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Novel Genetic Discoveries in Primary Immunodeficiency Disorders

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Abstract

The field of Immunology is one that has undergone great expansion in recent years. With the advent of new diagnostic modalities including a variety of genetic tests (discussed elsewhere in this journal), the ability to diagnose a patient with a primary immunodeficiency disorder (PIDD) has become a more streamlined process. With increased availability of genetic testing for those with suspected or known PIDD, there has been a significant increase in the number of genes associated with this group of disorders. This is of great importance as a misdiagnosis of these rare diseases can lead to a delay in what can be critical treatment options. At times, those options can include life-saving medications or procedures. Presentation of patients with PIDD can vary greatly based on the specific genetic defect and the part(s) of the immune system that is affected by the variation. PIDD disorders lead to varying levels of increased risk of infection ranging from a mild increase such as with selective IgA deficiency to a profound risk with severe combined immunodeficiency. These diseases can also cause a variety of other clinical findings including autoimmunity and gastrointestinal disease.

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References

  1. Tangye SG, Al-Herz W, Bousfiha A, Chatila T, Cunningham-Rundles C, Etzioni A et al (2020) Human inborn errors of immunity: 2019 update on the classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol 40(1):24–64

    Article  Google Scholar 

  2. Tangye SG, Al-Herz W, Bousfiha A, Cunningham-Rundles C, Franco JL, Holland SM et al (2021) The ever-increasing array of novel inborn errors of immunity: an interim update by the IUIS Committee. J Clin Immunol 41(3):666–679

    Article  Google Scholar 

  3. Bacchelli C, Moretti FA, Carmo M, Adams S, Stanescu HC, Pearce K et al (2017) Mutations in linker for activation of T cells (LAT) lead to a novel form of severe combined immunodeficiency. J Allergy Clin Immunol 139(2):634–42 e5

  4. Keller B, Zaidman I, Yousefi OS, Hershkovitz D, Stein J, Unger S et al (2016) Early onset combined immunodeficiency and autoimmunity in patients with loss-of-function mutation in LAT. J Exp Med 213(7):1185–1199

    Article  CAS  Google Scholar 

  5. Lev A, Lee YN, Sun G, Hallumi E, Simon AJ, Zrihen KS et al (2021) Inherited SLP76 deficiency in humans causes severe combined immunodeficiency, neutrophil and platelet defects. J Exp Med 218(3):e20201062

  6. Oud MM, Tuijnenburg P, Hempel M, van Vlies N, Ren Z, Ferdinandusse S et al (2017) Mutations in EXTL3 cause neuro-immuno-skeletal dysplasia syndrome. Am J Hum Genet 100(2):281–296

    Article  CAS  Google Scholar 

  7. Smits BM, Lelieveld PHC, Ververs FA, Turkenburg M, de Koning C, van Dijk M et al (2020) A dominant activating RAC2 variant associated with immunodeficiency and pulmonary disease. Clin Immunol 212:108248

  8. Sharapova SO, Haapaniemi E, Sakovich IS, Kostyuchenko LV, Donko A, Dulau-Florea A et al (2019) Heterozygous activating mutation in RAC2 causes infantile-onset combined immunodeficiency with susceptibility to viral infections. Clin Immunol 205:1–5

    Article  CAS  Google Scholar 

  9. Hsu AP, Donko A, Arrington ME, Swamydas M, Fink D, Das A et al (2019) Dominant activating RAC2 mutation with lymphopenia, immunodeficiency, and cytoskeletal defects. Blood 133(18):1977–1988

    Article  CAS  Google Scholar 

  10. Lougaris V, Chou J, Beano A, Wallace JG, Baronio M, Gazzurelli L et al (2019) A monoallelic activating mutation in RAC2 resulting in a combined immunodeficiency. J Allergy Clin Immunol 143(4):1649–53 e3

  11. Paganini I, Sestini R, Capone GL, Putignano AL, Contini E, Giotti I et al (2017) A novel PAX1 null homozygous mutation in autosomal recessive otofaciocervical syndrome associated with severe combined immunodeficiency. Clin Genet 92(6):664–668

    Article  CAS  Google Scholar 

  12. Yamazaki Y, Urrutia R, Franco LM, Giliani S, Zhang K, Alazami AM et al (2020) PAX1 is essential for development and function of the human thymus. Sci Immunol 5(44):eaax1036

  13. Bosticardo M, Yamazaki Y, Cowan J, Giardino G, Corsino C, Scalia G et al (2019) Heterozygous FOXN1 variants cause low TRECs and severe T cell lymphopenia, revealing a crucial role of FOXN1 in supporting early thymopoiesis. Am J Hum Genet 105(3):549–561

    Article  CAS  Google Scholar 

  14. Beziat V, Li J, Lin JX, Ma CS, Li P, Bousfiha A et al (2019) A recessive form of hyper-IgE syndrome by disruption of ZNF341-dependent STAT3 transcription and activity. Sci Immunol 3(24):eaat4956. https://doi.org/10.1126/sciimmunol.aat4956

  15. Frey-Jakobs S, Hartberger JM, Fliegauf M, Bossen C, Wehmeyer ML, Neubauer JC et al (2018) ZNF341 controls STAT3 expression and thereby immunocompetence. Sci Immunol 3(24):eaat4941. https://doi.org/10.1126/sciimmunol.aat4941

  16. Spencer S, Kostel Bal S, Egner W, Lango Allen H, Raza SI, Ma CA et al (2019) Loss of the interleukin-6 receptor causes immunodeficiency, atopy, and abnormal inflammatory responses. J Exp Med 216(9):1986–1998

    Article  CAS  Google Scholar 

  17. Schwerd T, Twigg SRF, Aschenbrenner D, Manrique S, Miller KA, Taylor IB et al (2017) A biallelic mutation in IL6ST encoding the GP130 co-receptor causes immunodeficiency and craniosynostosis. J Exp Med 214(9):2547–2562

    Article  CAS  Google Scholar 

  18. Shahin T, Aschenbrenner D, Cagdas D, Bal SK, Conde CD, Garncarz W et al (2019) Selective loss of function variants in IL6ST cause hyper-IgE syndrome with distinct impairments of T-cell phenotype and function. Haematologica 104(3):609–621

    Article  CAS  Google Scholar 

  19. Chen YH, Grigelioniene G, Newton PT, Gullander J, Elfving M, Hammarsjo A et al (2020) Absence of GP130 cytokine receptor signaling causes extended Stuve-Wiedemann syndrome. J Exp Med 217(3):e20191306

  20. Monies D, Abouelhoda M, Assoum M, Moghrabi N, Rafiullah R, Almontashiri N et al (2019) Lessons learned from large-scale, first-tier clinical exome sequencing in a highly consanguineous population. Am J Hum Genet 104(6):1182–1201

    Article  CAS  Google Scholar 

  21. Beziat V, Tavernier SJ, Chen YH, Ma CS, Materna M, Laurence A et al (2020) Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome. J Exp Med 217(6):e20191804

  22. Lyons JJ, Liu Y, Ma CA, Yu X, O’Connell MP, Lawrence MG et al (2017) ERBIN deficiency links STAT3 and TGF-beta pathway defects with atopy in humans. J Exp Med 214(3):669–680

    Article  CAS  Google Scholar 

  23. Ma CA, Stinson JR, Zhang Y, Abbott JK, Weinreich MA, Hauk PJ et al (2017) Germline hypomorphic CARD11 mutations in severe atopic disease. Nat Genet 49(8):1192–1201

    Article  CAS  Google Scholar 

  24. Klammt J, Neumann D, Gevers EF, Andrew SF, Schwartz ID, Rockstroh D et al (2018) Dominant-negative STAT5B mutations cause growth hormone insensitivity with short stature and mild immune dysregulation. Nat Commun 9(1):2105

    Article  Google Scholar 

  25. Volpi S, Cicalese MP, Tuijnenburg P, Tool ATJ, Cuadrado E, Abu-Halaweh M et al (2019) A combined immunodeficiency with severe infections, inflammation, and allergy caused by ARPC1B deficiency. J Allergy Clin Immunol 143(6):2296–2299

    Article  Google Scholar 

  26. Brigida I, Zoccolillo M, Cicalese MP, Pfajfer L, Barzaghi F, Scala S et al (2018) T-cell defects in patients with ARPC1B germline mutations account for combined immunodeficiency. Blood 132(22):2362–2374

    Article  CAS  Google Scholar 

  27. Kahr WH, Pluthero FG, Elkadri A, Warner N, Drobac M, Chen CH et al (2017) Loss of the Arp2/3 complex component ARPC1B causes platelet abnormalities and predisposes to inflammatory disease. Nat Commun 8:14816

    Article  CAS  Google Scholar 

  28. van der Crabben SN, Hennus MP, McGregor GA, Ritter DI, Nagamani SC, Wells OS et al (2016) Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease. J Clin Invest 126(8):2881–2892

    Article  Google Scholar 

  29. Cottineau J, Kottemann MC, Lach FP, Kang YH, Vely F, Deenick EK et al (2017) Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency. J Clin Invest 127(5):1991–2006

    Article  Google Scholar 

  30. Niehues T, Ozgur TT, Bickes M, Waldmann R, Schoning J, Brasen J et al (2020) Mutations of the gene FNIP1 associated with a syndromic autosomal recessive immunodeficiency with cardiomyopathy and pre-excitation syndrome. Eur J Immunol 50(7):1078–1080

    Article  CAS  Google Scholar 

  31. Saettini F, Poli C, Vengoechea J, Bonanomi S, Orellana JC, Fazio G et al (2021) Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in folliculin-interacting protein 1 deficiency. Blood 137(4):493–499

    Article  CAS  Google Scholar 

  32. Keller MD, Pandey R, Li D, Glessner J, Tian L, Henrickson SE, et al (2016) Mutation in IRF2BP2 is responsible for a familial form of common variable immunodeficiency disorder. J Allergy Clin Immunol 138(2):544–50 e4

  33. Huppke P, Weissbach S, Church JA, Schnur R, Krusen M, Dreha-Kulaczewski S et al (2017) Activating de novo mutations in NFE2L2 encoding NRF2 cause a multisystem disorder. Nat Commun 8(1):818

    Article  Google Scholar 

  34. Dimitrov B, Himmelreich N, Hipgrave Ederveen AL, Luchtenborg C, Okun JG, Breuer M et al (2018) Cutis laxa, exocrine pancreatic insufficiency and altered cellular metabolomics as additional symptoms in a new patient with ATP6AP1-CDG. Mol Genet Metab 123(3):364–374

    Article  CAS  Google Scholar 

  35. Jansen EJ, Timal S, Ryan M, Ashikov A, van Scherpenzeel M, Graham LA et al (2016) ATP6AP1 deficiency causes an immunodeficiency with hepatopathy, cognitive impairment and abnormal protein glycosylation. Nat Commun 7:11600

    Article  CAS  Google Scholar 

  36. Ondruskova N, Honzik T, Vondrackova A, Stranecky V, Tesarova M, Zeman J et al (2020) Severe phenotype of ATP6AP1-CDG in two siblings with a novel mutation leading to a differential tissue-specific ATP6AP1 protein pattern, cellular oxidative stress and hepatic copper accumulation. J Inherit Metab Dis 43(4):694–700

    Article  CAS  Google Scholar 

  37. Tvina A, Thomsen A, Palatnik A (2020) Prenatal and postnatal phenotype of a pathologic variant in the ATP6AP1 gene. Eur J Med Genet 63(6):103881

  38. Bouafia A, Lofek S, Bruneau J, Chentout L, Lamrini H, Trinquand A et al (2019) Loss of ARHGEF1 causes a human primary antibody deficiency. J Clin Invest 129(3):1047–1060

    Article  Google Scholar 

  39. Keller B, Shoukier M, Schulz K, Bhatt A, Heine I, Strohmeier V et al (2018) Germline deletion of CIN85 in humans with X chromosome-linked antibody deficiency. J Exp Med 215(5):1327–1336

    Article  CAS  Google Scholar 

  40. Schubert D, Klein MC, Hassdenteufel S, Caballero-Oteyza A, Yang L, Proietti M et al (2018) Plasma cell deficiency in human subjects with heterozygous mutations in Sec61 translocon alpha 1 subunit (SEC61A1). J Allergy Clin Immunol 141(4):1427–1438

    Article  CAS  Google Scholar 

  41. Takeda AJ, Maher TJ, Zhang Y, Lanahan SM, Bucklin ML, Compton SR et al (2019) Human PI3Kgamma deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology. Nat Commun 10(1):4364

    Article  Google Scholar 

  42. Thian M, Hoeger B, Kamnev A, Poyer F, Kostel Bal S, Caldera M et al (2020) Germline biallelic PIK3CG mutations in a multifaceted immunodeficiency with immune dysregulation. Haematologica 105(10):e488

  43. Kuhny M, Forbes LR, Cakan E, Vega-Loza A, Kostiuk V, Dinesh RK et al (2020) Disease-associated CTNNBL1 mutation impairs somatic hypermutation by decreasing nuclear AID. J Clin Invest 130(8):4411–4422

    CAS  Google Scholar 

  44. Yeh TW, Okano T, Naruto T, Yamashita M, Okamura M, Tanita K et al (2020) APRIL-dependent lifelong plasmacyte maintenance and immunoglobulin production in humans. J Allergy Clin Immunol 146(5):1109–20 e4

  45. Allenspach E, Torgerson TR (2016) Autoimmunity and primary immunodeficiency disorders. J Clin Immunol 36(Suppl 1):57–67

    Article  CAS  Google Scholar 

  46. Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ, Whitesell L et al (2001) The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 27(1):20–21

    Article  CAS  Google Scholar 

  47. Fernandez IZ, Baxter RM, Garcia-Perez JE, Vendrame E, Ranganath T, Kong DS et al (2019) A novel human IL2RB mutation results in T and NK cell-driven immune dysregulation. J Exp Med 216(6):1255–1267

    Article  CAS  Google Scholar 

  48. Zhang Z, Gothe F, Pennamen P, James JR, McDonald D, Mata CP et al (2019) Human interleukin-2 receptor beta mutations associated with defects in immunity and peripheral tolerance. J Exp Med 216(6):1311–1327

    Article  CAS  Google Scholar 

  49. Yang L, Chen S, Zhao Q, Sun Y, Nie H (2019) The critical role of Bach2 in shaping the balance between CD4(+) T cell subsets in immune-mediated diseases. Mediators Inflamm 2019:2609737

    Article  Google Scholar 

  50. Afzali B, Gronholm J, Vandrovcova J, O’Brien C, Sun HW, Vanderleyden I et al (2017) BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency. Nat Immunol 18(7):813–823

    Article  CAS  Google Scholar 

  51. Serwas NK, Hoeger B, Ardy RC, Stulz SV, Sui Z, Memaran N et al (2019) Human DEF6 deficiency underlies an immunodeficiency syndrome with systemic autoimmunity and aberrant CTLA-4 homeostasis. Nat Commun 10(1):3106

    Article  Google Scholar 

  52. Fournier B, Tusseau M, Villard M, Malcus C, Chopin E, Martin E et al (2021) DEF6 deficiency, a Mendelian susceptibility to EBV infection, lymphoma, and autoimmunity. J Allergy Clin Immunol 147(2):740–3 e9

  53. Hadjadj J, Castro CN, Tusseau M, Stolzenberg MC, Mazerolles F, Aladjidi N et al (2020) Early-onset autoimmunity associated with SOCS1 haploinsufficiency. Nat Commun 11(1):5341

    Article  CAS  Google Scholar 

  54. Thaventhiran JED, Lango Allen H, Burren OS, Rae W, Greene D, Staples E et al (2020) Whole-genome sequencing of a sporadic primary immunodeficiency cohort. Nature 583(7814):90–95

    Article  CAS  Google Scholar 

  55. Lee PY, Platt CD, Weeks S, Grace RF, Maher G, Gauthier K et al (2020) Immune dysregulation and multisystem inflammatory syndrome in children (MIS-C) in individuals with haploinsufficiency of SOCS1. J Allergy Clin Immunol 146(5):1194–200 e1

  56. Chan AY, Punwani D, Kadlecek TA, Cowan MJ, Olson JL, Mathes EF et al (2016) A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70. J Exp Med 213(2):155–165

    Article  CAS  Google Scholar 

  57. Canna SW, Marsh RA (2020) Pediatric hemophagocytic lymphohistiocytosis. Blood 135(16):1332–1343

    Article  Google Scholar 

  58. Ammann S, Schulz A, Krageloh-Mann I, Dieckmann NM, Niethammer K, Fuchs S et al (2016) Mutations in AP3D1 associated with immunodeficiency and seizures define a new type of Hermansky-Pudlak syndrome. Blood 127(8):997–1006

    Article  CAS  Google Scholar 

  59. Gayden T, Sepulveda FE, Khuong-Quang DA, Pratt J, Valera ET, Garrigue A et al (2018) Germline HAVCR2 mutations altering TIM-3 characterize subcutaneous panniculitis-like T cell lymphomas with hemophagocytic lymphohistiocytic syndrome. Nat Genet 50(12):1650–1657

    Article  CAS  Google Scholar 

  60. Wegehaupt O, Gross M, Wehr C, Marks R, Schmitt-Graeff A, Uhl M et al (2020) TIM-3 deficiency presenting with two clonally unrelated episodes of mesenteric and subcutaneous panniculitis-like T-cell lymphoma and hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 67(6):e28302

  61. Sonigo G, Battistella M, Beylot-Barry M, Ingen-Housz-Oro S, Franck N, Barete S et al (2020) HAVCR2 mutations are associated with severe hemophagocytic syndrome in subcutaneous panniculitis-like T-cell lymphoma. Blood 135(13):1058–1061

    Google Scholar 

  62. Chaweephisal P, Sosothikul D, Polprasert C, Wananukul S, Seksarn P (2021) Subcutaneous panniculitis-like T-cell lymphoma with hemophagocytic lymphohistiocytosis syndrome in children and its essential role of HAVCR2 gene mutation analysis. J Pediatr Hematol Oncol 43(1):e80–e84

    Article  CAS  Google Scholar 

  63. Mace EM, Paust S, Conte MI, Baxley RM, Schmit MM, Patil SL et al (2020) Human NK cell deficiency as a result of biallelic mutations in MCM10. J Clin Invest 130(10):5272–5286

    Article  CAS  Google Scholar 

  64. Baxley RM, Leung W, Schmit MM, Matson JP, Yin L, Oram MK et al (2021) Bi-allelic MCM10 variants associated with immune dysfunction and cardiomyopathy cause telomere shortening. Nat Commun 12(1):1626

    Article  CAS  Google Scholar 

  65. Castro CN, Rosenzwajg M, Carapito R, Shahrooei M, Konantz M, Khan A et al (2020) NCKAP1L defects lead to a novel syndrome combining immunodeficiency, lymphoproliferation, and hyperinflammation. J Exp Med 217(12):e20192275

  66. Cook SA, Comrie WA, Poli MC, Similuk M, Oler AJ, Faruqi AJ et al (2020) HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease. Science 369(6500):202–207

    Article  CAS  Google Scholar 

  67. Salzer E, Zoghi S, Kiss MG, Kage F, Rashkova C, Stahnke S et al (2020) The cytoskeletal regulator HEM1 governs B cell development and prevents autoimmunity. Sci Immunol 5(49):eabc3979. https://doi.org/10.1126/sciimmunol.abc3979

  68. Del Bel KL, Ragotte RJ, Saferali A, Lee S, Vercauteren SM, Mostafavi SA et al (2017) JAK1 gain-of-function causes an autosomal dominant immune dysregulatory and hypereosinophilic syndrome. J Allergy Clin Immunol 139(6):2016–20 e5

  69. Gruber CN, Calis JJA, Buta S, Evrony G, Martin JC, Uhl SA et al (2020) Complex autoinflammatory syndrome unveils fundamental principles of JAK1 kinase transcriptional and biochemical function. Immunity 53(3):672–84 e11

  70. Ma CA, Xi L, Cauff B, DeZure A, Freeman AF, Hambleton S et al (2017) Somatic STAT5b gain-of-function mutations in early onset nonclonal eosinophilia, urticaria, dermatitis, and diarrhea. Blood 129(5):650–653

    Article  CAS  Google Scholar 

  71. Rajala HL, Eldfors S, Kuusanmaki H, van Adrichem AJ, Olson T, Lagstrom S et al (2013) Discovery of somatic STAT5b mutations in large granular lymphocytic leukemia. Blood 121(22):4541–4550

    Article  CAS  Google Scholar 

  72. Kelsen JR, Russo P, Sullivan KE (2019) Early-onset inflammatory bowel disease. Immunol Allergy Clin North Am 39(1):63–79

    Article  Google Scholar 

  73. Kotlarz D, Marquardt B, Baroy T, Lee WS, Konnikova L, Hollizeck S et al (2018) Human TGF-beta1 deficiency causes severe inflammatory bowel disease and encephalopathy. Nat Genet 50(3):344–348

    Article  CAS  Google Scholar 

  74. Cuchet-Lourenco D, Eletto D, Wu C, Plagnol V, Papapietro O, Curtis J et al (2018) Biallelic RIPK1 mutations in humans cause severe immunodeficiency, arthritis, and intestinal inflammation. Science 361(6404):810–813

    Article  CAS  Google Scholar 

  75. Parlato M, Charbit-Henrion F, Pan J, Romano C, Duclaux-Loras R, Le Du MH et al (2018) Human ALPI deficiency causes inflammatory bowel disease and highlights a key mechanism of gut homeostasis. EMBO Mol Med 10(4):e8483

  76. Li Q, Lee CH, Peters LA, Mastropaolo LA, Thoeni C, Elkadri A et al (2016) Variants in TRIM22 that affect NOD2 signaling are associated with very-early-onset inflammatory bowel disease. gastroenterology 150(5):1196–207

  77. Ashton JJ, Mossotto E, Stafford IS, Haggarty R, Coelho TAF, Batra A et al (2020) Genetic sequencing of pediatric patients identifies mutations in monogenic inflammatory bowel disease genes that translate to distinct clinical phenotypes. Clin Transl Gastroenterol 11(2):e00129

  78. Ozen A, Comrie WA, Ardy RC, Dominguez Conde C, Dalgic B, Beser OF et al (2017) CD55 deficiency, early-onset protein-losing enteropathy, and thrombosis. N Engl J Med 377(1):52–61

    Article  CAS  Google Scholar 

  79. Bousfiha A, Jeddane L, Picard C, Al-Herz W, Ailal F, Chatila T et al (2020) Human inborn errors of immunity: 2019 update of the IUIS phenotypical classification. J Clin Immunol 40(1):66–81

    Article  Google Scholar 

  80. Jiang J, Zhao M, Chang C, Wu H, Lu Q (2020) Type I interferons in the pathogenesis and treatment of autoimmune diseases. Clin Rev Allergy Immunol 59(2):248–272

    Article  CAS  Google Scholar 

  81. Meuwissen ME, Schot R, Buta S, Oudesluijs G, Tinschert S, Speer SD et al (2016) Human USP18 deficiency underlies type 1 interferonopathy leading to severe pseudo-TORCH syndrome. J Exp Med 213(7):1163–1174

    Article  Google Scholar 

  82. Alsohime F, Martin-Fernandez M, Temsah MH, Alabdulhafid M, Le Voyer T, Alghamdi M et al (2020) JAK inhibitor therapy in a child with inherited USP18 deficiency. N Engl J Med 382(3):256–265

    Article  CAS  Google Scholar 

  83. Gruber C, Martin-Fernandez M, Ailal F, Qiu X, Taft J, Altman J et al (2020) Homozygous STAT2 gain-of-function mutation by loss of USP18 activity in a patient with type I interferonopathy. J Exp Med 217(5):e20192319

  84. Cho K, Yamada M, Agematsu K, Kanegane H, Miyake N, Ueki M et al (2018) Heterozygous mutations in OAS1 cause infantile-onset pulmonary alveolar proteinosis with hypogammaglobulinemia. Am J Hum Genet 102(3):480–486

    Article  CAS  Google Scholar 

  85. Crow YJ, Manel N (2015) Aicardi-Goutieres syndrome and the type I interferonopathies. Nat Rev Immunol 15(7):429–440

    Article  CAS  Google Scholar 

  86. Uggenti C, Lepelley A, Depp M, Badrock AP, Rodero MP, El-Daher MT et al (2020) cGAS-mediated induction of type I interferon due to inborn errors of histone pre-mRNA processing. Nat Genet 52(12):1364–1372

    Article  CAS  Google Scholar 

  87. Takenouchi T, Kosaki R, Niizuma T, Hata K, Kosaki K (2015) Macrothrombocytopenia and developmental delay with a de novo CDC42 mutation: yet another locus for thrombocytopenia and developmental delay. Am J Med Genet A 167A(11):2822–2825

    Article  Google Scholar 

  88. Takenouchi T, Okamoto N, Ida S, Uehara T, Kosaki K (2016) Further evidence of a mutation in CDC42 as a cause of a recognizable syndromic form of thrombocytopenia. Am J Med Genet A 170A(4):852–855

    Article  Google Scholar 

  89. Martinelli S, Krumbach OHF, Pantaleoni F, Coppola S, Amin E, Pannone L et al (2018) Functional dysregulation of CDC42 causes diverse developmental phenotypes. Am J Hum Genet 102(2):309–320

    Article  CAS  Google Scholar 

  90. Motokawa M, Watanabe S, Nakatomi A, Kondoh T, Matsumoto T, Morifuji K et al (2018) A hot-spot mutation in CDC42 (p.Tyr64Cys) and novel phenotypes in the third patient with Takenouchi-Kosaki syndrome. J Hum Genet 63(3):387–90

  91. Uehara T, Suzuki H, Okamoto N, Kondoh T, Ahmad A, O’Connor BC et al (2019) Pathogenetic basis of Takenouchi-Kosaki syndrome: electron microscopy study using platelets in patients and functional studies in a Caenorhabditis elegans model. Sci Rep 9(1):4418

    Article  Google Scholar 

  92. Bucciol G, Pillay B, Casas-Martin J, Delafontaine S, Proesmans M, Lorent N et al (2020) Systemic inflammation and myelofibrosis in a patient with Takenouchi-Kosaki syndrome due to CDC42 Tyr64Cys mutation. J Clin Immunol 40(4):567–570

    Article  Google Scholar 

  93. Verboon JM, Mahmut D, Kim AR, Nakamura M, Abdulhay NJ, Nandakumar SK et al (2020) Infantile Myelofibrosis and myeloproliferation with CDC42 dysfunction. J Clin Immunol 40(4):554–566

    Article  CAS  Google Scholar 

  94. Lam MT, Coppola S, Krumbach OHF, Prencipe G, Insalaco A, Cifaldi C et al (2019) A novel disorder involving dyshematopoiesis, inflammation, and HLH due to aberrant CDC42 function. J Exp Med 216(12):2778–2799

    Article  CAS  Google Scholar 

  95. Gernez Y, de Jesus AA, Alsaleem H, Macaubas C, Roy A, Lovell D et al (2019) Severe autoinflammation in 4 patients with C-terminal variants in cell division control protein 42 homolog (CDC42) successfully treated with IL-1beta inhibition. J Allergy Clin Immuno 144(4):1122–5 e6

  96. He T, Huang Y, Ling J, Yang J (2020) A new patient with NOCARH syndrome due to CDC42 defect. J Clin Immunol 40(4):571–575

    Article  Google Scholar 

  97. Bekhouche B, Tourville A, Ravichandran Y, Tacine R, Abrami L, Dussiot M et al (2020) A toxic palmitoylation of Cdc42 enhances NF-kappaB signaling and drives a severe autoinflammatory syndrome. J Allergy Clin Immunol 146(5):1201–4 e8

  98. Szczawinska-Poplonyk A, Ploski R, Bernatowska E, Pac M (2020) A novel CDC42 mutation in an 11-year old child manifesting as syndromic immunodeficiency, autoinflammation, hemophagocytic lymphohistiocytosis, and malignancy: a case report. Front Immunol 11:318

    Article  CAS  Google Scholar 

  99. Alehashemi S, Goldbach-Mansky R (2020) Human autoinflammatory diseases mediated by NLRP3-, Pyrin-, NLRP1-, and NLRC4-inflammasome dysregulation updates on diagnosis, treatment, and the respective roles of IL-1 and IL-18. Front Immunol 11:1840

    Article  CAS  Google Scholar 

  100. Yu CH, Moecking J, Geyer M, Masters SL (2018) Mechanisms of NLRP1-mediated autoinflammatory disease in humans and mice. J Mol Biol 430(2):142–152

    Article  CAS  Google Scholar 

  101. Zhong FL, Mamai O, Sborgi L, Boussofara L, Hopkins R, Robinson K et al (2016) Germline NLRP1 mutations cause skin inflammatory and cancer susceptibility syndromes via inflammasome activation. Cell 167(1):187–202 e17

  102. Drutman SB, Haerynck F, Zhong FL, Hum D, Hernandez NJ, Belkaya S et al (2019) Homozygous NLRP1 gain-of-function mutation in siblings with a syndromic form of recurrent respiratory papillomatosis. Proc Natl Acad Sci U S A 116(38):19055–19063

    Article  CAS  Google Scholar 

  103. Grandemange S, Sanchez E, Louis-Plence P, Tran Mau-Them F, Bessis D, Coubes C et al (2017) A new autoinflammatory and autoimmune syndrome associated with NLRP1 mutations: NAIAD (NLRP1-associated autoinflammation with arthritis and dyskeratosis). Ann Rheum Dis 76(7):1191–1198

    Article  CAS  Google Scholar 

  104. Tao P, Sun J, Wu Z, Wang S, Wang J, Li W et al (2020) A dominant autoinflammatory disease caused by non-cleavable variants of RIPK1. Nature 577(7788):109–114

    Article  CAS  Google Scholar 

  105. Lalaoui N, Boyden SE, Oda H, Wood GM, Stone DL, Chau D et al (2020) Mutations that prevent caspase cleavage of RIPK1 cause autoinflammatory disease. Nature 577(7788):103–108

    Article  CAS  Google Scholar 

  106. Damgaard RB, Walker JA, Marco-Casanova P, Morgan NV, Titheradge HL, Elliott PR et al (2016) The deubiquitinase OTULIN is an essential negative regulator of inflammation and autoimmunity. Cell 166(5):1215–30 e20

  107. Damgaard RB, Elliott PR, Swatek KN, Maher ER, Stepensky P, Elpeleg O et al (2019) OTULIN deficiency in ORAS causes cell type-specific LUBAC degradation, dysregulated TNF signalling and cell death. EMBO Mol Med 11(3):e9324

  108. Zhou Q, Yu X, Demirkaya E, Deuitch N, Stone D, Tsai WL et al (2016) Biallelic hypomorphic mutations in a linear deubiquitinase define otulipenia, an early-onset autoinflammatory disease. Proc Natl Acad Sci U S A 113(36):10127–10132

    Article  CAS  Google Scholar 

  109. Nabavi M, Shahrooei M, Rokni-Zadeh H, Vrancken J, Changi-Ashtiani M, Darabi K et al (2019) Auto-inflammation in a patient with a novel homozygous OTULIN mutation. J Clin Immunol 39(2):138–141

    Article  CAS  Google Scholar 

  110. Damgaard RB, Jolin HE, Allison MED, Davies SE, Titheradge HL, McKenzie ANJ et al (2020) OTULIN protects the liver against cell death, inflammation, fibrosis, and cancer. Cell Death Differ 27(5):1457–1474

    Article  CAS  Google Scholar 

  111. Aeschlimann FA, Batu ED, Canna SW, Go E, Gul A, Hoffmann P et al (2018) A20 haploinsufficiency (HA20): clinical phenotypes and disease course of patients with a newly recognised NF-kB-mediated autoinflammatory disease. Ann Rheum Dis 77(5):728–735

    Article  CAS  Google Scholar 

  112. Witzel M, Petersheim D, Fan Y, Bahrami E, Racek T, Rohlfs M et al (2017) Chromatin-remodeling factor SMARCD2 regulates transcriptional networks controlling differentiation of neutrophil granulocytes. Nat Genet 49(5):742–752

    Article  CAS  Google Scholar 

  113. Schim van der Loeff I, Sprenkeler EGG, Tool ATJ, Abinun M, Grainger A, Engelhardt KR et al (2020) Defective neutrophil development and specific granule deficiency caused by a homozygous splice-site mutation in SMARCD2. J Allergy Clin Immunol 147(6):2381–2385 e2

  114. Tummala H, Walne AJ, Williams M, Bockett N, Collopy L, Cardoso S et al (2016) DNAJC21 mutations link a cancer-prone bone marrow failure syndrome to corruption in 60S ribosome subunit maturation. Am J Hum Genet 99(1):115–124

    Article  CAS  Google Scholar 

  115. Dhanraj S, Matveev A, Li H, Lauhasurayotin S, Jardine L, Cada M et al (2017) Biallelic mutations in DNAJC21 cause Shwachman-Diamond syndrome. Blood 129(11):1557–1562

    Article  CAS  Google Scholar 

  116. Morini J, Nacci L, Babini G, Cesaro S, Valli R, Ottolenghi A et al (2019) Whole exome sequencing discloses heterozygous variants in the DNAJC21 and EFL1 genes but not in SRP54 in 6 out of 16 patients with Shwachman-Diamond syndrome carrying biallelic SBDS mutations. Br J Haematol 185(3):627–630

    Article  Google Scholar 

  117. D’Amours G, Lopes F, Gauthier J, Saillour V, Nassif C, Wynn R et al (2018) Refining the phenotype associated with biallelic DNAJC21 mutations. Clin Genet 94(2):252–258

    Article  Google Scholar 

  118. Stepensky P, Chacon-Flores M, Kim KH, Abuzaitoun O, Bautista-Santos A, Simanovsky N et al (2017) Mutations in EFL1, an SBDS partner, are associated with infantile pancytopenia, exocrine pancreatic insufficiency and skeletal anomalies in a Shwachman-Diamond like syndrome. J Med Genet 54(8):558–566

    Article  CAS  Google Scholar 

  119. Carapito R, Konantz M, Paillard C, Miao Z, Pichot A, Leduc MS et al (2017) Mutations in signal recognition particle SRP54 cause syndromic neutropenia with Shwachman-Diamond-like features. J Clin Invest 127(11):4090–4103

    Article  Google Scholar 

  120. Bellanne-Chantelot C, Schmaltz-Panneau B, Marty C, Fenneteau O, Callebaut I, Clauin S et al (2018) Mutations in the SRP54 gene cause severe congenital neutropenia as well as Shwachman-Diamond-like syndrome. Blood 132(12):1318–1331

    Article  CAS  Google Scholar 

  121. Schurch C, Schaefer T, Muller JS, Hanns P, Arnone M, Dumlin A et al (2021) SRP54 mutations induce congenital neutropenia via dominant-negative effects on XBP1 splicing. Blood 137(10):1340–1352

    Article  CAS  Google Scholar 

  122. Haapaniemi EM, Fogarty CL, Keskitalo S, Katayama S, Vihinen H, Ilander M et al (2017) Combined immunodeficiency and hypoglycemia associated with mutations in hypoxia upregulated 1. J Allergy Clin Immunol 139(4):1391–3 e11

  123. Kuhns DB, Fink DL, Choi U, Sweeney C, Lau K, Priel DL et al (2016) Cytoskeletal abnormalities and neutrophil dysfunction in WDR1 deficiency. Blood 128(17):2135–2143

    Article  CAS  Google Scholar 

  124. Standing AS, Malinova D, Hong Y, Record J, Moulding D, Blundell MP et al (2017) Autoinflammatory periodic fever, immunodeficiency, and thrombocytopenia (PFIT) caused by mutation in actin-regulatory gene WDR1. J Exp Med 214(1):59–71

    Article  CAS  Google Scholar 

  125. Pfajfer L, Mair NK, Jimenez-Heredia R, Genel F, Gulez N, Ardeniz O et al (2017) Mutations affecting the actin regulator WD repeat-containing protein 1 lead to aberrant lymphoid immunity. J Allergy Clin Immunol 142(5):1589–604 e11

  126. Goos H, Fogarty CL, Sahu B, Plagnol V, Rajamaki K, Nurmi K et al (2019) Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy. J Allergy Clin Immunol 144(5):1364–1376

    Article  CAS  Google Scholar 

  127. Arnadottir GA, Norddahl GL, Gudmundsdottir S, Agustsdottir AB, Sigurdsson S, Jensson BO et al (2018) A homozygous loss-of-function mutation leading to CYBC1 deficiency causes chronic granulomatous disease. Nat Commun 9(1):4447

    Article  Google Scholar 

  128. Izawa K, Martin E, Soudais C, Bruneau J, Boutboul D, Rodriguez R et al (2017) Inherited CD70 deficiency in humans reveals a critical role for the CD70-CD27 pathway in immunity to Epstein-Barr virus infection. J Exp Med 214(1):73–89

    Article  CAS  Google Scholar 

  129. Abolhassani H, Edwards ES, Ikinciogullari A, Jing H, Borte S, Buggert M et al (2017) Combined immunodeficiency and Epstein-Barr virus-induced B cell malignancy in humans with inherited CD70 deficiency. J Exp Med 214(1):91–106

    Article  CAS  Google Scholar 

  130. Caorsi R, Rusmini M, Volpi S, Chiesa S, Pastorino C, Sementa AR et al (2017) CD70 deficiency due to a novel mutation in a patient with severe chronic EBV infection presenting as a periodic fever. Front Immunol 8:2015

    Article  Google Scholar 

  131. Somekh I, Thian M, Medgyesi D, Gulez N, Magg T, Gallon Duque A et al (2019) CD137 deficiency causes immune dysregulation with predisposition to lymphomagenesis. Blood 134(18):1510–1516

    Article  CAS  Google Scholar 

  132. Alosaimi MF, Hoenig M, Jaber F, Platt CD, Jones J, Wallace J, et al. Immunodeficiency and EBV-induced lymphoproliferation caused by 4–1BB deficiency. J Allergy Clin Immunol. 2019;144(2):574–83 e5

  133. Daschkey S, Bienemann K, Schuster V, Kreth HW, Linka RM, Honscheid A et al (2016) Fatal lymphoproliferative disease in two siblings lacking functional FAAP24. J Clin Immunol 36(7):684–692

    Article  CAS  Google Scholar 

  134. Platt CD, Fried AJ, Hoyos-Bachiloglu R, Usmani GN, Schmidt B, Whangbo J et al (2017) Combined immunodeficiency with EBV positive B cell lymphoma and epidermodysplasia verruciformis due to a novel homozygous mutation in RASGRP1. Clin Immunol 183:142–144

    Article  CAS  Google Scholar 

  135. Salzer E, Cagdas D, Hons M, Mace EM, Garncarz W, Petronczki OY et al (2016) RASGRP1 deficiency causes immunodeficiency with impaired cytoskeletal dynamics. Nat Immunol 17(12):1352–1360

    Article  CAS  Google Scholar 

  136. Winter S, Martin E, Boutboul D, Lenoir C, Boudjemaa S, Petit A et al (2018) Loss of RASGRP1 in humans impairs T-cell expansion leading to Epstein-Barr virus susceptibility. EMBO Mol Med 10(2):188–199

    Article  CAS  Google Scholar 

  137. Mao H, Yang W, Latour S, Yang J, Winter S, Zheng J et al (2018) RASGRP1 mutation in autoimmune lymphoproliferative syndrome-like disease. J Allergy Clin Immunol 142(2):595–604 e16

  138. Somekh I, Marquardt B, Liu Y, Rohlfs M, Hollizeck S, Karakukcu M et al (2018) Novel mutations in RASGRP1 are associated with immunodeficiency, immune dysregulation, and EBV-induced lymphoma. J Clin Immunol 38(6):699–710

    Article  CAS  Google Scholar 

  139. Schober T, Magg T, Laschinger M, Rohlfs M, Linhares ND, Puchalka J et al (2017) A human immunodeficiency syndrome caused by mutations in CARMIL2. Nat Commun 8:14209

    Article  CAS  Google Scholar 

  140. Maccari ME, Speckmann C, Heeg M, Reimer A, Casetti F, Has C et al (2019) Profound immunodeficiency with severe skin disease explained by concomitant novel CARMIL2 and PLEC1 loss-of-function mutations. Clin Immunol 208:108228

  141. Wang Y, Ma CS, Ling Y, Bousfiha A, Camcioglu Y, Jacquot S et al (2016) Dual T cell- and B cell-intrinsic deficiency in humans with biallelic RLTPR mutations. J Exp Med 213(11):2413–2435

    Article  CAS  Google Scholar 

  142. Sorte HS, Osnes LT, Fevang B, Aukrust P, Erichsen HC, Backe PH et al (2016) A potential founder variant in CARMIL2/RLTPR in three Norwegian families with warts, molluscum contagiosum, and T-cell dysfunction. Mol Genet Genomic Med 4(6):604–616

    Article  CAS  Google Scholar 

  143. Alazami AM, Al-Helale M, Alhissi S, Al-Saud B, Alajlan H, Monies D et al (2018) Novel CARMIL2 mutations in patients with variable clinical dermatitis, infections, and combined immunodeficiency. Front Immunol 9:203

    Article  Google Scholar 

  144. Kurolap A, Eshach Adiv O, Konnikova L, Werner L, Gonzaga-Jauregui C, Steinberg M et al (2019) A unique presentation of infantile-onset colitis and eosinophilic disease without recurrent infections resulting from a novel homozygous CARMIL2 variant. J Clin Immunol 39(4):430–439

    Article  CAS  Google Scholar 

  145. Atschekzei F, Jacobs R, Wetzke M, Sogkas G, Schroder C, Ahrenstorf G et al (2019) A novel CARMIL2 mutation resulting in combined immunodeficiency manifesting with dermatitis, fungal, and viral skin infections as well as selective antibody deficiency. J Clin Immunol 39(3):274–276

    Article  Google Scholar 

  146. Magg T, Shcherbina A, Arslan D, Desai MM, Wall S, Mitsialis V et al (2019) CARMIL2 deficiency presenting as very early onset inflammatory bowel disease. Inflamm Bowel Dis 25(11):1788–1795

    Article  Google Scholar 

  147. Yonkof JR, Gupta A, Rueda CM, Mangray S, Prince BT, Rangarajan HG et al (2020) A novel pathogenic variant in CARMIL2 (RLTPR) causing CARMIL2 deficiency and EBV-associated smooth muscle tumors. Front Immunol 11:884

    Article  CAS  Google Scholar 

  148. Stremenova Spegarova J, Lawless D, Mohamad SMB, Engelhardt KR, Doody G, Shrimpton J et al (2020) Germline TET2 loss of function causes childhood immunodeficiency and lymphoma. Blood 136(9):1055–1066

    Article  Google Scholar 

  149. Bravo Garcia-Morato M, Calvo Apalategi A, Bravo-Gallego LY, Blazquez Moreno A, Simon-Fuentes M, Garmendia JV et al (2019) Impaired control of multiple viral infections in a family with complete IRF9 deficiency. J Allergy Clin Immunol 144(1):309–12 e10

  150. Hernandez N, Melki I, Jing H, Habib T, Huang SSY, Danielson J et al (2018) Life-threatening influenza pneumonitis in a child with inherited IRF9 deficiency. J Exp Med 215(10):2567–2585

    Article  CAS  Google Scholar 

  151. Hernandez N, Bucciol G, Moens L, Le Pen J, Shahrooei M, Goudouris E et al (2019) Inherited IFNAR1 deficiency in otherwise healthy patients with adverse reaction to measles and yellow fever live vaccines. J Exp Med 216(9):2057–2070

    Article  CAS  Google Scholar 

  152. Duncan CJ, Mohamad SM, Young DF, Skelton AJ, Leahy TR, Munday DC et al (2015) Human IFNAR2 deficiency: lessons for antiviral immunity. Sci Transl Med 7(307):307ra154

  153. Passarelli C, Civino A, Rossi MN, Cifaldi L, Lanari V, Moneta GM et al (2020) IFNAR2 deficiency causing dysregulation of NK cell functions and presenting with hemophagocytic lymphohistiocytosis. Front Genet 11:937

    Article  Google Scholar 

  154. Ogunjimi B, Zhang SY, Sorensen KB, Skipper KA, Carter-Timofte M, Kerner G et al (2017) Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections. J Clin Invest 127(9):3543–3556

    Article  Google Scholar 

  155. Lafaille FG, Harschnitz O, Lee YS, Zhang P, Hasek ML, Kerner G et al (2019) Human SNORA31 variations impair cortical neuron-intrinsic immunity to HSV-1 and underlie herpes simplex encephalitis. Nat Med 25(12):1873–1884

    Article  CAS  Google Scholar 

  156. Hait AS, Olagnier D, Sancho-Shimizu V, Skipper KA, Helleberg M, Larsen SM et al (2020) Defects in LC3B2 and ATG4A underlie HSV2 meningitis and reveal a critical role for autophagy in antiviral defense in humans. Sci Immunol 5(54):eabc2691

  157. Witalisz-Siepracka A, Klein K, Prinz D, Leidenfrost N, Schabbauer G, Dohnal A et al (2018) Loss of JAK1 drives innate immune deficiency. Front Immunol 9:3108

    Article  CAS  Google Scholar 

  158. Daza-Cajigal V, Albuquerque AS, Pearson J, Hinley J, Mason AS, Stahlschmidt J et al (2019) Loss of Janus associated kinase 1 alters urothelial cell function and facilitates the development of bladder cancer. Front Immunol 10:2065

    Article  CAS  Google Scholar 

  159. Eletto D, Burns SO, Angulo I, Plagnol V, Gilmour KC, Henriquez F et al (2016) Biallelic JAK1 mutations in immunodeficient patient with mycobacterial infection. Nat Commun 7:13992

    Article  CAS  Google Scholar 

  160. Kong XF, Martinez-Barricarte R, Kennedy J, Mele F, Lazarov T, Deenick EK et al (2018) Disruption of an antimycobacterial circuit between dendritic and helper T cells in human SPPL2a deficiency. Nat Immunol 19(9):973–985

    Article  CAS  Google Scholar 

  161. Israel L, Wang Y, Bulek K, Della Mina E, Zhang Z, Pedergnana V et al (2017) Human adaptive immunity rescues an inborn error of innate immunity. Cell 168(5):789–800 e10

  162. Bucciol G, Moens L, Bosch B, Bossuyt X, Casanova JL, Puel A et al (2019) Lessons learned from the study of human inborn errors of innate immunity. J Allergy Clin Immunol 143(2):507–527

    Article  CAS  Google Scholar 

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  1. Division of Allergy and Immunology, Department of Pediatrics, Nationwide Children’s Hospital, The Ohio State University College of Medicine, Columbus, OH, USA

    Margaret T. Redmond, Rebecca Scherzer & Benjamin T. Prince

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  1. Margaret T. Redmond
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  2. Rebecca Scherzer
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Redmond, M.T., Scherzer, R. & Prince, B.T. Novel Genetic Discoveries in Primary Immunodeficiency Disorders. Clinic Rev Allerg Immunol 63, 55–74 (2022). https://doi.org/10.1007/s12016-021-08881-2

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