{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T04:23:31Z","timestamp":1772252611906,"version":"3.50.1"},"reference-count":54,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2022,6,30]],"date-time":"2022-06-30T00:00:00Z","timestamp":1656547200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007388","name":"Compagnia di San Paolo","doi-asserted-by":"publisher","award":["ROL 20573"],"award-info":[{"award-number":["ROL 20573"]}],"id":[{"id":"10.13039\/100007388","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007388","name":"Compagnia di San Paolo","doi-asserted-by":"publisher","award":["P30CA012197"],"award-info":[{"award-number":["P30CA012197"]}],"id":[{"id":"10.13039\/100007388","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007388","name":"Compagnia di San Paolo","doi-asserted-by":"publisher","award":["T32-GM095440"],"award-info":[{"award-number":["T32-GM095440"]}],"id":[{"id":"10.13039\/100007388","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007388","name":"Compagnia di San Paolo","doi-asserted-by":"publisher","award":["T32-AI007401"],"award-info":[{"award-number":["T32-AI007401"]}],"id":[{"id":"10.13039\/100007388","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Wake Forest Innovations, Comprehensive Cancer Centre of Wake Forest University National Cancer Institute","award":["ROL 20573"],"award-info":[{"award-number":["ROL 20573"]}]},{"name":"Wake Forest Innovations, Comprehensive Cancer Centre of Wake Forest University National Cancer Institute","award":["P30CA012197"],"award-info":[{"award-number":["P30CA012197"]}]},{"name":"Wake Forest Innovations, Comprehensive Cancer Centre of Wake Forest University National Cancer Institute","award":["T32-GM095440"],"award-info":[{"award-number":["T32-GM095440"]}]},{"name":"Wake Forest Innovations, Comprehensive Cancer Centre of Wake Forest University National Cancer Institute","award":["T32-AI007401"],"award-info":[{"award-number":["T32-AI007401"]}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["ROL 20573"],"award-info":[{"award-number":["ROL 20573"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P30CA012197"],"award-info":[{"award-number":["P30CA012197"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["T32-GM095440"],"award-info":[{"award-number":["T32-GM095440"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["T32-AI007401"],"award-info":[{"award-number":["T32-AI007401"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>The TREX1 exonuclease degrades DNA to prevent aberrant nucleic-acid sensing through the cGAS-STING pathway, and dominant Aicardi\u2013Gouti\u00e8res Syndrome type 1 (AGS1) represents one of numerous TREX1-related autoimmune diseases. Monoallelic TREX1 mutations were identified in patients showing early-onset cerebrovascular disease, ascribable to small vessel disease, and CADASIL-like neuroimaging. We report the clinical-neuroradiological features of two patients with AGS-like (Patient A) and CADASIL-like (Patient B) phenotypes carrying the heterozygous p.A136V and p.R174G TREX1 variants, respectively. Genetic findings, obtained by a customized panel including 183 genes associated with monogenic stroke, were combined with interferon signature testing and biochemical assays to determine the mutations\u2019 effects in vitro. Our results for the p.A136V variant are inconsistent with prior biochemistry-pathology correlates for dominant AGS-causing TREX1 mutants. The p.R174G variant modestly altered exonuclease activity in a manner consistent with perturbation of substrate interaction rather than catalysis, which represents the first robust enzymological data for a TREX1 variant identified in a CADASIL-like patient. In conclusion, functional analysis allowed us to interpret the impact of TREX1 variants on patients\u2019 phenotypes. While the p.A136V variant is unlikely to be causative for AGS in Patient A, Patient B\u2019s phenotype is potentially related to the p.R174G variant. Therefore, further functional investigations of TREX1 variants found in CADASIL-like patients are warranted to determine any causal link and interrogate the molecular disease mechanism(s).<\/jats:p>","DOI":"10.3390\/genes13071179","type":"journal-article","created":{"date-parts":[[2022,6,30]],"date-time":"2022-06-30T20:53:02Z","timestamp":1656622382000},"page":"1179","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Genotype-Phenotype Correlation and Functional Insights for Two Monoallelic TREX1 Missense Variants Affecting the Catalytic Core"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8249-2015","authenticated-orcid":false,"given":"Giulia","family":"Amico","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, 16132 Genoa, Italy"},{"name":"Laboratory of Genetics and Genomics of Rare Diseases, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8136-1574","authenticated-orcid":false,"given":"Wayne O.","family":"Hemphill","sequence":"additional","affiliation":[{"name":"Center for Structural Biology, Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC 27101, USA"},{"name":"Department of Biochemistry, University of Colorado Boulder, Boulder, CO 80303, USA"},{"name":"Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4730-5322","authenticated-orcid":false,"given":"Mariasavina","family":"Severino","sequence":"additional","affiliation":[{"name":"Neuroradiology Unit\u2014IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudio","family":"Moratti","sequence":"additional","affiliation":[{"name":"Neuroradiology Unit, Azienda Unit\u00e0 Sanitaria Locale\u2014IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rosario","family":"Pascarella","sequence":"additional","affiliation":[{"name":"Neuroradiology Unit, Azienda Unit\u00e0 Sanitaria Locale\u2014IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8096-7806","authenticated-orcid":false,"given":"Marta","family":"Bertamino","sequence":"additional","affiliation":[{"name":"Physical Medicine and Rehabilitation Unit, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3567-6118","authenticated-orcid":false,"given":"Flavia","family":"Napoli","sequence":"additional","affiliation":[{"name":"Departments of Pediatrics, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7129-868X","authenticated-orcid":false,"given":"Stefano","family":"Volpi","sequence":"additional","affiliation":[{"name":"Autoinflammatory Diseases and Immunodeficiencies Center, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesca","family":"Rosamilia","sequence":"additional","affiliation":[{"name":"Biostatistic Unit, Health Science Department (DISSAL), University of Genoa, 16132 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara","family":"Signa","sequence":"additional","affiliation":[{"name":"Autoinflammatory Diseases and Immunodeficiencies Center, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fred","family":"Perrino","sequence":"additional","affiliation":[{"name":"Center for Structural Biology, Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC 27101, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7530-818X","authenticated-orcid":false,"given":"Marialuisa","family":"Zedde","sequence":"additional","affiliation":[{"name":"Neurology Unit, Stroke Unit, Azienda Unit\u00e0 Sanitaria Locale\u2014IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8732-1955","authenticated-orcid":false,"given":"Isabella","family":"Ceccherini","sequence":"additional","affiliation":[{"name":"Laboratory of Genetics and Genomics of Rare Diseases, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"on behalf of the Gaslini Stroke Study Group","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"16357","DOI":"10.1016\/S0021-9258(17)34015-2","article-title":"Identification of a 3\u2032\u21925\u2032-exonuclease that removes cytosine arabinoside monophosphate from 3\u2032 termini of DNA","volume":"269","author":"Perrino","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"17022","DOI":"10.1074\/jbc.M100623200","article-title":"Excision of 3\u2032 Termini by the Trex1 and TREX2 3\u2032\u21925\u2032 Exonucleases CHARACTERIZATION OF THE RECOMBINANT PROTEINS","volume":"276","author":"Mazur","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1111\/j.1432-1033.1993.tb18269.x","article-title":"Proof-reading 3\u2032\u21925\u2032 exonucleases isolated from rat liver nuclei","volume":"217","author":"Belyakova","year":"1993","journal-title":"Eur. J. Biochem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"19655","DOI":"10.1074\/jbc.274.28.19655","article-title":"Identification and Expression of the TREX1 and TREX2 cDNA Sequences Encoding Mammalian 3\u2032\u21925\u2032 Exonucleases","volume":"274","author":"Mazur","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"10537","DOI":"10.1074\/jbc.M700039200","article-title":"The Crystal Structure of TREX1 Explains the 3\u2032 Nucleotide Specificity and Reveals a Polyproline II Helix for Protein Partnering","volume":"282","author":"Choudhury","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"28881","DOI":"10.1074\/jbc.M113.503391","article-title":"The TREX1 C-terminal Region Controls Cellular Localization through Ubiquitination","volume":"288","author":"Orebaugh","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1016\/j.immuni.2015.07.022","article-title":"Cytosolic nuclease TREX1 regulates oligosaccharyltransferase activity independent of nuclease activity to suppress immune activation","volume":"43","author":"Hasan","year":"2015","journal-title":"Immunity"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2600","DOI":"10.1016\/j.celrep.2017.02.051","article-title":"Mitotic Phosphorylation of TREX1 C Terminus Disrupts TREX1 Regulation of the Oligosaccharyltransferase Complex","volume":"18","author":"Kucej","year":"2017","journal-title":"Cell Rep."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.molcel.2006.06.005","article-title":"The Exonuclease TREX1 Is in the SET Complex and Acts in Concert with NM23-H1 to Degrade DNA during Granzyme A-Mediated Cell Death","volume":"23","author":"Chowdhury","year":"2006","journal-title":"Mol. Cell"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"6719","DOI":"10.1128\/MCB.24.15.6719-6727.2004","article-title":"Gene-Targeted Mice Lacking the Trex1 (DNase III) 3\u2032\u21925\u2032 DNA Exonuclease Develop Inflammatory Myocarditis","volume":"24","author":"Morita","year":"2004","journal-title":"Mol. Cell. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"102894","DOI":"10.1016\/j.dnarep.2020.102894","article-title":"TREX1\u2013Apex predator of cytosolic DNA metabolism","volume":"94","author":"Simpson","year":"2020","journal-title":"DNA Repair"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"5993","DOI":"10.4049\/jimmunol.1400737","article-title":"TREX1 Deficiency Triggers Cell-Autonomous Immunity in a cGAS-Dependent Manner","volume":"192","author":"Ablasser","year":"2014","journal-title":"J. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"348","DOI":"10.4049\/jimmunol.1900220","article-title":"T Cells Produce IFN-\u03b1 in the TREX1 D18N Model of Lupus-like Autoimmunity","volume":"204","author":"Simpson","year":"2020","journal-title":"J. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2157","DOI":"10.4049\/jimmunol.1600722","article-title":"Loss of Trex1 in Dendritic Cells Is Sufficient To Trigger Systemic Autoimmunity","volume":"197","author":"Peschke","year":"2016","journal-title":"J. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1126\/science.1232458","article-title":"Cyclic GMP-AMP Synthase Is a Cytosolic DNA Sensor That Activates the Type I Interferon Pathway","volume":"339","author":"Sun","year":"2013","journal-title":"Science"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1362","DOI":"10.1016\/j.celrep.2013.05.008","article-title":"Structure of human cGAS reveals a conserved family of second-messenger enzymes in innate immunity","volume":"3","author":"Kranzusch","year":"2013","journal-title":"Cell Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1038\/nature12305","article-title":"Structural mechanism of cytosolic DNA sensing by cGAS","volume":"498","author":"Civril","year":"2013","journal-title":"Nature"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1016\/j.cell.2013.07.023","article-title":"Structure-Function Analysis of STING Activation by c[G(2\u2032,5\u2032)pA(3\u2032,5\u2032)p] and Targeting by Antiviral DMXAA","volume":"154","author":"Gao","year":"2013","journal-title":"Cell"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1016\/j.cell.2018.06.026","article-title":"Structure of the human cGAS\u2013DNA complex reveals enhanced control of immune surveillance","volume":"174","author":"Zhou","year":"2018","journal-title":"Cell"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1016\/j.cell.2007.10.017","article-title":"Trex1 Exonuclease Degrades ssDNA to Prevent Chronic Checkpoint Activation and Autoimmune Disease","volume":"131","author":"Yang","year":"2007","journal-title":"Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1016\/j.cell.2008.06.032","article-title":"Trex1 prevents cell-intrinsic initiation of autoimmunity","volume":"134","author":"Stetson","year":"2008","journal-title":"Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1080\/08916934.2018.1522305","article-title":"TREX1 D18N mice fail to process erythroblast DNA resulting in inflammation and dysfunctional erythropoiesis","volume":"51","author":"Rego","year":"2018","journal-title":"Autoimmunity"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1016\/j.molcel.2020.12.037","article-title":"ER-directed TREX1 limits cGAS activation at micronuclei","volume":"81","author":"Mohr","year":"2021","journal-title":"Mol. Cell"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1111\/j.1749-6632.2011.06220.x","article-title":"Type I interferonopathies: A novel set of inborn errors of immunity","volume":"1238","author":"Crow","year":"2011","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1016\/S1474-4422(13)70258-8","article-title":"Assessment of interferon-related biomarkers in Aicardi-Gouti\u00e8res Syndrome associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR: A case-control study","volume":"12","author":"Rice","year":"2013","journal-title":"Lancet Neurol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1007\/s10875-015-0147-3","article-title":"Human Disease Phenotypes Associated With Mutations in TREX1","volume":"35","author":"Rice","year":"2015","journal-title":"J. Clin. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"40246","DOI":"10.1074\/jbc.M111.297903","article-title":"The TREX1 Exonuclease R114H Mutation in Aicardi-Gouti\u00e8res Syndrome and Lupus Reveals Dimeric Structure Requirements for DNA Degradation Activity","volume":"286","author":"Orebaugh","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1086\/513443","article-title":"Heterozygous Mutations in TREX1 Cause Familial Chilblain Lupus and Dominant Aicardi-Gouti\u00e8res Syndrome","volume":"80","author":"Rice","year":"2007","journal-title":"Am. J. Hum. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"31649","DOI":"10.1074\/jbc.M806155200","article-title":"The TREX1 Double-stranded DNA Degradation Activity Is Defective in Dominant Mutations Associated with Autoimmune Disease","volume":"283","author":"Lehtinen","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"32373","DOI":"10.1074\/jbc.M111.276287","article-title":"Dominant Mutations of the TREX1 Exonuclease Gene in Lupus and Aicardi-Gouti\u00e8res Syndrome","volume":"286","author":"Fye","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.1038\/ng2082","article-title":"C-terminal truncations in human 3\u2032-5\u2032 DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy","volume":"39","author":"Richards","year":"2007","journal-title":"Nat. Genet."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2188","DOI":"10.1007\/s00415-013-7050-8","article-title":"Heterozygous TREX1 mutations in early-onset cerebrovascular disease","volume":"260","author":"Pelzer","year":"2013","journal-title":"J. Neurol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e2007","DOI":"10.1212\/WNL.0000000000008544","article-title":"How common are single gene mutations as a cause for lacunar stroke?","volume":"93","author":"Tan","year":"2019","journal-title":"Neurology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"106","DOI":"10.12688\/wellcomeopenres.12631.1","article-title":"Rare variants of the 3\u2019-5\u2019 DNA exonuclease TREX1 in early onset small vessel stroke","volume":"2","author":"McGlasson","year":"2017","journal-title":"Wellcome Open Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/bs.mie.2019.05.004","article-title":"Measuring TREX1 and TREX2 exonuclease activities","volume":"625","author":"Hemphill","year":"2019","journal-title":"Methods Enzymol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2","DOI":"10.3174\/ajnr.A7362","article-title":"Spectrum of Neuroradiologic Findings Associated with Monogenic Interferonopathies","volume":"43","author":"Benjamin","year":"2022","journal-title":"Am. J. Neuroradiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"319","DOI":"10.2147\/IJGM.S293377","article-title":"ROHHAD (Rapid-onset Obesity with Hypoventilation, Hypothalamic Dysfunction, Autonomic Dysregulation) Syndrome\u2014What Every Pediatrician Should Know About the Etiopathogenesis, Diagnosis and Treatment: A Review","volume":"14","author":"Lazea","year":"2021","journal-title":"Int. J. Gen. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1016\/S1474-4422(13)70124-8","article-title":"Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration","volume":"12","author":"Wardlaw","year":"2013","journal-title":"Lancet Neurol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"15212","DOI":"10.1074\/jbc.M500108200","article-title":"The Human TREX2 3\u2032 \u2192 5\u2032-Exonuclease Structure Suggests a Mechanism for Efficient Nonprocessive DNA Catalysis","volume":"280","author":"Perrino","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"21441","DOI":"10.1074\/jbc.M803629200","article-title":"Cooperative DNA Binding and Communication across the Dimer Interface in the TREX2 3\u2032 \u2192 5\u2032-Exonuclease","volume":"283","author":"Perrino","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1062","DOI":"10.1016\/j.ajhg.2018.04.003","article-title":"Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity","volume":"102","author":"Raraigh","year":"2018","journal-title":"Am. J. Hum. Genet."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"5117","DOI":"10.1073\/pnas.1423804112","article-title":"Exonuclease TREX1 degrades double-stranded DNA to prevent spontaneous lupus-like inflammatory disease","volume":"112","author":"Grieves","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1515","DOI":"10.1038\/ejhg.2016.63","article-title":"Guidelines for diagnostic next-generation sequencing","volume":"24","author":"Matthijs","year":"2016","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"D514","DOI":"10.1093\/nar\/gki033","article-title":"Online Mendelian Inheritance in Man (OMIM), a knowledgebase of human genes and genetic disorders","volume":"33","author":"Hamosh","year":"2005","journal-title":"Nucleic Acids Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"D886","DOI":"10.1093\/nar\/gky1016","article-title":"CADD: Predicting the deleteriousness of variants throughout the human genome","volume":"47","author":"Rentzsch","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_46","first-page":"7","article-title":"Predicting Functional Effect of Human Missense Mutations Using PolyPhen-2","volume":"76","author":"Adzhubei","year":"2013","journal-title":"Curr. Protoc. Hum. Genet."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3812","DOI":"10.1093\/nar\/gkg509","article-title":"SIFT: Predicting amino acid changes that affect protein function","volume":"31","author":"Ng","year":"2003","journal-title":"Nucleic Acids Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1978","DOI":"10.1093\/bioinformatics\/bty897","article-title":"VarSome: The human genomic variant search engine","volume":"35","author":"Kopanos","year":"2019","journal-title":"Bioinformatics"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"D862","DOI":"10.1093\/nar\/gkv1222","article-title":"ClinVar: Public archive of interpretations of clinically relevant variants","volume":"44","author":"Landrum","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_50","first-page":"405","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. Off. J. Am. Coll. Med. Genet."},{"key":"ref_51","first-page":"1399","article-title":"Next-generation sequencing for constitutional variants in the clinical laboratory, 2021 revision: A technical standard of the American College of Medical Genetics and Genomics (ACMG)","volume":"23","author":"Rehder","year":"2021","journal-title":"Genet. Med. Off. J. Am. Coll. Med. Genet."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1007\/s10875-019-00645-0","article-title":"Efficacy and Adverse Events During Janus Kinase Inhibitor Treatment of SAVI Syndrome","volume":"39","author":"Volpi","year":"2019","journal-title":"J. Clin. Immunol."},{"key":"ref_53","unstructured":"The PyMOL Molecular Graphics System, Version 2.0 Schr\u00f6dinger, LLC."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1002\/0471250953.bi0506s15","article-title":"Comparative Protein Structure Modeling Using MODELLER","volume":"15","author":"Eswar","year":"2006","journal-title":"Curr. Protoc. 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