{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T17:28:33Z","timestamp":1792517313248,"version":"4.5.0"},"reference-count":37,"publisher":"Springer Science and Business Media LLC","issue":"2","license":[{"start":{"date-parts":[[2019,12,19]],"date-time":"2019-12-19T00:00:00Z","timestamp":1576713600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"},{"start":{"date-parts":[[2019,12,19]],"date-time":"2019-12-19T00:00:00Z","timestamp":1576713600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"}],"funder":[{"DOI":"10.13039\/501100000066","name":"Canadian Child Health Clinician Scientist Program","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000066","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012280","name":"Rare Disease Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100012280","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Clin Immunol"],"published-print":{"date-parts":[[2020,2]]},"DOI":"10.1007\/s10875-019-00731-3","type":"journal-article","created":{"date-parts":[[2019,12,19]],"date-time":"2019-12-19T03:02:17Z","timestamp":1576724537000},"page":"267-276","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["A Germline Mutation in the C2 Domain of PLC\u03b32 Associated with Gain-of-Function Expands the Phenotype for PLCG2-Related Diseases"],"prefix":"10.1007","volume":"40","author":[{"given":"Taylor","family":"Novice","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amina","family":"Kariminia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kate L.","family":"Del Bel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henry","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehul","family":"Sharma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chinten J.","family":"Lim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jay","family":"Read","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark Vander","family":"Lugt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark C.","family":"Hannibal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"O\u2019Dwyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirie","family":"Hosler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Scharnitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason M","family":"Rizzo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Zacur","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Priatel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sayeh","family":"Abdossamadi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Bohm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Junker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart E.","family":"Turvey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirk R.","family":"Schultz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4036-2105","authenticated-orcid":false,"given":"Jacob","family":"Rozmus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,12,19]]},"reference":[{"issue":"18","key":"731_CR1","doi-asserted-by":"publisher","first-page":"4677","DOI":"10.1093\/emboj\/cdg457","volume":"22","author":"M Nishida","year":"2003","unstructured":"Nishida M, Sugimoto K, Hara Y, et al. Amplification of receptor signaling by Ca2+ entry-mediated translocation and activation of PLC\u03b32 in B lymphocytes. EMBO J. 2003;22(18):4677\u201388.","journal-title":"EMBO J"},{"issue":"4","key":"731_CR2","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1056\/NEJMoa1102140","volume":"366","author":"MJ Ombrello","year":"2012","unstructured":"Ombrello MJ, Remmers EF, Sun G, et al. Cold urticarial, immunodeficiency, and autoimmunity related to PLCG2 deletions. N Engl J Med. 2012;366(4):330\u20138.","journal-title":"N Engl J Med"},{"issue":"4","key":"731_CR3","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1016\/j.ajhg.2012.08.006","volume":"91","author":"Q Zhou","year":"2012","unstructured":"Zhou Q, Lee GS, Brady J, et al. A hypermorphic missense mutation in PLCG2, encoding phospholipase C\u03b32, causes a dominantly inherited autoinflammatory disease with immunodeficiency. Am J Hum Genet. 2012;91(4):713\u201320.","journal-title":"Am J Hum Genet"},{"key":"731_CR4","doi-asserted-by":"publisher","first-page":"2863","DOI":"10.3389\/fimmu.2018.02863","volume":"9","author":"JF Neves","year":"2018","unstructured":"Neves JF, Doffinger R, Barcena-Morales G, et al. Novel PLCG2 mutation in a patient with APLAID and cutis laxa. Front Immunol. 2018;9:2863.","journal-title":"Front Immunol"},{"issue":"1","key":"731_CR5","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1001\/jamaoncol.2014.218","volume":"1","author":"KJ Maddocks","year":"2015","unstructured":"Maddocks KJ, Ruppert AS, Lozanski G, et al. Etiology of Ibrutinib therapy discontinuation and outcomes in patients with chronic lymphocytic leukemia. JAMA Oncol. 2015 Apr;1(1):80\u20137.","journal-title":"JAMA Oncol"},{"key":"731_CR6","doi-asserted-by":"publisher","first-page":"11589","DOI":"10.1038\/ncomms11589","volume":"7","author":"JA Burger","year":"2016","unstructured":"Burger JA, Landau DA, Taylor-Weiner A, et al. Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition. Nat Commun. 2016 May 20;7:11589. https:\/\/doi.org\/10.1038\/ncomms11589.","journal-title":"Nat Commun"},{"issue":"5","key":"731_CR7","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1093\/bioinformatics\/btp698","volume":"26","author":"H Li","year":"2009","unstructured":"Li H, Durbin R. Fast and accurate long-read alignment with Burrows-Wheeler transform. Bioinformatics. 2009;26(5):589\u201395.","journal-title":"Bioinformatics."},{"issue":"16","key":"731_CR8","doi-asserted-by":"publisher","first-page":"2078","DOI":"10.1093\/bioinformatics\/btp352","volume":"25","author":"H Li","year":"2009","unstructured":"Li H, Handsaker B, Wysoker A, et al. The sequence alignment\/map format and SAMtools. Bioinformatics. 2009;25(16):2078\u20139.","journal-title":"Bioinformatics."},{"issue":"2","key":"731_CR9","doi-asserted-by":"publisher","first-page":"80","DOI":"10.4161\/fly.19695","volume":"6","author":"P Cingolani","year":"2012","unstructured":"Cingolani P, Platts A, Wang L, et al. A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3. Fly (Austin). 2012;6(2):80\u201392.","journal-title":"Fly (Austin)"},{"issue":"1","key":"731_CR10","doi-asserted-by":"publisher","first-page":"308","DOI":"10.1093\/nar\/29.1.308","volume":"29","author":"ST Sherry","year":"2001","unstructured":"Sherry ST. Ward MH, Kholodov M, et al. dbSNP: the NCBI database of genetic variation. Nucleic Acids Res. 2001;29(1):308\u201311.","journal-title":"Nucleic Acids Res"},{"issue":"Database issue","key":"731_CR11","doi-asserted-by":"publisher","first-page":"D945","DOI":"10.1093\/nar\/gkq929","volume":"39","author":"SA Forbes","year":"2011","unstructured":"Forbes SA, Bindal N, Bamford S, et al. COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer. Nucleic Acids Res. 2011;39(Database issue):D945\u201350.","journal-title":"Nucleic Acids Res"},{"issue":"8","key":"731_CR12","doi-asserted-by":"publisher","first-page":"1155","DOI":"10.1093\/bioinformatics\/btr100","volume":"27","author":"AP Fejes","year":"2011","unstructured":"Fejes AP, Khodabakhshi AH, Birol I, et al. Human variation database: an open-source database template for genomic discovery. Bioinformatics. 2011;27(8):1155\u20136.","journal-title":"Bioinformatics."},{"issue":"7616","key":"731_CR13","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1038\/nature19057","volume":"536","author":"M Lek","year":"2016","unstructured":"Lek M, Karczewski KJ, Minikel EV, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536(7616):285\u201391.","journal-title":"Nature."},{"key":"731_CR14","unstructured":"1000 Genomes Project Consortium, Auton A, Brooks LD, et al. Nature. 2015;526(7571):68\u201374."},{"issue":"D1","key":"731_CR15","doi-asserted-by":"publisher","first-page":"D862","DOI":"10.1093\/nar\/gkv1222","volume":"44","author":"MJ Landrum","year":"2016","unstructured":"Landrum MJ, Lee JM, Benson M, et al. ClinVar: public archive of interpretations of clinically relevant variants. Nucleic Acids Res. 2016;44(D1):D862\u20138.","journal-title":"Nucleic Acids Res"},{"issue":"D1","key":"731_CR16","doi-asserted-by":"publisher","first-page":"D886","DOI":"10.1093\/nar\/gky1016","volume":"47","author":"P Rentzsch","year":"2019","unstructured":"Rentzsch P, Witten D, Cooper GM, Shendure J, Kircher M. CADD: predicting the deleteriousness of variants throughout the human genome. Nucleic Acids Res. 2019;47(D1):D886\u201394.","journal-title":"Nucleic Acids Res"},{"issue":"5","key":"731_CR17","first-page":"761","volume":"31","author":"D Quang","year":"2015","unstructured":"Quang D. Chen Y, Xie X. DANN: a deep learning approach for annotating the pathogenicity of genetic variants. 2015;31(5):761\u20133.","journal-title":"DANN: a deep learning approach for annotating the pathogenicity of genetic variants"},{"issue":"4","key":"731_CR18","doi-asserted-by":"publisher","first-page":"877","DOI":"10.1016\/j.ajhg.2016.08.016","volume":"99","author":"NM Ioannidis","year":"2016","unstructured":"Ioannidis NM, Rothstein JH, Pejaver V, et al. REVEL: an ensemble method for predicting the pathogenicity of rare missense variants. Am J Hum Genet. 2016;99(4):877\u201385.","journal-title":"Am J Hum Genet"},{"issue":"8","key":"731_CR19","doi-asserted-by":"publisher","first-page":"2125","DOI":"10.1093\/hmg\/ddu733","volume":"24","author":"C Dong","year":"2015","unstructured":"Dong C, Wei P, Jian X, et al. Comparison and integration of deleteriousness prediction methods for nonsynonymous SNVs in whole exome sequencing studies. Hum Mol Genet. 2015;24(8):2125\u201337.","journal-title":"Hum Mol Genet"},{"issue":"12","key":"731_CR20","doi-asserted-by":"publisher","first-page":"1581","DOI":"10.1038\/ng.3703","volume":"48","author":"KA Jagadeesh","year":"2016","unstructured":"Jagadeesh KA, Wenger AM, Berger MJ, et al. M-CAP eliminates a majority of variants of uncertain significance in clinical exomes at high sensitivity. Nat Genet. 2016;48(12):1581\u20136.","journal-title":"Nat Genet"},{"key":"731_CR21","doi-asserted-by":"publisher","first-page":"10576","DOI":"10.1038\/srep10576","volume":"5","author":"Q Lu","year":"2015","unstructured":"Lu Q, Hu Y, Sun J, et al. A statistical framework to predict functional non-coding regions in the human genome through integrated analysis of annotation data. Sci Rep. 2015;5:10576.","journal-title":"Sci Rep"},{"issue":"4","key":"731_CR22","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1038\/nmeth0410-248","volume":"7","author":"IA Adzhubei","year":"2010","unstructured":"Adzhubei IA, Schmidt S, Peshkin L, et al. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7(4):248\u20139.","journal-title":"Nat Methods"},{"issue":"4","key":"731_CR23","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1038\/nmeth.2890","volume":"11","author":"JM Schwarz","year":"2014","unstructured":"Schwarz JM, Cooper DN, Schuelke M, et al. MutationTaster2: mutation prediction for the deep-sequencing age. Nat Methods. 2014;11(4):361\u20132.","journal-title":"Nat Methods"},{"issue":"Web Server issu","key":"731_CR24","doi-asserted-by":"publisher","first-page":"W452","DOI":"10.1093\/nar\/gks539","volume":"40","author":"NL Sim","year":"2012","unstructured":"Sim NL, Kumar P, Hu J, et al. SIFT web server: predicting effects of amino acid substitutions on proteins. Nucleic Acids Res. 2012;40(Web Server issue):W452\u20137.","journal-title":"Nucleic Acids Res"},{"key":"731_CR25","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1186\/1479-7364-8-11","volume":"8","author":"HA Shihab","year":"2014","unstructured":"Shihab HA, Gough J, Mort M, et al. Ranking non-synonymous single nucleotide polymorphisms based on disease concepts. Hum Genomics. 2014;8:11. https:\/\/doi.org\/10.1186\/1479-7364-8-11.","journal-title":"Hum Genomics"},{"issue":"16","key":"731_CR26","doi-asserted-by":"publisher","first-page":"2745","DOI":"10.1093\/bioinformatics\/btv195","volume":"31","author":"Y Choi","year":"2015","unstructured":"Choi Y, Chan AP. PROVEAN web server: a tool to predict the functional effect of amino acid substitutions and indels. Bioinformatics. 2015;31(16):2745\u20137.","journal-title":"Bioinformatics."},{"issue":"12","key":"731_CR27","doi-asserted-by":"publisher","first-page":"7305","DOI":"10.4049\/jimmunol.1000434","volume":"184","author":"C Foerster","year":"2010","unstructured":"Foerster C, Voelxen N, Rakhmanov M, et al. B cell receptor-mediated calcium signaling is impaired in B lymphocytes of type Ia patients with common variable immunodeficiency. J Immunol. 2010;184(12):7305\u201313.","journal-title":"J Immunol"},{"issue":"6","key":"731_CR28","doi-asserted-by":"publisher","first-page":"1353","DOI":"10.1111\/j.1538-7836.2010.03838.x","volume":"8","author":"M Elvers","year":"2010","unstructured":"Elvers M, Pozgaj R, Pleines I, et al. Platelet hyperreactivity and a prothrombotic phenotype in mice with a gain-of-function mutation in phospholipase Cgamma2. J Thromb Haemost. 2010;8(6):1353\u201363.","journal-title":"J Thromb Haemost"},{"issue":"9","key":"731_CR29","doi-asserted-by":"publisher","first-page":"690","DOI":"10.1038\/nri2152","volume":"7","author":"S Feske","year":"2007","unstructured":"Feske S. Calcium signaling in lymphocyte activation and disease. Nat Rev Immunol. 2007;7(9):690\u2013702.","journal-title":"Nat Rev Immunol"},{"issue":"Pt 6","key":"731_CR30","doi-asserted-by":"publisher","first-page":"927","DOI":"10.1242\/jcs.061051","volume":"123","author":"T Numaga","year":"2010","unstructured":"Numaga T, Nishida M, Kiyonaka S, et al. Ca2+ influx and protein scaffolding via TRPC3 sustain PKCbeta and ERK activation in B cells. J Cell Sci. 2010;123(Pt 6):927\u201338.","journal-title":"J Cell Sci"},{"issue":"11","key":"731_CR31","doi-asserted-by":"publisher","first-page":"5354","DOI":"10.4049\/jimmunol.1301326","volume":"191","author":"M Engelke","year":"2013","unstructured":"Engelke M, Oellerich T, Dittmann K, et al. Cutting edge: feed-forward activation of phospholipase C\u03b32 via C2 domain-mediated binding to SLP65. J Immunol. 2013;191(11):5354\u20138.","journal-title":"J Immunol"},{"issue":"13","key":"731_CR32","doi-asserted-by":"publisher","first-page":"5569","DOI":"10.1073\/pnas.0701005104","volume":"104","author":"M Gymnopoulos","year":"2007","unstructured":"Gymnopoulos M, Elsliger MA, Vogt PK. Rare cancer-specific mutations in PIK3CA show gain of function. PNAS. 2007;104(13):5569\u201374.","journal-title":"PNAS."},{"key":"731_CR33","unstructured":"Szymanski AM, Baysac K, Marcy H, et al. PLCG2 variants influence CVID susceptibility: expanding the spectrum of PLCG2-associated immune dysregulation. 20218 ACR\/ARHP Annual Meeting. Abstract Number: 1971."},{"issue":"8","key":"731_CR34","doi-asserted-by":"publisher","first-page":"2237","DOI":"10.1002\/eji.200425054","volume":"34","author":"SE Bell","year":"2004","unstructured":"Bell SE, Vigorito E, McAdams S, et al. PLCgamma2 regulates Bcl-2 levels and is required for survival rather than differentiation of marginal zone and follicular B cells. Eur J Immunol. 2004;34(8):2237\u201347.","journal-title":"Eur J Immunol"},{"issue":"1","key":"731_CR35","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/S1074-7613(00)00005-4","volume":"13","author":"D Wang","year":"2000","unstructured":"Wang D, Feng J, Marine JC, et al. Phospholipase Cgamma2 is essential in the functions of B cell and several Fc receptors. Immunity. 2000;13(1):25\u201335.","journal-title":"Immunity."},{"issue":"3","key":"731_CR36","doi-asserted-by":"publisher","first-page":"681","DOI":"10.1084\/jem.20082100","volume":"206","author":"M Hikida","year":"2009","unstructured":"Hikida M, Casola S, Takahashi N, et al. PLC-gamma2 is essential for formation and maintenance of memory B cells. J Exp Med. 2009;206(3):681\u20139.","journal-title":"J Exp Med"},{"issue":"3","key":"731_CR37","doi-asserted-by":"publisher","first-page":"607","DOI":"10.1084\/jem.20091673","volume":"207","author":"SL Rowland","year":"2010","unstructured":"Rowland SL, DePersis CL, Torres RM, Pelanda R. Ras activation of Erk restores impaired tonic BCR signaling and rescues immature B cell differentiation. J Exp Med. 2010;207(3):607\u201321.","journal-title":"J Exp Med"}],"container-title":["Journal of Clinical Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10875-019-00731-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s10875-019-00731-3\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10875-019-00731-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,8]],"date-time":"2025-04-08T02:28:46Z","timestamp":1744079326000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s10875-019-00731-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12,19]]},"references-count":37,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2020,2]]}},"alternative-id":["731"],"URL":"https:\/\/doi.org\/10.1007\/s10875-019-00731-3","relation":{},"ISSN":["0271-9142","1573-2592"],"issn-type":[{"value":"0271-9142","type":"print"},{"value":"1573-2592","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,12,19]]},"assertion":[{"value":"27 September 2018","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 December 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 December 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Written informed consent for genetic testing and participation for all three patients was provided by the parent and\/or for their children in accordance with the Declaration of Helsinki. Blood was collected from healthy pediatric sex-matched donors after consent at BC Children\u2019s Hospital or through the BC Children\u2019s Hospital BioBank. This research study was approved by the University of British Columbia institutional review board.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with Ethical Standards"}}]}}