Michael D Keller1, Rahul Pandey2, Dong Li2, Joseph Glessner2, Lifeng Tian2, Sarah E Henrickson3, Ivan K Chinn4, Linda Monaco-Shawver5, Jennifer Heimall3, Cuiping Hou2, Frederick G Otieno2, Soma Jyonouchi3, Leonard Calabrese6, Joris van Montfrans7, Jordan S Orange8, Hakon Hakonarson9. 1. Division of Allergy and Immunology, Children's National Medical Center, Washington, DC. 2. Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pa. 3. Division of Allergy and Immunology, Children's Hospital of Philadelphia, Philadelphia, Pa. 4. Division of Immunology, Allergy, and Rheumatology, Texas Children's Hospital, Houston, Tex; Baylor Genomics Institute, Baylor College of Medicine, Houston, Tex. 5. Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pa; Division of Allergy and Immunology, Children's Hospital of Philadelphia, Philadelphia, Pa. 6. Department of Rheumatologic and Immunologic Disease, Cleveland Clinic, Cleveland, Ohio. 7. Department of Pediatric Immunology and Infectious Diseases, Wilhelmina Children's Hospital, University Medical Center, Utrecht, The Netherlands. 8. Division of Immunology, Allergy, and Rheumatology, Texas Children's Hospital, Houston, Tex. Electronic address: orange@bcm.edu. 9. Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pa. Electronic address: hakonarson@email.chop.edu.
Abstract
BACKGROUND: Genome-wide association studies have shown a pattern of rare copy number variations and single nucleotide polymorphisms in patients with common variable immunodeficiency disorder (CVID), which was recognizable by a support vector machine (SVM) algorithm. However, rare monogenic causes of CVID might lack such a genetic fingerprint. OBJECTIVE: We sought to identify a unique monogenic cause of familial immunodeficiency and evaluate the use of SVM to identify patients with possible monogenic disorders. METHODS: A family with multiple members with a diagnosis of CVID was screened by using whole-exome sequencing. The proband and other subjects with mutations associated with CVID-like phenotypes were screened through the SVM algorithm from our recent CVID genome-wide association study. RT-PCR, protein immunoblots, and in vitro plasmablast differentiation assays were performed on patient and control EBV lymphoblastoids cell lines. RESULTS: Exome sequencing identified a novel heterozygous mutation in IRF2BP2 (c.1652G>A:p.[S551N]) in affected family members. Transduction of the mutant gene into control human B cells decreased production of plasmablasts in vitro, and IRF2BP2 transcripts and protein expression were increased in proband versus control EBV-immortalized lymphoblastoid cell lines. The SVM algorithm categorized the proband and subjects with other immunodeficiency-associated gene variants in TACI, BAFFR, ICOS, CD21, LRBA, and CD27 as genetically dissimilar from polygenic CVID. CONCLUSION: A novel IRFBP2 mutation was identified in a family with autosomal dominant CVID. Transduction experiments suggest that the mutant protein has an effect on B-cell differentiation and is likely a monogenic cause of the family's CVID phenotype. Successful grouping by the SVM algorithm suggests that our family and other subjects with rare immunodeficiency disorders cluster separately and lack the genetic pattern present in polygenic CVID cases.
BACKGROUND: Genome-wide association studies have shown a pattern of rare copy number variations and single nucleotide polymorphisms in patients with common variable immunodeficiency disorder (CVID), which was recognizable by a support vector machine (SVM) algorithm. However, rare monogenic causes of CVID might lack such a genetic fingerprint. OBJECTIVE: We sought to identify a unique monogenic cause of familial immunodeficiency and evaluate the use of SVM to identify patients with possible monogenic disorders. METHODS: A family with multiple members with a diagnosis of CVID was screened by using whole-exome sequencing. The proband and other subjects with mutations associated with CVID-like phenotypes were screened through the SVM algorithm from our recent CVID genome-wide association study. RT-PCR, protein immunoblots, and in vitro plasmablast differentiation assays were performed on patient and control EBV lymphoblastoids cell lines. RESULTS: Exome sequencing identified a novel heterozygous mutation in IRF2BP2 (c.1652G>A:p.[S551N]) in affected family members. Transduction of the mutant gene into control human B cells decreased production of plasmablasts in vitro, and IRF2BP2 transcripts and protein expression were increased in proband versus control EBV-immortalized lymphoblastoid cell lines. The SVM algorithm categorized the proband and subjects with other immunodeficiency-associated gene variants in TACI, BAFFR, ICOS, CD21, LRBA, and CD27 as genetically dissimilar from polygenic CVID. CONCLUSION: A novel IRFBP2 mutation was identified in a family with autosomal dominant CVID. Transduction experiments suggest that the mutant protein has an effect on B-cell differentiation and is likely a monogenic cause of the family's CVID phenotype. Successful grouping by the SVM algorithm suggests that our family and other subjects with rare immunodeficiency disorders cluster separately and lack the genetic pattern present in polygenic CVID cases.
Authors: W James Kent; Charles W Sugnet; Terrence S Furey; Krishna M Roskin; Tom H Pringle; Alan M Zahler; David Haussler Journal: Genome Res Date: 2002-06 Impact factor: 9.043
Authors: Menno C van Zelm; Julie Smet; Brigitte Adams; Françoise Mascart; Liliane Schandené; Françoise Janssen; Alina Ferster; Chiung-Chi Kuo; Shoshana Levy; Jacques J M van Dongen; Mirjam van der Burg Journal: J Clin Invest Date: 2010-03-08 Impact factor: 14.808
Authors: Joris M van Montfrans; Andy I M Hoepelman; Sigrid Otto; Marielle van Gijn; Lisette van de Corput; Roel A de Weger; Linda Monaco-Shawver; Pinaki P Banerjee; Elisabeth A M Sanders; Cornelia M Jol-van der Zijde; Michael R Betts; Jordan S Orange; Andries C Bloem; Kiki Tesselaar Journal: J Allergy Clin Immunol Date: 2011-12-24 Impact factor: 10.793
Authors: Allen C T Teng; Drew Kuraitis; Shelley A Deeke; Ali Ahmadi; Stephen G Dugan; Brian L M Cheng; Matthew G Crowson; Patrick G Burgon; Erik J Suuronen; Hsiao-Huei Chen; Alexandre F R Stewart Journal: FASEB J Date: 2010-08-11 Impact factor: 5.191
Authors: Menno C van Zelm; Ismail Reisli; Mirjam van der Burg; Diana Castaño; Carel J M van Noesel; Maarten J D van Tol; Cristina Woellner; Bodo Grimbacher; Pablo J Patiño; Jacques J M van Dongen; José L Franco Journal: N Engl J Med Date: 2006-05-04 Impact factor: 91.245
Authors: S Melkorka Maggadottir; Jin Li; Joseph T Glessner; Yun Rose Li; Zhi Wei; Xiao Chang; Frank D Mentch; Kelly A Thomas; Cecilia E Kim; Yan Zhao; Cuiping Hou; Fengxiang Wang; Silje F Jørgensen; Elena E Perez; Kathleen E Sullivan; Jordan S Orange; Tom H Karlsen; Helen Chapel; Charlotte Cunningham-Rundles; Hakon Hakonarson Journal: J Allergy Clin Immunol Date: 2015-02-10 Impact factor: 10.793
Authors: Benjamin Gathmann; Nizar Mahlaoui; Laurence Gérard; Eric Oksenhendler; Klaus Warnatz; Ilka Schulze; Gerhard Kindle; Taco W Kuijpers; Rachel T van Beem; David Guzman; Sarita Workman; Pere Soler-Palacín; Javier De Gracia; Torsten Witte; Reinhold E Schmidt; Jiri Litzman; Eva Hlavackova; Vojtech Thon; Michael Borte; Stephan Borte; Dinakantha Kumararatne; Conleth Feighery; Hilary Longhurst; Matthew Helbert; Anna Szaflarska; Anna Sediva; Bernd H Belohradsky; Alison Jones; Ulrich Baumann; Isabelle Meyts; Necil Kutukculer; Per Wågström; Nermeen Mouftah Galal; Joachim Roesler; Evangelia Farmaki; Natalia Zinovieva; Peter Ciznar; Efimia Papadopoulou-Alataki; Kirsten Bienemann; Sirje Velbri; Zoya Panahloo; Bodo Grimbacher Journal: J Allergy Clin Immunol Date: 2014-02-28 Impact factor: 10.793
Authors: Ragnar O Vilmundarson; Niloufar Heydarikhorneh; An Duong; Tiffany Ho; Kianoosh Keyhanian; Fariborz Soheili; Hsiao-Huei Chen; Alexandre F R Stewart Journal: Front Immunol Date: 2022-07-04 Impact factor: 8.786
Authors: Sarah K Baxter; Tom Walsh; Silvia Casadei; Mary M Eckert; Eric J Allenspach; David Hagin; Gesmar Segundo; Ming K Lee; Suleyman Gulsuner; Brian H Shirts; Kathleen E Sullivan; Michael D Keller; Troy R Torgerson; Mary-Claire King Journal: J Allergy Clin Immunol Date: 2021-04-20 Impact factor: 10.793
Authors: Jenny Klintman; Niamh Appleby; Basile Stamatopoulos; Katie Ridout; Toby A Eyre; Pauline Robbe; Laura Lopez Pascua; Samantha J L Knight; Helene Dreau; Maite Cabes; Niko Popitsch; Mats Ehinger; Jose I Martín-Subero; Elías Campo; Robert Månsson; Davide Rossi; Jenny C Taylor; Dimitrios V Vavoulis; Anna Schuh Journal: Blood Date: 2021-05-20 Impact factor: 22.113