Bizien, L
(author)
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Barzaghi, F
(author)
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Abolhassani, HKarolinska Institutet
(author)
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Tayoun, AA
(author)
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Aiuti, A
(author)
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Darazam, IA
(author)
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Allende, LM
(author)
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Alonso-Arias, R
(author)
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Arias, AA
(author)
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Aytekin, G
(author)
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Bergman, P
(author)
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Bondesan, S
(author)
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Bryceson, YT
(author)
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Bustos, IG
(author)
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Cabrera-Marante, O
(author)
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Carcel, S
(author)
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Carrera, P
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Casari, G
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Chaïbi, K
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Colobran, R
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Condino-Neto, A
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Covill, LE
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El Zein, L
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Flores, C
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Gregersen, PK
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Gut, M
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Haerynck, F
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Halwani, R
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Hancerli, S
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Hammarström, L
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Hatipoğlu, N
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Karbuz, A
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Keles, S
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Kyheng, C
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Leon-Lopez, R
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Franco, JL
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Mansouri, D
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Martinez-Picado, J
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Akcan, OM
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Migeotte, I
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Morange, PE
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Morelle, G
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Martin-Nalda, A
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Novelli, G
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Novelli, A
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Ozcelik, T
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Palabiyik, F
(author)
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Pan-Hammarström, Q
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Pérez de Diego, R
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Planas-Serra, L
(author)
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Pleguezuelo, DE
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Prando, C
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Pujol, A
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Reyes, LF
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Rivière, JG
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Rodriguez-Gallego, C
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Rojas, J
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Rovere-Querini, P
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Schlüter, A
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Shahrooei, M
(author)
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Sobh, A
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Soler-Palacin, P
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Tandjaoui-Lambiotte, Y
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Tipu, I
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Tresoldi, C
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Troya, J
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van de Beek, D
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Zatz, M
(author)
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Zawadzki, P
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Al-Muhsen, SZ
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Baris-Feldman, H
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Butte, MJ
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Constantinescu, SN
(author)
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Cooper, MA
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Dalgard, CL
(author)
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Fellay, J
(author)
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Heath, JR
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Lau, YL
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Lifton, RP
(author)
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Maniatis, T
(author)
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Mogensen, TH
(author)
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von Bernuth, H
(author)
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Lermine, A
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Vidaud, M
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Boland, A
(author)
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Deleuze, JF
(author)
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Nussbaum, R
(author)
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Kahn-Kirby, A
(author)
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Mentre, F
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Tubiana, S
(author)
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Gorochov, G
(author)
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Tubach, F
(author)
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Hausfater, P
(author)
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Meyts, I
(author)
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Zhang, SY
(author)
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Puel, A
(author)
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Notarangelo, LD
(author)
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Boisson-Dupuis, S
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Su, HC
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Boisson, B
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Jouanguy, E
(author)
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Casanova, JL
(author)
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Zhang, Q
(author)
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Abel, L
(author)
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Cobat, A
(author)
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Karolinska Institutet
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Matuozzo, D
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Talouarn, E
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Marchal, A
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Manry, J
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Seeleuthner, Y
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Zhang, Y
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Bolze, A
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Chaldebas, M
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Milisavljevic, B
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Gervais, A
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Bastard, P
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Asano, T
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Bizien, L
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Barzaghi, F
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Abolhassani, H
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Tayoun, AA
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Aiuti, A
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Darazam, IA
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Allende, LM
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Arias, AA
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El Zein, L
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Flores, C
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Gregersen, PK
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Gut, M
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Haerynck, F
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Halwani, R
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Hancerli, S
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Hammarström, L
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Hatipoğlu, N
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Karbuz, A
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Keles, S
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Kyheng, C
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Franco, JL
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Tresoldi, C
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Troya, J
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van de Beek, D
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Zatz, M
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Zawadzki, P
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Al-Muhsen, SZ
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Baris-Feldman, H
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Butte, MJ
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Constantinescu, ...
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Cooper, MA
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Dalgard, CL
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Fellay, J
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Heath, JR
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Lau, YL
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Lifton, RP
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Maniatis, T
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Mogensen, TH
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von Bernuth, H
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Lermine, A
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Vidaud, M
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Boland, A
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Deleuze, JF
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Nussbaum, R
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Kahn-Kirby, A
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Mentre, F
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Tubiana, S
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Gorochov, G
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Tubach, F
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Hausfater, P
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Meyts, I
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Zhang, SY
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Puel, A
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Notarangelo, LD
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Boisson-Dupuis, ...
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Su, HC
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Jouanguy, E
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