@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 {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} } @article {564, title = {Tuberculosis and impaired IL-23-dependent IFN-γ immunity in humans homozygous for a common missense variant.}, journal = {Sci Immunol}, volume = {3}, year = {2018}, month = {2018 Dec 21}, abstract = {

Inherited IL-12Rβ1 and TYK2 deficiencies impair both IL-12- and IL-23-dependent IFN-γ immunity and are rare monogenic causes of tuberculosis, each found in less than 1/600,000 individuals. We show that homozygosity for the common P1104A allele, which is found in about 1/600 Europeans and between 1/1000 and 1/10,000 individuals in regions other than East Asia, is more frequent in a cohort of patients with tuberculosis from endemic areas than in ethnicity-adjusted controls ( = 8.37 {\texttimes} 10; odds ratio, 89.31; 95\% CI, 14.7 to 1725). Moreover, the frequency of P1104A in Europeans has decreased, from about 9\% to 4.2\%, over the past 4000 years, consistent with purging of this variant by endemic tuberculosis. Surprisingly, we also show that TYK2 P1104A impairs cellular responses to IL-23, but not to IFN-α, IL-10, or even IL-12, which, like IL-23, induces IFN-γ via activation of TYK2 and JAK2. Moreover, TYK2 P1104A is properly docked on cytokine receptors and can be phosphorylated by the proximal JAK, but lacks catalytic activity. Last, we show that the catalytic activity of TYK2 is essential for IL-23, but not IL-12, responses in cells expressing wild-type JAK2. In contrast, the catalytic activity of JAK2 is redundant for both IL-12 and IL-23 responses, because the catalytically inactive P1057A JAK2, which is also docked and phosphorylated, rescues signaling in cells expressing wild-type TYK2. In conclusion, homozygosity for the catalytically inactive P1104A missense variant of selectively disrupts the induction of IFN-γ by IL-23 and is a common monogenic etiology of tuberculosis.

}, issn = {2470-9468}, doi = {10.1126/sciimmunol.aau8714}, author = {Boisson-Dupuis, St{\'e}phanie and Ramirez-Alejo, Noe and Li, Zhi and Patin, Etienne and Rao, Geetha and Kerner, Gaspard and Lim, Che Kang and Krementsov, Dimitry N and Hernandez, Nicholas and Ma, Cindy S and Zhang, Qian and Markle, Janet and Martinez-Barricarte, Ruben and Payne, Kathryn and Fisch, Robert and Deswarte, Caroline and Halpern, Joshua and Bouaziz, Matthieu and Mulwa, Jeanette and Sivanesan, Durga and Lazarov, Tomi and Naves, Rodrigo and Garcia, Patricia and Itan, Yuval and Boisson, Bertrand and Checchi, Alix and Jabot-Hanin, Fabienne and Cobat, Aurelie and Guennoun, Andrea and Jackson, Carolyn C and Pekcan, Sevgi and Caliskaner, Zafer and Inostroza, Jaime and Costa-Carvalho, Beatriz Tavares and de Albuquerque, Jose Antonio Tavares and Garcia-Ortiz, Humberto and Orozco, Lorena and Ozcelik, Tayfun and Abid, Ahmed and Rhorfi, Ismail Abderahmani and Souhi, Hicham and Amrani, Hicham Naji and Zegmout, Adil and Geissmann, Fr{\'e}d{\'e}ric and Michnick, Stephen W and Muller-Fleckenstein, Ingrid and Fleckenstein, Bernhard and Puel, Anne and Ciancanelli, Michael J and Marr, Nico and Abolhassani, Hassan and Balcells, Mar{\'\i}a Elvira and Condino-Neto, Antonio and Strickler, Alexis and Abarca, Katia and Teuscher, Cory and Ochs, Hans D and Reisli, Ismail and Sayar, Esra H and El-Baghdadi, Jamila and Bustamante, Jacinta and Hammarstr{\"o}m, Lennart and Tangye, Stuart G and Pellegrini, Sandra and Quintana-Murci, Lluis and Abel, Laurent and Casanova, Jean-Laurent} }