{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T03:58:34Z","timestamp":1792468714632,"version":"4.5.0"},"reference-count":85,"publisher":"Elsevier BV","issue":"18","license":[{"start":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T00:00:00Z","timestamp":1756684800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T00:00:00Z","timestamp":1756684800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T00:00:00Z","timestamp":1756684800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-017"},{"start":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T00:00:00Z","timestamp":1756684800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T00:00:00Z","timestamp":1756684800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-012"},{"start":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T00:00:00Z","timestamp":1756684800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T00:00:00Z","timestamp":1756684800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-004"}],"funder":[{"DOI":"10.13039\/100031313","name":"Herbert Irving Comprehensive Cancer Center, Columbia University","doi-asserted-by":"publisher","award":["P30CA013696"],"award-info":[{"award-number":["P30CA013696"]}],"id":[{"id":"10.13039\/100031313","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000884","name":"Cancer Research Institute","doi-asserted-by":"publisher","award":["CRI5579"],"award-info":[{"award-number":["CRI5579"]}],"id":[{"id":"10.13039\/100000884","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100002224","name":"Melanoma Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100002224","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000861","name":"Burroughs Wellcome Fund","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000861","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["R01CA280414"],"award-info":[{"award-number":["R01CA280414"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["R37CA258829"],"award-info":[{"award-number":["R37CA258829"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["U54CA274506"],"award-info":[{"award-number":["U54CA274506"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["F30CA298572"],"award-info":[{"award-number":["F30CA298572"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["R01CA266446"],"award-info":[{"award-number":["R01CA266446"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005190","name":"Melanoma Research Alliance","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005190","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014276","name":"Pershing Square Sohn Cancer Research Alliance","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100014276","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["cell.com","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Cell"],"published-print":{"date-parts":[[2025,9]]},"DOI":"10.1016\/j.cell.2025.05.037","type":"journal-article","created":{"date-parts":[[2025,6,20]],"date-time":"2025-06-20T10:38:45Z","timestamp":1750415925000},"page":"4861-4879.e27","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":16,"title":["Scalable generation and functional classification of genetic variants in inborn errors of immunity to accelerate clinical diagnosis and treatment"],"prefix":"10.1016","volume":"188","author":[{"given":"Zachary H.","family":"Walsh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris J.","family":"Frangieh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neeharika","family":"Kothapalli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jay","family":"Levy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clarissa K.","family":"Heck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes C.","family":"Melms","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ron S.","family":"Gejman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Parin","family":"Shah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jared M.","family":"Pollard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akul","family":"Naik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah L.","family":"Grauman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei Haley","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley Sang Eun","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dusan","family":"Bogunovic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua D.","family":"Milner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2379-6702","authenticated-orcid":false,"given":"Benjamin","family":"Izar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.cell.2025.05.037_bib1","doi-asserted-by":"crossref","DOI":"10.3389\/fped.2024.1279112","article-title":"Current genetic diagnostics in inborn errors of immunity","volume":"12","author":"von Hardenberg","year":"2024","journal-title":"Front. Pediatr."},{"key":"10.1016\/j.cell.2025.05.037_bib2","doi-asserted-by":"crossref","first-page":"1780","DOI":"10.1016\/j.jaci.2015.12.1310","article-title":"Unbiased targeted next-generation sequencing molecular approach for primary immunodeficiency diseases","volume":"137","author":"Al-Mousa","year":"2016","journal-title":"J. Allergy Clin. Immunol."},{"key":"10.1016\/j.cell.2025.05.037_bib3","doi-asserted-by":"crossref","unstructured":"Gallo, V. (2016). Diagnostics of primary immunodeficiencies through next generation sequencing. https:\/\/doi.org\/10.26226\/morressier.57bc1758d462b80290b4d256.","DOI":"10.26226\/morressier.57bc1758d462b80290b4d256"},{"key":"10.1016\/j.cell.2025.05.037_bib4","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1016\/j.jaci.2016.08.003","article-title":"Exome and genome sequencing for inborn errors of immunity","volume":"138","author":"Meyts","year":"2016","journal-title":"J. Allergy Clin. Immunol."},{"key":"10.1016\/j.cell.2025.05.037_bib5","article-title":"Targeted NGS platforms for genetic screening and gene discovery in primary Immunodeficiencies","volume":"10","author":"Cifaldi","year":"2019","journal-title":"Front. Immunol."},{"key":"10.1016\/j.cell.2025.05.037_bib6","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1016\/j.jaci.2013.08.032","article-title":"Targeted next-generation sequencing: a novel diagnostic tool for primary immunodeficiencies","volume":"133","author":"Nijman","year":"2014","journal-title":"J. Allergy Clin. Immunol."},{"key":"10.1016\/j.cell.2025.05.037_bib7","doi-asserted-by":"crossref","first-page":"D980","DOI":"10.1093\/nar\/gkt1113","article-title":"ClinVar: public archive of relationships among sequence variation and human phenotype","volume":"42","author":"Landrum","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"10.1016\/j.cell.2025.05.037_bib8","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2018.00369","article-title":"Activated PI3 kinase delta syndrome: From genetics to therapy","volume":"9","author":"Michalovich","year":"2018","journal-title":"Front. Immunol."},{"key":"10.1016\/j.cell.2025.05.037_bib9","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1038\/nri.2016.93","article-title":"PI3K\u03b4 and primary immunodeficiencies","volume":"16","author":"Lucas","year":"2016","journal-title":"Nat. Rev. Immunol."},{"key":"10.1016\/j.cell.2025.05.037_bib10","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1126\/science.1243292","article-title":"Phosphoinositide 3-kinase \u03b4 gene mutation predisposes to respiratory infection and airway damage","volume":"342","author":"Angulo","year":"2013","journal-title":"Science"},{"key":"10.1016\/j.cell.2025.05.037_bib11","doi-asserted-by":"crossref","first-page":"1764","DOI":"10.1172\/JCI81746","article-title":"A human immunodeficiency caused by mutations in the PIK3R1 gene","volume":"125","author":"Deau","year":"2015","journal-title":"J. Clin. Invest."},{"key":"10.1016\/j.cell.2025.05.037_bib12","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1038\/ni.2771","article-title":"Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110\u03b4 result in T cell senescence and human immunodeficiency","volume":"15","author":"Lucas","year":"2014","journal-title":"Nat. Immunol."},{"key":"10.1016\/j.cell.2025.05.037_bib13","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1016\/j.jaci.2016.06.021","article-title":"Clinical spectrum and features of activated phosphoinositide 3-kinase \u03b4 syndrome: A large patient cohort study","volume":"139","author":"Coulter","year":"2017","journal-title":"J. Allergy Clin. Immunol."},{"key":"10.1016\/j.cell.2025.05.037_bib14","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/j.jaci.2016.03.022","article-title":"Clinical and immunologic phenotype associated with activated phosphoinositide 3-kinase \u03b4 syndrome 2: A cohort study","volume":"138","author":"Elkaim","year":"2016","journal-title":"J. Allergy Clin. Immunol."},{"key":"10.1016\/j.cell.2025.05.037_bib15","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1038\/s41590-018-0182-3","article-title":"Hyperactivated PI3K\u03b4 promotes self and commensal reactivity at the expense of optimal humoral immunity","volume":"19","author":"Preite","year":"2018","journal-title":"Nat. Immunol."},{"key":"10.1016\/j.cell.2025.05.037_bib16","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/j.jaci.2014.02.020","article-title":"Occurrence of B-cell lymphomas in patients with activated phosphoinositide 3-kinase \u03b4 syndrome","volume":"134","author":"Kracker","year":"2014","journal-title":"J. Allergy Clin. Immunol."},{"key":"10.1016\/j.cell.2025.05.037_bib17","doi-asserted-by":"crossref","first-page":"4095","DOI":"10.1016\/j.jaip.2021.07.044","article-title":"Clinical manifestations and outcomes of activated phosphoinositide 3-kinase \u03b4 syndrome from the USIDNET cohort","volume":"9","author":"Oh","year":"2021","journal-title":"J. Allergy Clin. Immunol. Pract."},{"key":"10.1016\/j.cell.2025.05.037_bib18","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2018.00446","article-title":"Exhaustion of the CD8+ T cell compartment in patients with mutations in phosphoinositide 3-kinase delta","volume":"9","author":"Wentink","year":"2018","journal-title":"Front. Immunol."},{"key":"10.1016\/j.cell.2025.05.037_bib19","doi-asserted-by":"crossref","first-page":"1783","DOI":"10.1038\/s41423-020-0379-x","article-title":"Hyperactive PI3K\u03b4 predisposes naive T cells to activation via aerobic glycolysis programs","volume":"18","author":"Jia","year":"2021","journal-title":"Cell. Mol. Immunol."},{"key":"10.1016\/j.cell.2025.05.037_bib20","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1016\/j.jaci.2017.11.042","article-title":"Mutations in PI3K110\u03b4 cause impaired natural killer cell function partially rescued by rapamycin treatment","volume":"142","author":"Ruiz-Garc\u00eda","year":"2018","journal-title":"J. Allergy Clin. Immunol."},{"key":"10.1016\/j.cell.2025.05.037_bib21","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2018.01758","article-title":"Genetic defects in phosphoinositide 3-kinase \u03b4 influence CD8+ T cell survival, differentiation, and function","volume":"9","author":"Cannons","year":"2018","journal-title":"Front. Immunol."},{"key":"10.1016\/j.cell.2025.05.037_bib22","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1016\/j.jaci.2018.04.030","article-title":"Activating PIK3CD mutations impair human cytotoxic lymphocyte differentiation and function and EBV immunity","volume":"143","author":"Edwards","year":"2019","journal-title":"J. Allergy Clin. Immunol."},{"key":"10.1016\/j.cell.2025.05.037_bib23","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1016\/j.jaci.2019.01.033","article-title":"Activating mutations in PIK3CD disrupt the differentiation and function of human and murine CD4+ T cells","volume":"144","author":"Bier","year":"2019","journal-title":"J. Allergy Clin. Immunol."},{"key":"10.1016\/j.cell.2025.05.037_bib24","article-title":"Primary immunodeficiencies: A decade of progress and a promising future","volume":"11","author":"Meyts","year":"2020","journal-title":"Front. Immunol."},{"key":"10.1016\/j.cell.2025.05.037_bib25","doi-asserted-by":"crossref","first-page":"1650","DOI":"10.1016\/j.jaci.2018.06.039","article-title":"Primary immunodeficiency disorder caused by phosphoinositide 3\u2013kinase \u03b4 deficiency","volume":"142","author":"Sogkas","year":"2018","journal-title":"J. Allergy Clin. Immunol."},{"key":"10.1016\/j.cell.2025.05.037_bib26","doi-asserted-by":"crossref","first-page":"e483","DOI":"10.3324\/haematol.2018.208397","article-title":"Immunodeficiency, autoimmune thrombocytopenia and enterocolitis caused by autosomal recessive deficiency of PIK3CD-encoded phosphoinositide 3-kinase \u03b4","volume":"104","author":"Swan","year":"2019","journal-title":"Haematologica"},{"key":"10.1016\/j.cell.2025.05.037_bib27","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/j.ajhg.2013.06.005","article-title":"Mutations in PIK3R1 cause SHORT syndrome","volume":"93","author":"Dyment","year":"2013","journal-title":"Am. J. Hum. Genet."},{"key":"10.1016\/j.cell.2025.05.037_bib28","article-title":"Paradoxical dominant negative activity of an immunodeficiency-associated activating PIK3R1 variant","author":"Tomlinson","year":"2024","journal-title":"bioRxiv"},{"key":"10.1016\/j.cell.2025.05.037_bib29","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.ajhg.2013.05.023","article-title":"SHORT syndrome with partial lipodystrophy due to impaired phosphatidylinositol 3 kinase signaling","volume":"93","author":"Chudasama","year":"2013","journal-title":"Am. J. Hum. Genet."},{"key":"10.1016\/j.cell.2025.05.037_bib30","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1111\/cge.12688","article-title":"Clinical reappraisal of SHORT syndrome with PIK3R1 mutations: towards recommendation for molecular testing and management","volume":"89","author":"Avila","year":"2015","journal-title":"Clin. Genet."},{"key":"10.1016\/j.cell.2025.05.037_bib31","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.clim.2017.03.004","article-title":"Mutations in PIK3R1 can lead to APDS2, SHORT syndrome or a combination of the two","volume":"179","author":"Bravo Garc\u00eda-Morato","year":"2017","journal-title":"Clin. Immunol."},{"key":"10.1016\/j.cell.2025.05.037_bib32","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1111\/cei.12706","article-title":"Activating PI3K\u03b4 mutations in a cohort of 669 patients with primary immunodeficiency","volume":"183","author":"Elgizouli","year":"2016","journal-title":"Clin. Exp. Immunol."},{"key":"10.1016\/j.cell.2025.05.037_bib33","doi-asserted-by":"crossref","first-page":"1152","DOI":"10.1016\/j.jaci.2017.03.026","article-title":"Novel PIK3CD mutations affecting N-terminal residues of p110\u03b4 cause activated PI3K\u03b4 syndrome (APDS) in humans","volume":"140","author":"Takeda","year":"2017","journal-title":"J. Allergy Clin. Immunol."},{"key":"10.1016\/j.cell.2025.05.037_bib34","doi-asserted-by":"crossref","first-page":"2307","DOI":"10.1182\/blood-2017-08-801191","article-title":"Effective \u201cactivated PI3K\u03b4 syndrome\u201d-targeted therapy with the PI3K\u03b4 inhibitor leniolisib","volume":"130","author":"Rao","year":"2017","journal-title":"Blood"},{"key":"10.1016\/j.cell.2025.05.037_bib35","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1021\/acsmedchemlett.7b00293","article-title":"Discovery of CDZ173 (leniolisib), representing a structurally novel class of PI3K delta-selective inhibitors","volume":"8","author":"Hoegenauer","year":"2017","journal-title":"ACS Med. Chem. Lett."},{"key":"10.1016\/j.cell.2025.05.037_bib36","doi-asserted-by":"crossref","first-page":"3092","DOI":"10.1182\/bloodadvances.2023011000","article-title":"Long-term treatment with selective PI3K\u03b4 inhibitor leniolisib in adults with activated PI3K\u03b4 syndrome","volume":"8","author":"Rao","year":"2024","journal-title":"Blood Adv."},{"key":"10.1016\/j.cell.2025.05.037_bib37","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/j.jaci.2023.09.032","article-title":"Interim analysis: Open-label extension study of leniolisib for patients with APDS","volume":"153","author":"Rao","year":"2024","journal-title":"J. Allergy Clin. Immunol."},{"key":"10.1016\/j.cell.2025.05.037_bib38","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1182\/blood.2022018546","article-title":"A randomized, placebo-controlled phase 3 trial of the PI3K\u03b4 inhibitor leniolisib for activated PI3K\u03b4 syndrome","volume":"141","author":"Rao","year":"2023","journal-title":"Blood"},{"key":"10.1016\/j.cell.2025.05.037_bib39","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1038\/nature24644","article-title":"Programmable base editing of A\u22c5T to G\u22c5C in genomic DNA without DNA cleavage","volume":"551","author":"Gaudelli","year":"2017","journal-title":"Nature"},{"key":"10.1016\/j.cell.2025.05.037_bib40","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1038\/s41587-020-0561-9","article-title":"Genome editing with CRISPR-Cas nucleases, base editors, transposases and prime editors","volume":"38","author":"Anzalone","year":"2020","journal-title":"Nat. Biotechnol."},{"key":"10.1016\/j.cell.2025.05.037_bib41","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1038\/s41587-024-02235-x","article-title":"Mapping variant effects on anti-tumor hallmarks of primary human T cells with base-editing screens","volume":"43","author":"Walsh","year":"2025","journal-title":"Nat. Biotechnol."},{"key":"10.1016\/j.cell.2025.05.037_bib42","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1038\/s41587-020-0453-z","article-title":"Phage-assisted evolution of an adenine base editor with improved Cas domain compatibility and activity","volume":"38","author":"Richter","year":"2020","journal-title":"Nat. Biotechnol."},{"key":"10.1016\/j.cell.2025.05.037_bib43","doi-asserted-by":"crossref","DOI":"10.1186\/s13073-020-00809-3","article-title":"Improved analysis of CRISPR fitness screens and reduced off-target effects with the BAGEL2 gene essentiality classifier","volume":"13","author":"Kim","year":"2021","journal-title":"Genome Med."},{"key":"10.1016\/j.cell.2025.05.037_bib44","doi-asserted-by":"crossref","first-page":"3923","DOI":"10.1172\/JCI75746","article-title":"A human immunodeficiency caused by mutations in the PIK3R1 gene","volume":"124","author":"Deau","year":"2014","journal-title":"J. Clin. Invest."},{"key":"10.1016\/j.cell.2025.05.037_bib45","doi-asserted-by":"crossref","DOI":"10.1084\/jem.20221020","article-title":"Human PIK3R1 mutations disrupt lymphocyte differentiation to cause activated PI3K\u03b4 syndrome 2","volume":"220","author":"Nguyen","year":"2023","journal-title":"J. Exp. Med."},{"key":"10.1016\/j.cell.2025.05.037_bib46","doi-asserted-by":"crossref","DOI":"10.1186\/s12969-024-00955-7","article-title":"Activated phosphoinositide 3-kinase \u03b4 syndrome caused by PIK3CD mutations: expanding the phenotype","volume":"22","author":"Zhao","year":"2024","journal-title":"Pediatr. Rheumatol. Online J."},{"key":"10.1016\/j.cell.2025.05.037_bib47","article-title":"Recommendations for application of the functional evidence PS3\/BS3 criterion using the ACMG\/AMP sequence variant interpretation framework","volume":"12","author":"Brnich","year":"2019","journal-title":"Genome Med."},{"key":"10.1016\/j.cell.2025.05.037_bib48","doi-asserted-by":"crossref","DOI":"10.1186\/s13073-019-0698-7","article-title":"Recommendations for the collection and use of multiplexed functional data for clinical variant interpretation","volume":"11","author":"Gelman","year":"2019","journal-title":"Genome Med."},{"key":"10.1016\/j.cell.2025.05.037_bib49","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pcbi.0030241","article-title":"Stereochemical criteria for prediction of the effects of proline mutations on protein stability","volume":"3","author":"Bajaj","year":"2007","journal-title":"PLoS Comput. Biol."},{"key":"10.1016\/j.cell.2025.05.037_bib50","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1016\/j.cell.2017.07.029","article-title":"The PI3K pathway in human disease","volume":"170","author":"Fruman","year":"2017","journal-title":"Cell"},{"key":"10.1016\/j.cell.2025.05.037_bib51","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1021\/acs.jmedchem.5b01483","volume":"59","author":"Heffron","year":"2016","journal-title":"J. Med. Chem."},{"key":"10.1016\/j.cell.2025.05.037_bib52","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","article-title":"Highly accurate protein structure prediction with AlphaFold","volume":"596","author":"Jumper","year":"2021","journal-title":"Nature"},{"key":"10.1016\/j.cell.2025.05.037_bib53","doi-asserted-by":"crossref","DOI":"10.1126\/science.adg7492","article-title":"Accurate proteome-wide missense variant effect prediction with AlphaMissense","volume":"381","author":"Cheng","year":"2023","journal-title":"Science"},{"key":"10.1016\/j.cell.2025.05.037_bib54","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1038\/s41586-023-06835-6","article-title":"Base-editing mutagenesis maps alleles to tune human T cell functions","volume":"625","author":"Schmidt","year":"2024","journal-title":"Nature"},{"key":"10.1016\/j.cell.2025.05.037_bib55","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1038\/s41587-022-01533-6","article-title":"Evolution of an adenine base editor into a small, efficient cytosine base editor with low off-target activity","volume":"41","author":"Neugebauer","year":"2023","journal-title":"Nat. Biotechnol."},{"key":"10.1016\/j.cell.2025.05.037_bib56","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/s41589-022-01163-8","article-title":"Engineering a precise adenine base editor with minimal bystander editing","volume":"19","author":"Chen","year":"2023","journal-title":"Nat. Chem. Biol."},{"key":"10.1016\/j.cell.2025.05.037_bib57","doi-asserted-by":"crossref","DOI":"10.1016\/j.clim.2024.110400","article-title":"A randomised, placebo-controlled, phase III trial of leniolisib in activated phosphoinositide 3-kinase delta (PI3K\u03b4) syndrome (APDS): Adolescent and adult subgroup analysis","volume":"270","author":"Rao","year":"2025","journal-title":"Clin. Immunol."},{"key":"10.1016\/j.cell.2025.05.037_bib58","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1038\/s41586-019-1325-x","article-title":"TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion","volume":"571","author":"Khan","year":"2019","journal-title":"Nature"},{"key":"10.1016\/j.cell.2025.05.037_bib59","doi-asserted-by":"crossref","DOI":"10.1126\/sciimmunol.aai8593","article-title":"The TCF1-Bcl6 axis counteracts type I interferon to repress exhaustion and maintain T cell stemness","volume":"1","author":"Wu","year":"2016","journal-title":"Sci. Immunol."},{"key":"10.1016\/j.cell.2025.05.037_bib60","doi-asserted-by":"crossref","first-page":"2163","DOI":"10.4049\/jimmunol.178.4.2163","article-title":"A role for mammalian target of rapamycin in regulating T cell activation versus anergy","volume":"178","author":"Zheng","year":"2007","journal-title":"J. Immunol."},{"key":"10.1016\/j.cell.2025.05.037_bib61","doi-asserted-by":"crossref","first-page":"W739","DOI":"10.1093\/nar\/gkac382","article-title":"SynergyFinder 3.0: an interactive analysis and consensus interpretation of multi-drug synergies across multiple samples","volume":"50","author":"Ianevski","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"10.1016\/j.cell.2025.05.037_bib62","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2023.1208567","article-title":"Activated PI3K\u03b4 syndrome - reviewing challenges in diagnosis and treatment","volume":"14","author":"Vanselow","year":"2023","journal-title":"Front. Immunol."},{"key":"10.1016\/j.cell.2025.05.037_bib63","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"10.1016\/j.cell.2025.05.037_bib64","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1038\/s41586-021-03855-y","article-title":"Rare variant contribution to human disease in 281,104 UK Biobank exomes","volume":"597","author":"Wang","year":"2021","journal-title":"Nature"},{"key":"10.1016\/j.cell.2025.05.037_bib65","doi-asserted-by":"crossref","first-page":"1508","DOI":"10.1007\/s10875-022-01352-z","article-title":"The 2022 update of IUIS phenotypical classification for human Inborn Errors of immunity","volume":"42","author":"Bousfiha","year":"2022","journal-title":"J. Clin. Immunol."},{"key":"10.1016\/j.cell.2025.05.037_bib66","unstructured":"Human Inborn Errors of Immunity: 2024 Update on the Classification from the International Union of Immunological Societies Expert Committee."},{"key":"10.1016\/j.cell.2025.05.037_bib67","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1016\/j.ajhg.2020.10.015","article-title":"Multiplexed functional assessment of genetic variants in CARD11","volume":"107","author":"Meitlis","year":"2020","journal-title":"Am. J. Hum. Genet."},{"key":"10.1016\/j.cell.2025.05.037_bib68","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1016\/j.ajhg.2018.07.016","article-title":"A multiplex homology-directed DNA repair assay reveals the impact of more than 1,000 BRCA1 missense substitution variants on protein function","volume":"103","author":"Starita","year":"2018","journal-title":"Am. J. Hum. Genet."},{"key":"10.1016\/j.cell.2025.05.037_bib69","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1038\/s41586-018-0461-z","article-title":"Accurate classification of BRCA1 variants with saturation genome editing","volume":"562","author":"Findlay","year":"2018","journal-title":"Nature"},{"key":"10.1016\/j.cell.2025.05.037_bib70","doi-asserted-by":"crossref","first-page":"6707","DOI":"10.1016\/j.cell.2024.08.047","article-title":"Saturation mutagenesis-reinforced functional assays for disease-related genes","volume":"187","author":"Ma","year":"2024","journal-title":"Cell"},{"key":"10.1016\/j.cell.2025.05.037_bib71","article-title":"Individuals with JAK1 variants are affected by syndromic features encompassing autoimmunity, atopy, colitis, and dermatitis","volume":"221","author":"Horesh","year":"2024","journal-title":"J. Exp. Med."},{"key":"10.1016\/j.cell.2025.05.037_bib72","doi-asserted-by":"crossref","first-page":"2167","DOI":"10.1016\/j.molcel.2023.06.009","article-title":"Base editor screens for in situ mutational scanning at scale","volume":"83","author":"Lue","year":"2023","journal-title":"Mol. Cell"},{"key":"10.1016\/j.cell.2025.05.037_bib73","doi-asserted-by":"crossref","first-page":"1064","DOI":"10.1016\/j.cell.2021.01.012","article-title":"Massively parallel assessment of human variants with base editor screens","volume":"184","author":"Hanna","year":"2021","journal-title":"Cell"},{"key":"10.1016\/j.cell.2025.05.037_bib74","doi-asserted-by":"crossref","first-page":"2695","DOI":"10.1016\/j.jaip.2024.08.012","article-title":"Artificial intelligence and machine learning for inborn errors of immunity: Current state and future promise","volume":"12","author":"Martinson","year":"2024","journal-title":"J. Allergy Clin. Immunol. Pract."},{"key":"10.1016\/j.cell.2025.05.037_bib75","doi-asserted-by":"crossref","DOI":"10.1186\/s13059-014-0554-4","article-title":"MAGeCK enables robust identification of essential genes from genome-scale CRISPR\/Cas9 knockout screens","volume":"15","author":"Li","year":"2014","journal-title":"Genome Biol."},{"key":"10.1016\/j.cell.2025.05.037_bib76","doi-asserted-by":"crossref","DOI":"10.14806\/ej.17.1.200","article-title":"Cutadapt removes adapter sequences from high-throughput sequencing reads","volume":"17","author":"Martin","year":"2011","journal-title":"EMBnet J."},{"key":"10.1016\/j.cell.2025.05.037_bib77","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1038\/nmeth.2089","article-title":"NIH Image to ImageJ: 25 years of image analysis","volume":"9","author":"Schneider","year":"2012","journal-title":"Nat. Methods"},{"key":"10.1016\/j.cell.2025.05.037_bib78","doi-asserted-by":"crossref","first-page":"1947","DOI":"10.1038\/s41592-024-02409-0","article-title":"Genomics 2 Proteins portal: a resource and discovery tool for linking genetic screening outputs to protein sequences and structures","volume":"21","author":"Kwon","year":"2024","journal-title":"Nat. Methods"},{"key":"10.1016\/j.cell.2025.05.037_bib79","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1093\/bioinformatics\/btu048","article-title":"Cas-OFFinder: a fast and versatile algorithm that searches for potential off-target sites of Cas9 RNA-guided endonucleases","volume":"30","author":"Bae","year":"2014","journal-title":"Bioinformatics"},{"key":"10.1016\/j.cell.2025.05.037_bib80","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1038\/nbt.3437","article-title":"Optimized sgRNA design to maximize activity and minimize off-target effects of CRISPR-Cas9","volume":"34","author":"Doench","year":"2016","journal-title":"Nat. Biotechnol."},{"key":"10.1016\/j.cell.2025.05.037_bib81","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1002\/pro.3943","article-title":"UCSF ChimeraX: Structure visualization for researchers, educators, and developers","volume":"30","author":"Pettersen","year":"2021","journal-title":"Protein Sci."},{"key":"10.1016\/j.cell.2025.05.037_bib82","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-022-28137-7","article-title":"Improved gRNA secondary structures allow editing of target sites resistant to CRISPR-Cas9 cleavage","volume":"13","author":"Riesenberg","year":"2022","journal-title":"Nat. Commun."},{"key":"10.1016\/j.cell.2025.05.037_bib83","doi-asserted-by":"crossref","first-page":"2456","DOI":"10.1016\/j.cell.2023.03.035","article-title":"Massively parallel base editing to map variant effects in human hematopoiesis","volume":"186","author":"Martin-Rufino","year":"2023","journal-title":"Cell"},{"key":"10.1016\/j.cell.2025.05.037_bib84","doi-asserted-by":"crossref","DOI":"10.1186\/1471-2105-13-134","article-title":"Primer-BLAST: a tool to design target-specific primers for polymerase chain reaction","volume":"13","author":"Ye","year":"2012","journal-title":"BMC Bioinformatics"},{"key":"10.1016\/j.cell.2025.05.037_bib85","doi-asserted-by":"crossref","first-page":"D609","DOI":"10.1093\/nar\/gkae1010","article-title":"UniProt: The universal protein knowledgebase in 2025","volume":"53","year":"2025","journal-title":"Nucleic Acids Res."}],"container-title":["Cell"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0092867425006245?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0092867425006245?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T21:07:27Z","timestamp":1767820047000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0092867425006245"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9]]},"references-count":85,"journal-issue":{"issue":"18","published-print":{"date-parts":[[2025,9]]}},"alternative-id":["S0092867425006245"],"URL":"https:\/\/doi.org\/10.1016\/j.cell.2025.05.037","relation":{},"ISSN":["0092-8674"],"issn-type":[{"value":"0092-8674","type":"print"}],"subject":[],"published":{"date-parts":[[2025,9]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Scalable generation and functional classification of genetic variants in inborn errors of immunity to accelerate clinical diagnosis and treatment","name":"articletitle","label":"Article Title"},{"value":"Cell","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.cell.2025.05.037","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2025 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.","name":"copyright","label":"Copyright"}]}}