@article {1006, title = {Detection of homozygous and hemizygous complete or partial exon deletions by whole-exome sequencing.}, journal = {NAR Genom Bioinform}, volume = {3}, year = {2021}, month = {2021 Jun}, pages = {lqab037}, abstract = {

The detection of copy number variations (CNVs) in whole-exome sequencing (WES) data is important, as CNVs may underlie a number of human genetic disorders. The recently developed HMZDelFinder algorithm can detect rare homozygous and hemizygous (HMZ) deletions in WES data more effectively than other widely used tools. Here, we present HMZDelFinder_opt, an approach that outperforms HMZDelFinder for the detection of HMZ deletions, including partial exon deletions in particular, in WES data from laboratory patient collections that were generated over time in different experimental conditions. We show that using an optimized reference control set of WES data, based on a PCA-derived Euclidean distance for coverage, strongly improves the detection of HMZ complete exon deletions both in real patients carrying validated disease-causing deletions and in simulated data. Furthermore, we develop a sliding window approach enabling HMZDelFinder_opt to identify HMZ partial deletions of exons that are undiscovered by HMZDelFinder. HMZDelFinder_opt is a timely and powerful approach for detecting HMZ deletions, particularly partial exon deletions, in WES data from inherently heterogeneous laboratory patient collections.

}, issn = {2631-9268}, doi = {10.1093/nargab/lqab037}, author = {Bigio, Benedetta and Seeleuthner, Yoann and Kerner, Gaspard and Migaud, M{\'e}lanie and Rosain, J{\'e}r{\'e}mie and Boisson, Bertrand and Nasca, Carla and Puel, Anne and Bustamante, Jacinta and Casanova, Jean-Laurent and Abel, Laurent and Cobat, Aurelie} } @article {1003, title = {Inhibition of HECT E3 ligases as potential therapy for COVID-19.}, journal = {Cell Death Dis}, volume = {12}, year = {2021}, month = {2021 03 24}, pages = {310}, abstract = {

SARS-CoV-2 is responsible for the ongoing world-wide pandemic which has already taken more than two million lives. Effective treatments are urgently needed. The enzymatic activity of the HECT-E3 ligase family members has been implicated in the cell egression phase of deadly RNA viruses such as Ebola through direct interaction of its VP40 Protein. Here we report that HECT-E3 ligase family members such as NEDD4 and WWP1 interact with and ubiquitylate the SARS-CoV-2 Spike protein. Furthermore, we find that HECT family members are overexpressed in primary samples derived from COVID-19 infected patients and COVID-19 mouse models. Importantly, rare germline activating variants in the NEDD4 and WWP1 genes are associated with severe COVID-19 cases. Critically, I3C, a natural NEDD4 and WWP1 inhibitor from Brassicaceae, displays potent antiviral effects and inhibits viral egression. In conclusion, we identify the HECT family members of E3 ligases as likely novel biomarkers for COVID-19, as well as new potential targets of therapeutic strategy easily testable in clinical trials in view of the established well-tolerated nature of the Brassicaceae natural compounds.

}, keywords = {Adult, Aged, Animals, Antiviral Agents, Chlorocebus aethiops, COVID-19, Endosomal Sorting Complexes Required for Transport, Female, Humans, Indoles, Male, Mice, Mice, Inbred BALB C, Middle Aged, Nedd4 Ubiquitin Protein Ligases, SARS-CoV-2, Spike Glycoprotein, Coronavirus, Ubiquitin-Protein Ligases, Ubiquitination, Vero Cells}, issn = {2041-4889}, doi = {10.1038/s41419-021-03513-1}, author = {Novelli, Giuseppe and Liu, Jing and Biancolella, Michela and Alonzi, Tonino and Novelli, Antonio and Patten, J J and Cocciadiferro, Dario and Agolini, Emanuele and Colona, Vito Luigi and Rizzacasa, Barbara and Giannini, Rosalinda and Bigio, Benedetta and Goletti, Delia and Capobianchi, Maria Rosaria and Grelli, Sandro and Mann, Justin and McKee, Trevor D and Cheng, Ke and Amanat, Fatima and Krammer, Florian and Guarracino, Andrea and Pepe, Gerardo and Tomino, Carlo and Tandjaoui-Lambiotte, Yacine and Uzunhan, Yurdagul and Tubiana, Sarah and Ghosn, Jade and Notarangelo, Luigi D and Su, Helen C and Abel, Laurent and Cobat, Aurelie and Elhanan, Gai and Grzymski, Joseph J and Latini, Andrea and Sidhu, Sachdev S and Jain, Suresh and Davey, Robert A and Casanova, Jean-Laurent and Wei, Wenyi and Pandolfi, Pier Paolo} } @article {904, title = {Autoantibodies against type I IFNs in patients with life-threatening COVID-19.}, journal = {Science}, volume = {370}, year = {2020}, month = {2020 10 23}, abstract = {

Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-ω (IFN-ω) (13 patients), against the 13 types of IFN-α (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6\% of women and 12.5\% of men.

}, keywords = {Adult, Aged, Aged, 80 and over, Antibodies, Neutralizing, Asymptomatic Infections, Autoantibodies, Betacoronavirus, Case-Control Studies, Coronavirus Infections, COVID-19, Critical Illness, Female, Humans, Immunoglobulin G, Interferon alpha-2, Interferon Type I, Male, Middle Aged, Pandemics, Pneumonia, Viral, SARS-CoV-2}, issn = {1095-9203}, doi = {10.1126/science.abd4585}, author = {Bastard, Paul and Rosen, Lindsey B and Zhang, Qian and Michailidis, Eleftherios and Hoffmann, Hans-Heinrich and Zhang, Yu and Dorgham, Karim and Philippot, Quentin and Rosain, J{\'e}r{\'e}mie and B{\'e}ziat, Vivien and Manry, Jeremy and Shaw, Elana and Haljasm{\"a}gi, Liis and Peterson, P{\"a}rt and Lorenzo, Lazaro and Bizien, Lucy and Trouillet-Assant, Sophie and Dobbs, Kerry and de Jesus, Adriana Almeida and Belot, Alexandre and Kallaste, Anne and Catherinot, Emilie and Tandjaoui-Lambiotte, Yacine and Le Pen, J{\'e}r{\'e}mie and Kerner, Gaspard and Bigio, Benedetta and Seeleuthner, Yoann and Yang, Rui and Bolze, Alexandre and Spaan, Andr{\'a}s N and Delmonte, Ottavia M and Abers, Michael S and Aiuti, Alessandro and Casari, Giorgio and Lampasona, Vito and Piemonti, Lorenzo and Ciceri, Fabio and Bilguvar, Kaya and Lifton, Richard P and Vasse, Marc and Smadja, David M and Migaud, M{\'e}lanie and Hadjadj, J{\'e}rome and Terrier, Benjamin and Duffy, Darragh and Quintana-Murci, Lluis and van de Beek, Diederik and Roussel, Lucie and Vinh, Donald C and Tangye, Stuart G and Haerynck, Filomeen and Dalmau, David and Martinez-Picado, Javier and Brodin, Petter and Nussenzweig, Michel C and Boisson-Dupuis, St{\'e}phanie and Rodr{\'\i}guez-Gallego, Carlos and Vogt, Guillaume and Mogensen, Trine H and Oler, Andrew J and Gu, Jingwen and Burbelo, Peter D and Cohen, Jeffrey I and Biondi, Andrea and Bettini, Laura Rachele and D{\textquoteright}Angio, Mariella and Bonfanti, Paolo and Rossignol, Patrick and Mayaux, Julien and Rieux-Laucat, Fr{\'e}d{\'e}ric and Husebye, Eystein S and Fusco, Francesca and Ursini, Matilde Valeria and Imberti, Luisa and Sottini, Alessandra and Paghera, Simone and Quiros-Roldan, Eugenia and Rossi, Camillo and Castagnoli, Riccardo and Montagna, Daniela and Licari, Amelia and Marseglia, Gian Luigi and Duval, Xavier and Ghosn, Jade and Tsang, John S and Goldbach-Mansky, Raphaela and Kisand, Kai and Lionakis, Michail S and Puel, Anne and Zhang, Shen-Ying and Holland, Steven M and Gorochov, Guy and Jouanguy, Emmanuelle and Rice, Charles M and Cobat, Aurelie and Notarangelo, Luigi D and Abel, Laurent and Su, Helen C and Casanova, Jean-Laurent} } @article {812, title = {A genome-wide case-only test for the detection of digenic inheritance in human exomes.}, journal = {Proc Natl Acad Sci U S A}, volume = {117}, year = {2020}, month = {2020 08 11}, pages = {19367-19375}, abstract = {

Whole-exome sequencing (WES) has facilitated the discovery of genetic lesions underlying monogenic disorders. Incomplete penetrance and variable expressivity suggest a contribution of additional genetic lesions to clinical manifestations and outcome. Some monogenic disorders may therefore actually be digenic. However, only a few digenic disorders have been reported, all discovered by candidate gene approaches applied to at least one locus. We propose here a two-locus genome-wide test for detecting digenic inheritance in WES data. This approach uses the gene as the unit of analysis and tests all pairs of genes to detect pairwise gene {\texttimes} gene interactions underlying disease. It is a case-only method, which has several advantages over classic case-control tests, in particular by avoiding recruitment of controls. Our simulation studies based on real WES data identified two major sources of type I error inflation in this case-only test: linkage disequilibrium and population stratification. Both were corrected by specific procedures. Moreover, our case-only approach is more powerful than the corresponding case-control test for detecting digenic interactions in various population stratification scenarios. Finally, we confirmed the potential of our unbiased, genome-wide approach by successfully identifying a previously reported digenic lesion in patients with craniosynostosis. Our case-only test is a powerful and timely tool for detecting digenic inheritance in WES data from patients.

}, keywords = {Craniosynostoses, Epistasis, Genetic, Exome, Genetic Linkage, Genetic Variation, Genome-Wide Association Study, High-Throughput Nucleotide Sequencing, Humans, Models, Genetic, Multifactorial Inheritance, Whole Exome Sequencing}, issn = {1091-6490}, doi = {10.1073/pnas.1920650117}, author = {Kerner, Gaspard and Bouaziz, Matthieu and Cobat, Aurelie and Bigio, Benedetta and Timberlake, Andrew T and Bustamante, Jacinta and Lifton, Richard P and Casanova, Jean-Laurent and Abel, Laurent} } @article {903, title = {Inborn errors of type I IFN immunity in patients with life-threatening COVID-19.}, journal = {Science}, volume = {370}, year = {2020}, month = {2020 10 23}, abstract = {

Clinical outcome upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ranges from silent infection to lethal coronavirus disease 2019 (COVID-19). We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern Toll-like receptor 3 (TLR3)- and interferon regulatory factor 7 (IRF7)-dependent type I interferon (IFN) immunity to influenza virus in 659 patients with life-threatening COVID-19 pneumonia relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally defined LOF variants underlying autosomal-recessive or autosomal-dominant deficiencies in 23 patients (3.5\%) 17 to 77 years of age. We show that human fibroblasts with mutations affecting this circuit are vulnerable to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection.

}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Alleles, Asymptomatic Infections, Betacoronavirus, Child, Child, Preschool, Coronavirus Infections, COVID-19, Female, Genetic Loci, Genetic Predisposition to Disease, Humans, Infant, Interferon Regulatory Factor-7, Interferon Type I, Loss of Function Mutation, Male, Middle Aged, Pandemics, Pneumonia, Viral, Receptor, Interferon alpha-beta, SARS-CoV-2, Toll-Like Receptor 3, Young Adult}, issn = {1095-9203}, doi = {10.1126/science.abd4570}, author = {Zhang, Qian and Bastard, Paul and Liu, Zhiyong and Le Pen, J{\'e}r{\'e}mie and Moncada-Velez, Marcela and Chen, Jie and Ogishi, Masato and Sabli, Ira K D and Hodeib, Stephanie and Korol, Cecilia and Rosain, J{\'e}r{\'e}mie and Bilguvar, Kaya and Ye, Junqiang and Bolze, Alexandre and Bigio, Benedetta and Yang, Rui and Arias, Andr{\'e}s Augusto and Zhou, Qinhua and Zhang, Yu and Onodi, Fanny and Korniotis, Sarantis and Karpf, L{\'e}a and Philippot, Quentin and Chbihi, Marwa and Bonnet-Madin, Lucie and Dorgham, Karim and Smith, Nika{\"\i}a and Schneider, William M and Razooky, Brandon S and Hoffmann, Hans-Heinrich and Michailidis, Eleftherios and Moens, Leen and Han, Ji Eun and Lorenzo, Lazaro and Bizien, Lucy and Meade, Philip and Neehus, Anna-Lena and Ugurbil, Aileen Camille and Corneau, Aur{\'e}lien and Kerner, Gaspard and Zhang, Peng and Rapaport, Franck and Seeleuthner, Yoann and Manry, Jeremy and Masson, Cecile and Schmitt, Yohann and Schluter, Agatha and Le Voyer, Tom and Khan, Taushif and Li, Juan and Fellay, Jacques and Roussel, Lucie and Shahrooei, Mohammad and Alosaimi, Mohammed F and Mansouri, Davood and Al-Saud, Haya and Al-Mulla, Fahd and Almourfi, Feras and Al-Muhsen, Saleh Zaid and Alsohime, FAHd and Al Turki, Saeed and Hasanato, Rana and van de Beek, Diederik and Biondi, Andrea and Bettini, Laura Rachele and D{\textquoteright}Angio{\textquoteright}, Mariella and Bonfanti, Paolo and Imberti, Luisa and Sottini, Alessandra and Paghera, Simone and Quiros-Roldan, Eugenia and Rossi, Camillo and Oler, Andrew J and Tompkins, Miranda F and Alba, Camille and Vandernoot, Isabelle and Goffard, Jean-Christophe and Smits, Guillaume and Migeotte, Isabelle and Haerynck, Filomeen and Soler-Palacin, Pere and Martin-Nalda, Andrea and Colobran, Roger and Morange, Pierre-Emmanuel and Keles, Sevgi and {\c C}{\"o}lkesen, Fatma and Ozcelik, Tayfun and Yasar, Kadriye Kart and Senoglu, Sevtap and Karabela, {\c S}emsi Nur and Rodr{\'\i}guez-Gallego, Carlos and Novelli, Giuseppe and Hraiech, Sami and Tandjaoui-Lambiotte, Yacine and Duval, Xavier and Laou{\'e}nan, C{\'e}dric and Snow, Andrew L and Dalgard, Clifton L and Milner, Joshua D and Vinh, Donald C and Mogensen, Trine H and Marr, Nico and Spaan, Andr{\'a}s N and Boisson, Bertrand and Boisson-Dupuis, St{\'e}phanie and Bustamante, Jacinta and Puel, Anne and Ciancanelli, Michael J and Meyts, Isabelle and Maniatis, Tom and Soumelis, Vassili and Amara, Ali and Nussenzweig, Michel and Garc{\'\i}a-Sastre, Adolfo and Krammer, Florian and Pujol, Aurora and Duffy, Darragh and Lifton, Richard P and Zhang, Shen-Ying and Gorochov, Guy and B{\'e}ziat, Vivien and Jouanguy, Emmanuelle and Sancho-Shimizu, Vanessa and Rice, Charles M and Abel, Laurent and Notarangelo, Luigi D and Cobat, Aurelie and Su, Helen C and Casanova, Jean-Laurent} }