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Genetic diagnosis of primary immunodeficiencies: A survey of the French national registry

2019; Elsevier BV; Volume: 143; Issue: 4 Linguagem: Inglês

10.1016/j.jaci.2018.12.994

ISSN

1097-6825

Autores

Nizar Mahlaoui, Capucine Pïcard, Perrine Bach, Laurence Costes, Virginie Courteille, Anja Ranohavimparany, Alexandre Alcaïs, Jean-Philippe Jaı̈s, Alain Fischer, Christine Bellanné‐Chantelot, Jacinta Bustamante, Sylvie Chollet‐Martin, Christian Drouet, Véronique Frémeaux‐Bacchi, Caroline Kannengiesser, Virginie Girardin, Nathalie Lambert, Valérie Proulle, Jérémie Rosain, Marie José Stasia, Dominique Stoppa Lyonnet, Ioannis Théodorou, Wadih Abou‐Chahla, D. Adoué, Nathalie Aladjidi, Zahir Amoura, Corinne Armari‐Alla, Brigitte Bader‐Meunier, Vincent Barlogis, Sophie Bayart, Yves Bertrand, Stéphane Blanche, Damien Bodet, Bernard Bonnotte, Raphaël Borie, Patrick Boutard, Claire Briandet, Jean‐Paul Brion, Jacques Brouard, Liana Carausu, Émilie Catherinot, Nathalie Cheikh, Sarah Beaussant-Cohen, Louis‐Jean Couderc, P. Cougoul, Gérard Couillault, Geneviève de Saint Basile, Catherine Devoldère, Anne Deville, Éric Doré, Fabienne Dulieu, I. Durieu, Natacha Entz Werle, Claire Fieschi, Fanny Fouyssac, Pierre Frange, Vincent Gajdos, Lionel Galicier, Virginie Gandemer, Martine Gardembas, C. Gaud, B. Grosbois, Aurélien Guffroy, Corinne Guitton, Gaëlle Guillerm, É. Hachulla, M. Hamidou, Sophie Haro, Yves Hatchuel, Olivier Hermine, C. Hoarau, Bruno Hoën, A. Hot, S. Humbert, Arnaud Jaccard, Serge Jacquot, R. Jaussaud, Pierre-Yves Jeandel, Éric Jeziorski, Kamila Kébaïli, Anne‐Sophie Korganow, Olivier Lambotte, Fanny Lanternier, C. Larroche, Alain Le Quellec, Emmanuelle Le Moigne, Vincent Le Moing, David de Launay, Yvon Lebranchu, Marc Lecuit, Guillaume Lefèvre, Richard Lemal, Valérie Li-Thiao-Te, Olivier Lortholary, Marion Malphettes, Aude Marie‐Cardine, Nicolas Martin Silva, A. Masseau, Christian Massot, Françoise Mazingue, Étienne Merlin, Gérard Michel, Frédéric Millot, Béatrice Monlibert, Fabrice Monpoux, Despina Moshous, Luc Mouthon, Martine Münzer, Bénédicte Neven, Raphaëlle Nové-Josserand, D. Nouar, Éric Oksenhendler, O Marie, Anne Pagnier, Marlène Pasquet, Isabelle Pellier, Yves Pérel, Antoinette Perlat, Christophe Piguet, Dominique Plantaz, Pierre Quartier, Frédéric Rieux‐Laucat, P. Roblot, Pierre‐Simon Rohrlich, Bruno Royer, V. Salle, F. Sarrot-Reynauld, Amélie Servettaz, Jean-Louis Stéphan, N. Schleinitz, Felipe Suárez, L. Swiader, Sophie Taque, Caroline Thomas, Olivier Tournilhac, C. Thumerelle, Jean-Pierre Vannier, Jean‐François Viallard,

Tópico(s)

Pneumocystis jirovecii pneumonia detection and treatment

Resumo

Since the mid-1980s, continuous progress in genetics and genomics has accelerated the rapid identification of causative genetic variants leading to primary immunodeficiencies (PIDs; >300 genes),1Picard C. Bobby Gaspar H. Al-Herz W. Bousfiha A. Casanova J.L. Chatila T. et al.International Union of Immunological Societies: 2017 Primary Immunodeficiency Diseases Committee Report on Inborn Errors of Immunity.J Clin Immunol. 2018; 38: 96-128Crossref PubMed Scopus (541) Google Scholar with the noticeable exception of B-cell disorders, such as common variable immunodeficiency (CVID). The identification of these mutations not only validates a clinical diagnosis but also is useful in several other respects (more accurate prognosis on phenotype/genotype correlation, targeted therapy, and genetic counseling). When possible, every patient with a PID should receive a genetic diagnosis. By taking advantage of the French national PID registry run by the French National Reference Center for PIDs (CEREDIH),2CEREDIH: the French PID study groupThe French National Registry of Primary Immunodeficiency Disease.Clin Immunol. 2010; 135: 264-272Crossref PubMed Scopus (127) Google Scholar we retrospectively analyzed the patients' genetic diagnosis status. As of September 7, 2018, 3405 of the 6602 registered patients had undergone genetic testing (Table I, Table II, Table III, Table IV), and 2859 of these patients (43.3% of the total and 84% of those tested) received a genetic diagnosis. Mutations in 157 different genes had been identified (see Table E1 in this article's Online Repository at www.jacionline.org). After excluding cases with pending results, the overall diagnostic success rate was very high (2859/3270 [87%]). The data in Table II show that genetic tests were performed much more frequently for patients with severe combined immunodeficiency (SCID), combined immunodeficiency (CID), innate immune deficiencies, autoimmune syndromes, or hemophagocytic lymphohistiocytosis than for those with B-cell immunodeficiencies (excluding well-defined agammaglobulinemia and immunoglobulin class-switch deficiency, Table III). Quite surprisingly, the decade of birth had little influence on the likelihood of genetic testing, with the exception of patients born before 1968 (Table IV). Hence the (genetic) diagnostic delay was long for many patients (see below).Table IGenetic testing and diagnosis in patients with a PID in the CEREDIH registryNo.PercentNo. of patients in the CEREDIH registry6602100.0Genetic testing not performed (or status unknown)319748.4Genetic testing performed340551.6Mutation found285983.9Mutation not found41112.1Pending results1354.0 Open table in a new tab Table IIGenetic testing and diagnosis as a function of the main PID categoriesWhole registryTested patients (%)Pending resultsMutations found (%)All PIDs66023405 (50.6)1352859 (84.0)CVID1509195 (12.9)3448 (24.6)B-cell IDs (excluding CVID)1755351 (20.0)25236 (67.2)SCID403355 (88.1)6334 (96.9)CIDs15761356 (86.1)321224 (90.3)AI/HLH619518 (83.7)12456 (88.0)Innate ID673609 (90.5)19561 (92.3)AI, Autoimmune and immune dysregulation syndromes; B-cell ID, B-cell immunodeficiencies (excluding CVID); HIgM, hyper-IgM syndromes (excluding CD40 and CD40 ligand deficiencies); HLH, hemophagocytic lymphohistiocytosis; ID, immune deficiency; Innate ID, immunodeficiencies of the innate immune system. Open table in a new tab Table IIIGenetic diagnosis as a function of the decade of birthWhole registryTested patients (%)Pending resultsMutations found (%)Decade of birth66023405 (50.6)1352859 (84.0) 90%) had CVID or hypogammaglobulinemia and thus were unlikely to receive a genetic diagnosis. Thus these factors were unlikely to significantly affect our overall results. Over recent years, remarkable progress has been made in reducing the time interval between clinical and genetic diagnosis for all types of PIDs. We observed a slight geographic bias in the likelihood of genetic diagnosis reflecting distribution of overall patients' place of living, indicating that the network of test laboratories operates effectively. Nevertheless, the proportion of patients for whom conventional genetic testing has not given a diagnosis remains for some groups of PID. The first group comprises patients who have not been tested because they have been registered very recently and patients in whom an ill-defined diagnosis (eg, CVID) has not prompted genetic testing. The gene identification rate has not yet reached a plateau; thus it is extremely likely that many other causative mutations in previously unsuspected genes will be found in the near future.Fig E2Genetic testing and diagnosis by PID group, age, and sex. Abbreviations are the same as in Table II. Dark gray bars correspond to the proportion of patients with a genetic diagnosis.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Fig E3Genetic testing and diagnosis as a function of year of birth (n = 6602 patients). Dark gray bars correspond to the proportion of patients with a genetic diagnosis.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Fig E4Genetic testing and diagnosis as a function of the year of clinical diagnosis (n = 6252 patients). Dark gray bars correspond to the proportion of patients with a genetic diagnosis.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Fig E5Genetic testing and diagnosis as a function of the year of clinical diagnosis and the PID group (n = 6252 patients). The abbreviations are the same as in Fig E2. Dark gray bars correspond to the proportion of patients with a genetic diagnosis.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Fig E6Prevalence of patients with a PID in mainland France. A, All living patients with a PID and a documented place of residence (n = 5593 patients; overall prevalence, 8.64 per 105 inhabitants; P < .0001, Moran I test and Geary C test). B, All living patients with a PID with a genetic diagnosis and a documented place of residence (n = 2153 patients; prevalence, 3.33 per 105 inhabitants; P < .0001, Moran I test and Geary C test).View Large Image Figure ViewerDownload Hi-res image Download (PPT)Table E1Numbers of patients with a genetic diagnosisGeneNo. of patientsGeneNo. of patientsGeneNo. of patientsATM330CYBA10CASP102BTK209RPSA10CD79A2WAS200NCF29CFH2Del 22q11.2176ZAP709IL10RA2CYBB164CFI8MyD882STAT3-LOF102RFXAP7PGM32IL2RG89C86CFP2RAG178IL10RB6STX112STAT168MST1 (STK4)6TBK12PRF165TTC376TCF32RFXANK55CARD95TINF22TNFRSF6 (FAS)97CD3E5ARPC1B1CD40LG (TNFSF5)52IL17RA5BLNK1UNC13D52IRAK45C91ADA44LIG45CD201DCLRE1C44MHC2TA5CD211BIRC439TERT5CD271SH2D1A38UNC93B15CD3D1JAK33511q234CD3G1NCF135AK24CD3Z1C233C34CD40 (TNFRSF5)1PIK3CD-GOF33CARD114CD551RAB27A29CD194CD701TTC7A29CORO1A4CEBPE1GATA228IFNGR24CHD71RAG228IKAROS4CSF2RA1TACI28IL2Ralpha4DKC11FOXP327ITK4FOXN11IKBKG (NEMO)22MSN4GINS11AIRE21NFKB24ICOS1CTLA421NFKBIA4IGHM1ITGB221ORAI14IKBKB1STXBP221PNP4IL17F1RMRP19RLTPR4IL12B1DOCK817STAT3-GOF4ILR101IL12RB114TLR34KRAS1C713TRNT14LCK1IL7R13ACT13MAGT11PIK3R113BAFFR3MYSM11AICDA12CD8A3PARN1C512PRKDC3PLCG21CXCR412HOIL1 (RBCK1)3PRKDC1IFNGR112IL21R3PSTPIP11C611LAD33RECQL41TNFSF6 (FASL)11NFKB13SAMHD11POLE111PRKCD3SKIV2L1TMEM17311RTEL13STIM11C410SMARCAL13TERC1DNMT3B10TRIF3TRAF31LRBA10BLM2TCN21LYST10C1s2UNG1ZBTB241GOF, Gain of function; LOF, loss of function. Open table in a new tab Table E2Genetic diagnosis frequency among patients with a well-characterized PIDNo.Genetic diagnosis, no.PercentTotal105590686AT36833090CGD24621889WAS23820084XLP927784GS2332988LAD1242188CHS291034APECED252184APECED, Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy; AT, ataxia telangiectasia; CGD, chronic granulomatous disease; CHS, Chediak-Higashi syndrome; GS2, Griscelli syndrome, type 2; LAD1, leukocyte adhesion deficiency type 1; XLP, X-linked lymphoproliferative disease; WAS, Wiskott-Aldrich syndrome. Open table in a new tab Table E3Genetic diagnosis frequency by decade of birth among patients with a PID (distributed in 29 entries)PID categoriesCEREDIH registry (n = 6602)Genetic documentation (n = 2859)No. (%)<19681968-19771978-19871988-19971998-20072008-2018Overall no. of patients∗Percentages refer to the overall number of patients (n = 6602).N = 1441Patients with a genetic documentation†Percentages refer to the number of patients in the same decade.N = 119Overall no. of patients∗Percentages refer to the overall number of patients (n = 6602).N = 618Patients with a genetic documentation†Percentages refer to the number of patients in the same decade.N = 192Overall no. of patients∗Percentages refer to the overall number of patients (n = 6602).N = 921Patients with a genetic documentation†Percentages refer to the number of patients in the same decade.N = 425Overall no. of patients∗Percentages refer to the overall number of patients (n = 6602).N = 1190Patients with a genetic documentation†Percentages refer to the number of patients in the same decade.N = 654Overall no. of patients∗Percentages refer to the overall number of patients (n = 6602).N = 1500Patients with a genetic documentation†Percentages refer to the number of patients in the same decade.N = 825Overall no. of patients∗Percentages refer to the overall number of patients (n = 6602).N = 932Patients with a genetic documentation†Percentages refer to the number of patients in the same decade.N = 644Agammaglobulinemia2952157318 (6.1%)13 (6.05%)24 (8.14%)18 (8.37%)45 (15.25%)30 (13.95%)65 (22.03%)50 (23.26%)83 (28.14%)64 (29.77%)60 (20.34%)40 (18.6%)ALPS132113868 (6.06%)7 (6.19%)10 (7.58%)10 (8.85%)27 (20.45%)22 (19.47%)33 (25%)29 (25.66%)30 (22.73%)26 (23.01%)24 (18.18%)19 (16.81%)APECED2521841 (4%)0 (0%)0 (0%)0 (0%)5 (20%)4 (19.05%)4 (16%)2 (9.52%)10 (40%)10 (47.62%)5 (20%)5 (23.81%)Asplenia3710278 (21.62%)2 (20%)0 (0%)0 (0%)3 (8.11%)1 (10%)5 (13.51%)4 (40%)13 (35.14%)2 (20%)8 (21.62%)1 (10%)Ataxia telangiectasia and other DNA-breakage disorders3683469415 (4.08%)13 (3.76%)58 (15.76%)56 (16.18%)75 (20.38%)71 (20.52%)92 (25%)89 (25.72%)79 (21.47%)72 (20.81%)49 (13.32%)45 (13.01%)Autoimmune and autoinflammatory and immune dysregulation syndromes5822382 (3.45%)1 (4.55%)0 (0%)0 (0%)5 (8.62%)3 (13.64%)8 (13.79%)1 (4.55%)24 (41.38%)9 (40.91%)19 (32.76%)8 (36.36%)CD27 deficiency111000 (0%)0 (0%)0 (0%)0 (0%)0 (0%)0 (0%)0 (0%)0 (0%)0 (0%)0 (0%)1 (100%)1 (100%)CGD246218899 (3.66%)5 (2.29%)25 (10.16%)23 (10.55%)54 (21.95%)47 (21.56%)56 (22.76%)50 (22.94%)61 (24.8%)55 (25.23%)41 (16.67%)38 (17.43%)CHS2910340 (0%)0 (0%)2 (6.9%)1 (10%)10 (34.48%)2 (20%)5 (17.24%)0 (0%)7 (24.14%)2 (20%)5 (17.24%)5 (50%)CID8445746843 (5.09%)18 (3.14%)34 (4.03%)15 (2.61%)126 (14.93%)75 (13.07%)188 (22.27%)135 (23.52%)266 (31.52%)192 (33.45%)187 (22.16%)139 (24.22%)Complement deficiencies1061059911 (10.38%)11 (10.48%)7 (6.6%)7 (6.67%)17 (16.04%)17 (16.19%)29 (27.36%)29 (27.62%)22 (20.75%)21 (20%)20 (18.87%)20 (19.05%)CSR defects and HIgM syndromes3313396 (18.18%)3 (23.08%)7 (21.21%)2 (15.38%)2 (6.06%)0 (0%)9 (27.27%)6 (46.15%)8 (24.24%)2 (15.38%)1 (3.03%)0 (0%)CVID1509483807 (53.48%)16 (33.33%)253 (16.77%)4 (8.33%)220 (14.58%)6 (12.5%)148 (9.81%)8 (16.67%)65 (4.31%)9 (18.75%)16 (1.06%)5 (10.42%)Early-onset multiorgan autoimmune disease551000 (0%)0 (0%)0 (0%)0 (0%)1 (20%)1 (20%)0 (0%)0 (0%)4 (80%)4 (80%)0 (0%)0 (0%)FHLH197140710 (0%)0 (0%)4 (2.03%)0 (0%)15 (7.61%)6 (4.29%)59 (29.95%)34 (24.29%)59 (29.95%)49 (35%)60 (30.46%)51 (36.43%)GS23330911 (3.03%)1 (3.33%)2 (6.06%)0 (0%)2 (6.06%)1 (3.33%)7 (21.21%)7 (23.33%)14 (42.42%)14 (46.67%)7 (21.21%)7 (23.33%)HIES126103828 (6.35%)7 (6.8%)13 (10.32%)9 (8.74%)26 (20.63%)24 (23.3%)32 (25.4%)25 (24.27%)30 (23.81%)23 (22.33%)17 (13.49%)15 (14.56%)HSE1715882 (11.76%)2 (13.33%)1 (5.88%)1 (6.67%)3 (17.65%)2 (13.33%)9 (52.94%)8 (53.33%)1 (5.88%)1 (6.67%)1 (5.88%)1 (6.67%)Hypogammaglobulinemia142781466 (32.66%)0 (0%)117 (8.2%)0 (0%)120 (8.41%)0 (0%)198 (13.88%)2 (25%)399 (27.96%)2 (25%)127 (8.9%)4 (50%)IPEX/IPEX-like4737790 (0%)0 (0%)0 (0%)0 (0%)1 (2.13%)1 (2.7%)5 (10.64%)5 (13.51%)16 (34.04%)12 (32.43%)25 (53.19%)19 (51.35%)LAD24241000 (0%)0 (0%)0 (0%)0 (0%)6 (25%)6 (25%)7 (29.17%)7 (29.17%)6 (25%)6 (25%)5 (20.83%)5 (20.83%)MonoMAC2928973 (10.34%)3 (10.71%)3 (10.34%)3 (10.71%)2 (6.9%)2 (7.14%)12 (41.38%)11 (39.29%)8 (27.59%)8 (28.57%)1 (3.45%)1 (3.57%)MSMD5852904 (6.9%)3 (5.77%)7 (12.07%)7 (13.46%)7 (12.07%)7 (13.46%)11 (18.97%)9 (17.31%)17 (29.31%)14 (26.92%)12 (20.69%)12 (23.08%)Other innate PIDs13997709 (6.47%)5 (5.15%)13 (9.35%)11 (11.34%)14 (10.07%)10 (10.31%)27 (19.42%)17 (17.53%)47 (33.81%)30 (30.93%)29 (20.86%)24 (24.74%)SCID403334830 (0%)0 (0%)12 (2.98%)10 (2.99%)64 (15.88%)45 (13.47%)83 (20.6%)62 (18.56%)122 (30.27%)110 (32.93%)122 (30.27%)107 (32.04%)Unclassified PIDs67006 (8.96%)0 (0%)6 (8.96%)0 (0%)12 (17.91%)0 (0%)11 (16.42%)0 (0%)16 (23.88%)0 (0%)16 (23.88%)0 (0%)WAS238201846 (2.52%)2 (1%)14 (5.88%)11 (5.47%)34 (14.29%)23 (11.44%)63 (26.47%)48 (23.88%)63 (26.47%)60 (29.85%)58 (24.37%)57 (28.36%)WHIM1712714 (23.53%)3 (25%)2 (11.76%)1 (8.33%)4 (23.53%)3 (25%)3 (17.65%)1 (8.33%)4 (23.53%)4 (33.33%)0 (0%)0 (0%)XLP9277844 (4.35%)4 (5.19%)4 (4.35%)3 (3.9%)21 (22.83%)16 (20.78%)21 (22.83%)15 (19.48%)26 (28.26%)24 (31.17%)16 (17.39%)15 (19.48%)ALPS, Autoimmune lymphoproliferative syndrome; APECED, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy; CGD, chronic granulomatous disease; CHS, Chediak-Higashi syndrome; CSR, class-switch recombination; FHLH, familial hemophagocytic lymphohistiocytosis; GS2, Griscelli syndrome, type 2; HIES, hyper-IgE syndrome; HSE, herpes simplex encephalitis; IPEX, immunodysregulation, polyendocrinopathy, enteropathy X-linked; LAD, leukocyte adhesion deficiency; MonoMAC, monocytopenia and Mycobacterium avium complex syndrome; MSMD, Mendelian susceptibility to mycobacterial infections; WAS, Wiskott-Aldrich syndrome; WHIM, warts, hypogammaglobulinemia, immunodeficiency, and myelokathexis; XLP, X-linked lymphoproliferative disease.∗ Percentages refer to the overall number of patients (n = 6602).† Percentages refer to the number of patients in the same decade. Open table in a new tab GOF, Gain of function; LOF, loss of function. APECED, Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy; AT, ataxia telangiectasia; CGD, chronic granulomatous disease; CHS, Chediak-Higashi syndrome; GS2, Griscelli syndrome, type 2; LAD1, leukocyte adhesion deficiency type 1; XLP, X-linked lymphoproliferative disease; WAS, Wiskott-Aldrich syndrome. ALPS, Autoimmune lymphoproliferative syndrome; APECED, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy; CGD, chronic granulomatous disease; CHS, Chediak-Higashi syndrome; CSR, class-switch recombination; FHLH, familial hemophagocytic lymphohistiocytosis; GS2, Griscelli syndrome, type 2; HIES, hyper-IgE syndrome; HSE, herpes simplex encephalitis; IPEX, immunodysregulation, polyendocrinopathy, enteropathy X-linked; LAD, leukocyte adhesion deficiency; MonoMAC, monocytopenia and Mycobacterium avium complex syndrome; MSMD, Mendelian susceptibility to mycobacterial infections; WAS, Wiskott-Aldrich syndrome; WHIM, warts, hypogammaglobulinemia, immunodeficiency, and myelokathexis; XLP, X-linked lymphoproliferative disease.

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