1932

Abstract

It was first demonstrated in the late nineteenth century that human deaths from fever were typically due to infections. As the germ theory gained ground, it replaced the old, unproven theory that deaths from fever reflected a weak personal or even familial constitution. A new enigma emerged at the turn of the twentieth century, when it became apparent that only a small proportion of infected individuals die from primary infections with almost any given microbe. Classical genetics studies gradually revealed that severe infectious diseases could be driven by human genetic predisposition. This idea gained ground with the support of molecular genetics, in three successive, overlapping steps. First, many rare inborn errors of immunity were shown, from 1985 onward, to underlie multiple, recurrent infections with Mendelian inheritance. Second, a handful of rare and familial infections, also segregating as Mendelian traits but striking humans resistant to other infections, were deciphered molecularly beginning in 1996. Third, from 2007 onward, a growing number of rare or common sporadicinfections were shown to result from monogenic, but not Mendelian, inborn errors. A synthesis of the hitherto mutually exclusive germ and genetic theories is now in view.

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2021-01-24
2024-03-29
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Literature Cited

  1. 1. 
    Casanova JL, Abel L. 2005. Inborn errors of immunity to infection: the rule rather than the exception. J. Exp. Med. 202:197–201
    [Google Scholar]
  2. 2. 
    Koch R. 1882. Die Aetiologie der Tuberkulose. Berl. Klin. Wochenschr. 19:221–30
    [Google Scholar]
  3. 3. 
    Pasteur L1922–1939 Oeuvres complètes de Louis Pasteur, réunies par Pasteur Vallery-Radot Paris: Masson et Cie
  4. 4. 
    Nat. Microbiol. 2019. Failure to vaccinate and vaccine failure. Nat. Microbiol. 4:725
    [Google Scholar]
  5. 5. 
    de Kraker ME, Stewardson AJ, Harbarth S 2016. Will 10 million people die a year due to antimicrobial resistance by 2050. PLOS Med 13:e1002184
    [Google Scholar]
  6. 6. 
    Jain V, Duse A, Bausch DG 2018. Planning for large epidemics and pandemics: challenges from a policy perspective. Curr. Opin. Infect. Dis. 31:316–24
    [Google Scholar]
  7. 7. 
    Nicolle C. 1933. Les infections inapparentes. Scientia 33:181–271
    [Google Scholar]
  8. 8. 
    Casanova JL. 2015. Human genetic basis of interindividual variability in the course of infection. PNAS 112:E7118–27
    [Google Scholar]
  9. 9. 
    Casanova JL, Abel L. 2020. The human genetic determinism of life-threatening infectious diseases: genetic heterogeneity and physiological homogeneity. Hum. Genet. 139:681–94
    [Google Scholar]
  10. 10. 
    Alcais A, Quintana-Murci L, Thaler DS, Schurr E, Abel L, Casanova JL 2010. Life-threatening infectious diseases of childhood: single-gene inborn errors of immunity. Ann. N. Y. Acad. Sci. 1214:18–33
    [Google Scholar]
  11. 11. 
    Casanova JL, Abel L. 2013. The genetic theory of infectious diseases: a brief history and selected illustrations. Annu. Rev. Genom. Hum. Genet. 14:215–43
    [Google Scholar]
  12. 12. 
    Raoult D, Mouffok N, Bitam I, Piarroux R, Drancourt M 2013. Plague: history and contemporary analysis. J. Infect. 66:18–26
    [Google Scholar]
  13. 13. 
    Cairns J. 1997. Matters of Life and Death: Perspectives on Public Health, Molecular Biology, Cancer, and the Prospects for the Human Race Princeton, NJ: Princeton Univ. Press
  14. 14. 
    Dobson AP, Carper ER. 1996. Infectious diseases and human population history: Throughout history the establishment of disease has been a side effect of the growth of civilization. Bioscience 46:115–26
    [Google Scholar]
  15. 15. 
    Dubos RJ. 1955. Second thoughts on the germ theory. Sci. Am. 192:31–35
    [Google Scholar]
  16. 16. 
    Koo S, Marty FM, Baden LR 2011. Infectious complications associated with immunomodulating biologic agents. Hematol. Oncol. Clin. N. Am. 25:117–38
    [Google Scholar]
  17. 17. 
    Naniche D, Oldstone MB. 2000. Generalized immunosuppression: how viruses undermine the immune response. Cell Mol. Life Sci. 57:1399–407
    [Google Scholar]
  18. 18. 
    Petrova VN, Sawatsky B, Han AX, Laksono BM, Walz L et al. 2019. Incomplete genetic reconstitution of B cell pools contributes to prolonged immunosuppression after measles. Sci. Immunol. 4:eaay6125
    [Google Scholar]
  19. 19. 
    Bourke CD, Berkley JA, Prendergast AJ 2016. Immune dysfunction as a cause and consequence of malnutrition. Trends Immunol 37:386–98
    [Google Scholar]
  20. 20. 
    Yaguchi T, Kawakami Y. 2016. Cancer-induced heterogeneous immunosuppressive tumor microenvironments and their personalized modulation. Int. Immunol. 28:393–99
    [Google Scholar]
  21. 21. 
    Casanova JL. 2015. Severe infectious diseases of childhood as monogenic inborn errors of immunity. PNAS 112:E7128–37
    [Google Scholar]
  22. 22. 
    Borghesi A, Marzollo A, Michev A, Fellay J 2020. Susceptibility to infection in early life: a growing role for human genetics. Hum. Genet. 139:733–43
    [Google Scholar]
  23. 23. 
    Zhang SY, Jouanguy E, Zhang Q, Abel L, Puel A, Casanova JL 2019. Human inborn errors of immunity to infection affecting cells other than leukocytes: from the immune system to the whole organism. Curr. Opin. Immunol. 59:88–100
    [Google Scholar]
  24. 24. 
    Allison AC. 1954. Protection afforded by sickle cell trait against subtertian malarian infection. BMJ 1:290–94
    [Google Scholar]
  25. 25. 
    Casanova JL, Abel L. 2018. Human genetics of infectious diseases: unique insights into immunological redundancy. Semin. Immunol. 36:1–12
    [Google Scholar]
  26. 26. 
    Bruton OC. 1952. Agammaglobulinemia. Pediatrics 9:722–28
    [Google Scholar]
  27. 27. 
    Bruton OC. 1962. A decade with agammaglobulinemia. J. Pediatr. 60:672–76
    [Google Scholar]
  28. 28. 
    Janeway CA, Apt L, Gitlin D 1953. Agammaglobulinemia. Trans. Assoc. Am. Phys. 66:200–2
    [Google Scholar]
  29. 29. 
    Kostmann R. 1950. Hereditär reticulos—en ny systemsjukdom. Sven. Läkartidn. 47:2861
    [Google Scholar]
  30. 30. 
    Kostmann R. 1956. Infantile genetic agranulocytosis. Acta Pediatr. Scand. 45:1–78
    [Google Scholar]
  31. 31. 
    Buckley RH. 2020. Conversations with founders of the field of human inborn errors of immunity. J. Clin. Immunol. 40:1–8
    [Google Scholar]
  32. 32. 
    Lutz W. 1946. A propos de l'épidermodysplasie verruciforme. Dermatologica 92:30–43
    [Google Scholar]
  33. 33. 
    Crabbe PA, Heremans JF. 1967. Selective IgA deficiency with steatorrhea. A new syndrome. Am. J. Med. 42:319–26
    [Google Scholar]
  34. 34. 
    Wang N, Hammarstrom L. 2012. IgA deficiency: What is new. Curr. Opin. Allergy Clin. Immunol. 12:602–8
    [Google Scholar]
  35. 35. 
    Zhang Q, Boisson B, Béziat V, Puel A, Casanova JL 2018. Human hyper-IgE syndrome: singular or plural. Mamm. Genome 29:603–17
    [Google Scholar]
  36. 36. 
    Myerson RM, Koelle WA. 1956. Congenital absence of the spleen in an adult: report of a case associated with recurrent Waterhouse–Friderichsen syndrome. N. Engl. J. Med. 254:1131–32
    [Google Scholar]
  37. 37. 
    Hitzig WH, Biro Z, Bosch H, Huser HJ 1958. [Agammaglobulinemia & alymphocytosis with atrophy of lymphatic tissue. .] Helv. Paediatr. Acta 13:551–85 In German )
    [Google Scholar]
  38. 38. 
    DiGeorge AM. 1965. A new concept of the cellular basis of immunity. J. Pediatr. 67:907–8
    [Google Scholar]
  39. 39. 
    Bousfiha A, Jeddane L, Picard C, Al-Herz W, Ailal F et al. 2020. Human inborn errors of immunity: 2019 update of the IUIS Phenotypical Classification. J. Clin. Immunol. 40:66–81
    [Google Scholar]
  40. 40. 
    Tangye SG, Al-Herz W, Bousfiha A, Chatila T, Cunningham-Rundles C 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. 40:24–64
    [Google Scholar]
  41. 41. 
    Yamazaki Y, Urrutia R, Franco LM, Giliani S, Zhang K et al. 2020. PAX1 is essential for development and function of the human thymus. Sci. Immunol. 5:eaax1036
    [Google Scholar]
  42. 42. 
    Casanova JL, Abel L. 2007. Primary immunodeficiencies: a field in its infancy. Science 317:617–19
    [Google Scholar]
  43. 43. 
    Meyts I, Bosch B, Bolze A, Boisson B, Itan Y et al. 2016. Exome and genome sequencing for inborn errors of immunity. J. Allergy Clin. Immunol. 138:957–69
    [Google Scholar]
  44. 44. 
    Austen KF, Sheffer AL. 1965. Detection of hereditary angioneurotic edema by demonstration of a reduction in the second component of human complement. N. Engl. J. Med. 272:649–56
    [Google Scholar]
  45. 45. 
    Rosen FS, Pensky J, Donaldson V, Charache P 1965. Hereditary angioneurotic edema: two genetic variants. Science 148:957–58
    [Google Scholar]
  46. 46. 
    Hill HR, Quie PG. 1974. Raised serum-IgE levels and defective neutrophil chemotaxis in three children with eczema and recurrent bacterial infections. Lancet 303:18387
    [Google Scholar]
  47. 47. 
    Agnello V, De Bracco MM, Kunkel HG 1972. Hereditary C2 deficiency with some manifestations of systemic lupus erythematosus. J. Immunol. 108:837–40
    [Google Scholar]
  48. 48. 
    Moncada B, Day NK, Good RA, Windhorst DB 1972. Lupus-erythematosus-like syndrome with a familial defect of complement. N. Engl. J. Med. 286:689–93
    [Google Scholar]
  49. 49. 
    Peterson RD, Kelly WD, Good RA 1964. Ataxia-telangiectasia. Its association with a defective thymus, immunological-deficiency disease, and malignancy. Lancet 283:118993
    [Google Scholar]
  50. 50. 
    Bousfiha A, Jeddane L, Picard C, Ailal F, Gaspar HB et al. 2018. The 2017 IUIS Phenotypic Classification for Primary Immunodeficiencies. J. Clin. Immunol. 38:129–43
    [Google Scholar]
  51. 51. 
    Crow YJ. 2011. Type I interferonopathies: a novel set of inborn errors of immunity. Ann. N. Y. Acad. Sci. 1238:91–98
    [Google Scholar]
  52. 52. 
    Manthiram K, Zhou Q, Aksentijevich I, Kastner DL 2017. The monogenic autoinflammatory diseases define new pathways in human innate immunity and inflammation. Nat. Immunol. 18:832–42
    [Google Scholar]
  53. 53. 
    Masters SL, Simon A, Aksentijevich I, Kastner DL 2009. Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease. Annu. Rev. Immunol. 27:621–68
    [Google Scholar]
  54. 54. 
    Rodero MP, Crow YJ. 2016. Type I interferon–mediated monogenic autoinflammation: the type I interferonopathies, a conceptual overview. J. Exp. Med. 213:2527–38
    [Google Scholar]
  55. 55. 
    Casanova JL, Abel L. 2004. The human model: a genetic dissection of immunity to infection in natural conditions. Nat. Rev. Immunol. 4:55–66
    [Google Scholar]
  56. 56. 
    Quintana-Murci L, Alcais A, Abel L, Casanova JL 2007. Immunology in natura: clinical, epidemiological and evolutionary genetics of infectious diseases. Nat. Immunol. 8:1165–71
    [Google Scholar]
  57. 57. 
    Zhang Q, Frange P, Blanche S, Casanova JL 2017. Pathogenesis of infections in HIV-infected individuals: insights from primary immunodeficiencies. Curr. Opin. Immunol. 48:122–33
    [Google Scholar]
  58. 58. 
    Picard C, Casanova JL, Puel A 2011. Infectious diseases in patients with IRAK-4, MyD88, NEMO, or IκBα deficiency. Clin. Microbiol. Rev. 24:490–97
    [Google Scholar]
  59. 59. 
    Skokowa J, Dale DC, Touw IP, Zeidler C, Welte K 2017. Severe congenital neutropenias. Nat. Rev. Dis. Primers 3:17032
    [Google Scholar]
  60. 60. 
    Casanova JL, Abel L. 2002. Genetic dissection of immunity to mycobacteria: the human model. Annu. Rev. Immunol. 20:581–620
    [Google Scholar]
  61. 61. 
    Reichenbach J, Rosenzweig S, Doffinger R, Dupuis S, Holland SM, Casanova JL 2001. Mycobacterial diseases in primary immunodeficiencies. Curr. Opin. Allergy Clin. Immunol. 1:503–11
    [Google Scholar]
  62. 62. 
    Picard C, Puel A, Bustamante J, Ku CL, Casanova JL 2003. Primary immunodeficiencies associated with pneumococcal disease. Curr. Opin. Allergy Clin. Immunol. 3:451–59
    [Google Scholar]
  63. 63. 
    Sancho-Shimizu V, Zhang SY, Abel L, Tardieu M, Rozenberg F et al. 2007. Genetic susceptibility to herpes simplex virus 1 encephalitis in mice and humans. Curr. Opin. Allergy Clin. Immunol. 7:495–505
    [Google Scholar]
  64. 64. 
    Tangye SG, Latour S. 2020. Primary immunodeficiencies reveal the molecular requirements for effective host defense against EBV infection. Blood 135:644–55
    [Google Scholar]
  65. 65. 
    Leiding JW, Holland SM. 2012. Warts and all: human papillomavirus in primary immunodeficiencies. J. Allergy Clin. Immunol. 130:1030–48
    [Google Scholar]
  66. 66. 
    Puel A, Cypowyj S, Marodi L, Abel L, Picard C, Casanova JL 2012. Inborn errors of human IL-17 immunity underlie chronic mucocutaneous candidiasis. Curr. Opin. Allergy Clin. Immunol. 12:616–22
    [Google Scholar]
  67. 67. 
    Boisson B. 2020. The genetic basis of pneumococcal and staphylococcal infections: inborn errors of human TLR and IL-1R immunity. Hum. Genet. 139:98191
    [Google Scholar]
  68. 68. 
    Cypowyj S, Picard C, Marodi L, Casanova JL, Puel A 2012. Immunity to infection in IL-17-deficient mice and humans. Eur. J. Immunol. 42:2246–54
    [Google Scholar]
  69. 69. 
    Fortin A, Abel L, Casanova JL, Gros P 2007. Host genetics of mycobacterial diseases in mice and men: forward genetic studies of BCG-osis and tuberculosis. Annu. Rev. Genom. Hum. Genet. 8:163–92
    [Google Scholar]
  70. 70. 
    von Bernuth H, Picard C, Puel A, Casanova JL 2012. Experimental and natural infections in MyD88- and IRAK-4-deficient mice and humans. Eur. J. Immunol. 42:3126–35
    [Google Scholar]
  71. 71. 
    Zhang SY, Herman M, Ciancanelli MJ, Pérez de Diego R, Sancho-Shimizu V et al. 2013. TLR3 immunity to infection in mice and humans. Curr. Opin. Immunol. 25:19–33
    [Google Scholar]
  72. 72. 
    Tsukada S, Saffran DC, Rawlings DJ, Parolini O, Allen RC et al. 1993. Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia. Cell 72:279–90
    [Google Scholar]
  73. 73. 
    Vetrie D, Vorechovsky I, Sideras P, Holland J, Davies A et al. 1993. The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases. Nature 361:226–33
    [Google Scholar]
  74. 74. 
    Bonthron DT, Markham AF, Ginsburg D, Orkin SH 1985. Identification of a point mutation in the adenosine deaminase gene responsible for immunodeficiency. J. Clin. Investig. 76:894–97
    [Google Scholar]
  75. 75. 
    Royer-Pokora B, Kunkel LM, Monaco AP, Goff SC, Newburger PE et al. 1986. Cloning the gene for an inherited human disorder—chronic granulomatous disease—on the basis of its chromosomal location. Nature 322:32–38
    [Google Scholar]
  76. 76. 
    Picard C, von Bernuth H, Ghandil P, Chrabieh M, Levy O et al. 2010. Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency. Medicine 89:403–25
    [Google Scholar]
  77. 77. 
    Orth G, Jablonska S, Favre M, Croissant O, Jarzabek-Chorzelska M, Rzesa G 1978. Characterization of two types of human papillomaviruses in lesions of epidermodysplasia verruciformis. PNAS 75:1537–41
    [Google Scholar]
  78. 78. 
    Bustamante J. 2020. Mendelian susceptibility to mycobacterial disease: recent discoveries. Hum. Genet. 139:9931000
    [Google Scholar]
  79. 79. 
    Blank F, Schopflocher P, Poirier P, Riopelle JL 1957. Extensive Trichophyton infections of about fifty years’ duration in two sisters. Dermatologica 115:40–51
    [Google Scholar]
  80. 80. 
    Li J, Vinh DC, Casanova JL, Puel A 2017. Inborn errors of immunity underlying fungal diseases in otherwise healthy individuals. Curr. Opin. Microbiol. 40:46–57
    [Google Scholar]
  81. 81. 
    Purtilo DT, Cassel C, Yang JP 1974. Letter: Fatal infectious mononucleosis in familial lymphohistiocytosis. N. Engl. J. Med. 291:736
    [Google Scholar]
  82. 82. 
    Purtilo DT, DeFlorio D Jr, Hutt LM, Bhawan J, Yang JP et al. 1977. Variable phenotypic expression of an X-linked recessive lymphoproliferative syndrome. N. Engl. J. Med. 297:1077–80
    [Google Scholar]
  83. 83. 
    Chilgren RA, Quie PG, Meuwissen HJ, Hong R 1967. Chronic mucocutaneous candidiasis, deficiency of delayed hypersensitivity, and selective local antibody defect. Lancet 290:68893
    [Google Scholar]
  84. 84. 
    Smatti MK, Al-Sadeq DW, Ali NH, Pintus G, Abou-Saleh H, Nasrallah GK 2018. Epstein-Barr virus epidemiology, serology, and genetic variability of LMP-1 oncogene among healthy population: an update. Front. Oncol. 8:211
    [Google Scholar]
  85. 85. 
    Orth G. 2008. Host defenses against human papillomaviruses: lessons from epidermodysplasia verruciformis. Curr. Top. Microbiol. Immunol. 321:59–83
    [Google Scholar]
  86. 86. 
    Crequer A, Picard C, Patin E, D'Amico A, Abhyankar A et al. 2012. Inherited MST1 deficiency underlies susceptibility to EV-HPV infections. PLOS ONE 7:e44010
    [Google Scholar]
  87. 87. 
    Crequer A, Troeger A, Patin E, Ma CS, Picard C et al. 2012. Human RHOH deficiency causes T cell defects and susceptibility to EV-HPV infections. J. Clin. Investig. 122:3239–47
    [Google Scholar]
  88. 88. 
    Laffort C, Le Deist F, Favre M, Caillat-Zucman S, Radford-Weiss I et al. 2004. Severe cutaneous papillomavirus disease after haemopoietic stem-cell transplantation in patients with severe combined immune deficiency caused by common γc cytokine receptor subunit or JAK-3 deficiency. Lancet 363:2051–54
    [Google Scholar]
  89. 89. 
    de Jong SJ, Crequer A, Matos I, Hum D, Gunasekharan V et al. 2018. The human CIB1-EVER1-EVER2 complex governs keratinocyte-intrinsic immunity to β-papillomaviruses. J. Exp. Med. 215:2289–310
    [Google Scholar]
  90. 90. 
    Ramoz N, Rueda LA, Bouadjar B, Montoya LS, Orth G, Favre M 2002. Mutations in two adjacent novel genes are associated with epidermodysplasia verruciformis. Nat. Genet. 32:57981
    [Google Scholar]
  91. 91. 
    Duncan CJ, Mohamad SM, Young DF, Skelton AJ, Leahy TR et al. 2015. Human IFNAR2 deficiency: lessons for antiviral immunity. Sci. Transl. Med. 7:307ra154
    [Google Scholar]
  92. 92. 
    Glocker EO, Kotlarz D, Boztug K, Gertz EM, Schaffer AA et al. 2009. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N. Engl. J. Med. 361:2033–45
    [Google Scholar]
  93. 93. 
    Hernandez N, Bucciol G, Moens L, Le Pen J, Shahrooei M et al. 2019. Inherited IFNAR1 deficiency in otherwise healthy patients with adverse reaction to measles and yellow fever live vaccines. J. Exp. Med. 216:2057–70
    [Google Scholar]
  94. 94. 
    Huang Z, Peng K, Li X, Zhao R, You J et al. 2017. Mutations in interleukin-10 receptor and clinical phenotypes in patients with very early onset inflammatory bowel disease: a Chinese VEO-IBD Collaboration Group survey. Inflamm. Bowel Dis. 23:578–90
    [Google Scholar]
  95. 95. 
    Coffey AJ, Brooksbank RA, Brandau O, Oohashi T, Howell GR et al. 1998. Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene. Nat. Genet. 20:129–35
    [Google Scholar]
  96. 96. 
    Nichols KE, Harkin DP, Levitz S, Krainer M, Kolquist KA et al. 1998. Inactivating mutations in an SH2 domain–encoding gene in X-linked lymphoproliferative syndrome. PNAS 95:13765–70
    [Google Scholar]
  97. 97. 
    Sayos J, Wu C, Morra M, Wang N, Zhang X et al. 1998. The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM. Nature 395:462–69
    [Google Scholar]
  98. 98. 
    Palendira U, Low C, Bell AI, Ma CS, Abbott RJ et al. 2012. Expansion of somatically reverted memory CD8+ T cells in patients with X-linked lymphoproliferative disease caused by selective pressure from Epstein-Barr virus. J. Exp. Med. 209:913–24
    [Google Scholar]
  99. 99. 
    Palendira U, Low C, Chan A, Hislop AD, Ho E et al. 2011. Molecular pathogenesis of EBV susceptibility in XLP as revealed by analysis of female carriers with heterozygous expression of SAP. PLOS Biol 9:e1001187
    [Google Scholar]
  100. 100. 
    Rigaud S, Fondaneche MC, Lambert N, Pasquier B, Mateo V et al. 2006. XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome. Nature 444:110–14
    [Google Scholar]
  101. 101. 
    van Montfrans JM, Hoepelman AI, Otto S, van Gijn M, van de Corput L et al. 2012. CD27 deficiency is associated with combined immunodeficiency and persistent symptomatic EBV viremia. J. Allergy Clin. Immunol. 129:787–93.e6
    [Google Scholar]
  102. 102. 
    Abolhassani H, Edwards ES, Ikinciogullari A, Jing H, Borte S et al. 2017. Combined immunodeficiency and Epstein-Barr virus–induced B cell malignancy in humans with inherited CD70 deficiency. J. Exp. Med. 214:91–106
    [Google Scholar]
  103. 103. 
    Izawa K, Martin E, Soudais C, Bruneau J, Boutboul D 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. 214:73–89
    [Google Scholar]
  104. 104. 
    Huck K, Feyen O, Niehues T, Rüschendorf F, Hubner N et al. 2009. Girls homozygous for an IL-2-inducible T cell kinase mutation that leads to protein deficiency develop fatal EBV-associated lymphoproliferation. J. Clin. Investig. 119:1350–58
    [Google Scholar]
  105. 105. 
    Casanova JL, Jouanguy E, Lamhamedi S, Blanche S, Fischer A 1995. Immunological conditions of children with BCG disseminated infection. Lancet 346:581
    [Google Scholar]
  106. 106. 
    Mimouni J. 1951. Notre expérience de trois années de vaccination à Constantine; étude de 25 cas de complications. Alger. Méd. 55:1138–47
    [Google Scholar]
  107. 107. 
    Bustamante J, Boisson-Dupuis S, Abel L, Casanova JL 2014. Mendelian susceptibility to mycobacterial disease: genetic, immunological, and clinical features of inborn errors of IFN-γ immunity. Semin. Immunol. 26:454–70
    [Google Scholar]
  108. 108. 
    Kerner G, Rosain J, Guérin A, Al-Khabaz A, Oleaga-Quintas C et al. 2020. Inherited human IFNγ deficiency underlies mycobacterial disease. J. Clin. Investig. 130:63158–71
    [Google Scholar]
  109. 109. 
    Rosain J, Kong XF, Martinez-Barricarte R, Oleaga-Quintas C, Ramirez-Alejo N et al. 2019. Mendelian susceptibility to mycobacterial disease: 2014–2018 update. Immunol. Cell Biol. 97:360–67
    [Google Scholar]
  110. 110. 
    Rosenzweig SD, Holland SM. 2005. Defects in the interferon-γ and interleukin-12 pathways. Immunol. Rev. 203:38–47
    [Google Scholar]
  111. 111. 
    Wu UI, Holland SM. 2015. Host susceptibility to non-tuberculous mycobacterial infections. Lancet Infect. Dis. 15:968–80
    [Google Scholar]
  112. 112. 
    Boisson-Dupuis S, Ramirez-Alejo N, Li Z, Patin E, Rao G et al. 2018. Tuberculosis and impaired IL-23-dependent IFN-γ immunity in humans homozygous for a common TYK2 missense variant. Sci. Immunol. 3:30eaau8714
    [Google Scholar]
  113. 113. 
    Kong XF, Martinez-Barricarte R, Kennedy J, Mele F, Lazarov T et al. 2018. Disruption of an antimycobacterial circuit between dendritic and helper T cells in human SPPL2a deficiency. Nat. Immunol. 19:973–85
    [Google Scholar]
  114. 114. 
    Martinez-Barricarte R, Markle JG, Ma CS, Deenick EK, Ramirez-Alejo N et al. 2018. Human IFN-γ immunity to mycobacteria is governed by both IL-12 and IL-23. Sci. Immunol. 3:eaau6759
    [Google Scholar]
  115. 115. 
    Alangari AA, Al-Zamil F, Al-Mazrou A, Al-Muhsen S, Boisson-Dupuis S et al. 2011. Treatment of disseminated mycobacterial infection with high-dose IFN-γ in a patient with IL-12Rβ1 deficiency. Clin. Dev. Immunol. 2011:691956
    [Google Scholar]
  116. 116. 
    Holland SM. 2001. Immunotherapy of mycobacterial infections. Semin. Respir. Infect. 16:47–59
    [Google Scholar]
  117. 117. 
    Nathan CF, Murray HW, Wiebe ME, Rubin BY 1983. Identification of interferon-γ as the lymphokine that activates human macrophage oxidative metabolism and antimicrobial activity. J. Exp. Med. 158:670–89
    [Google Scholar]
  118. 118. 
    Schroder K, Hertzog PJ, Ravasi T, Hume DA 2004. Interferon-γ: an overview of signals, mechanisms and functions. J. Leukoc. Biol. 75:163–89
    [Google Scholar]
  119. 119. 
    Canales L, Middlemas RO 3rd, Louro JM, South MA 1969. Immunological observations in chronic mucocutaneous candidiasis. Lancet 294:56771
    [Google Scholar]
  120. 120. 
    Wells RS. 1970. Chronic oral candidiasis (autosomal recessive inheritance) (three cases). Proc. R. Soc. Med. 63:890–91
    [Google Scholar]
  121. 121. 
    Puel A, Cypowyj S, Bustamante J, Wright JF, Liu L et al. 2011. Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity. Science 332:65–68
    [Google Scholar]
  122. 122. 
    Boisson B, Wang C, Pedergnana V, Wu L, Cypowyj S et al. 2013. An ACT1 mutation selectively abolishes interleukin-17 responses in humans with chronic mucocutaneous candidiasis. Immunity 39:676–86
    [Google Scholar]
  123. 123. 
    Lévy R, Okada S, Béziat V, Moriya K, Liu C et al. 2016. Genetic, immunological, and clinical features of patients with bacterial and fungal infections due to inherited IL-17RA deficiency. PNAS 113:E8277–85
    [Google Scholar]
  124. 124. 
    Li J, Ritelli M, Ma CS, Rao G, Habib T et al. 2019. Chronic mucocutaneous candidiasis and connective tissue disorder in humans with impaired JNK1-dependent responses to IL-17A/F and TGF-β. Sci. Immunol. 4:eaax7965
    [Google Scholar]
  125. 125. 
    Ling Y, Cypowyj S, Aytekin C, Galicchio M, Camcioglu Y et al. 2015. Inherited IL-17RC deficiency in patients with chronic mucocutaneous candidiasis. J. Exp. Med. 212:619–31
    [Google Scholar]
  126. 126. 
    Kisand K, Boe Wolff AS, Podkrajsek KT, Tserel L, Link M et al. 2010. Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines. J. Exp. Med. 207:299–308
    [Google Scholar]
  127. 127. 
    Puel A, Doffinger R, Natividad A, Chrabieh M, Barcenas-Morales G et al. 2010. Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I. J. Exp. Med. 207:291–97
    [Google Scholar]
  128. 128. 
    Okada S, Markle JG, Deenick EK, Mele F, Averbuch D et al. 2015. Immunodeficiencies. Impairment of immunity to Candida and Mycobacterium in humans with bi-allelic RORC mutations. Science 349:606–13
    [Google Scholar]
  129. 129. 
    Béziat V, Li J, Lin JX, Ma CS, Li P et al. 2018. A recessive form of hyper-IgE syndrome by disruption of ZNF341-dependent STAT3 transcription and activity. Sci. Immunol. 3:eaat4956
    [Google Scholar]
  130. 130. 
    Liu L, Okada S, Kong XF, Kreins AY, Cypowyj S et al. 2011. Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis. J. Exp. Med. 208:1635–48
    [Google Scholar]
  131. 131. 
    Glocker EO, Hennigs A, Nabavi M, Schaffer AA, Woellner C et al. 2009. A homozygous CARD9 mutation in a family with susceptibility to fungal infections. N. Engl. J. Med. 361:1727–35
    [Google Scholar]
  132. 132. 
    Lanternier F, Pathan S, Vincent QB, Liu L, Cypowyj S et al. 2013. Deep dermatophytosis and inherited CARD9 deficiency. N. Engl. J. Med. 369:1704–14
    [Google Scholar]
  133. 133. 
    Corvilain E, Casanova JL, Puel A 2018. Inherited CARD9 deficiency: invasive disease caused by ascomycete fungi in previously healthy children and adults. J. Clin. Immunol. 38:656–93
    [Google Scholar]
  134. 134. 
    Drummond RA, Collar AL, Swamydas M, Rodriguez CA, Lim JK et al. 2015. CARD9-dependent neutrophil recruitment protects against fungal invasion of the central nervous system. PLOS Pathog 11:e1005293
    [Google Scholar]
  135. 135. 
    Hodeib S, Herberg JA, Levin M, Sancho-Shimizu V 2020. Human genetics of meningococcal infections. Hum. Genet. 139:96180
    [Google Scholar]
  136. 136. 
    de Beaucoudrey L, Samarina A, Bustamante J, Cobat A, Boisson-Dupuis S et al. 2010. Revisiting human IL-12Rβ1 deficiency: a survey of 141 patients from 30 countries. Medicine 89:381–402
    [Google Scholar]
  137. 137. 
    Fieschi C, Dupuis S, Catherinot E, Feinberg J, Bustamante J et al. 2003. Low penetrance, broad resistance, and favorable outcome of interleukin 12 receptor β1 deficiency: medical and immunological implications. J. Exp. Med. 197:527–35
    [Google Scholar]
  138. 138. 
    Altare F, Ensser A, Breiman A, Reichenbach J, Baghdadi JE et al. 2001. Interleukin-12 receptor β1 deficiency in a patient with abdominal tuberculosis. J. Infect. Dis. 184:231–36
    [Google Scholar]
  139. 139. 
    Boisson-Dupuis S. 2020. The monogenic basis of human tuberculosis. Hum. Genet. 139:10019
    [Google Scholar]
  140. 140. 
    Boisson-Dupuis S, El Baghdadi J, Parvaneh N, Bousfiha A, Bustamante J et al. 2011. IL-12Rβ1 deficiency in two of fifty children with severe tuberculosis from Iran, Morocco, and Turkey. PLOS ONE 6:e18524
    [Google Scholar]
  141. 141. 
    Caragol I, Raspall M, Fieschi C, Feinberg J, Larrosa MN et al. 2003. Clinical tuberculosis in 2 of 3 siblings with interleukin-12 receptor β1 deficiency. Clin. Infect. Dis. 37:302–6
    [Google Scholar]
  142. 142. 
    Ozbek N, Fieschi C, Yilmaz BT, de Beaucoudrey L, Demirhan B et al. 2005. Interleukin-12 receptor β1 chain deficiency in a child with disseminated tuberculosis. Clin. Infect. Dis. 40:e55–58
    [Google Scholar]
  143. 143. 
    Tabarsi P, Marjani M, Mansouri N, Farnia P, Boisson-Dupuis S et al. 2011. Lethal tuberculosis in a previously healthy adult with IL-12 receptor deficiency. J. Clin. Immunol. 31:537–39
    [Google Scholar]
  144. 144. 
    Kreins AY, Ciancanelli MJ, Okada S, Kong XF, Ramirez-Alejo N et al. 2015. Human TYK2 deficiency: mycobacterial and viral infections without hyper-IgE syndrome. J. Exp. Med. 212:1641–62
    [Google Scholar]
  145. 145. 
    Kerner G, Ramirez-Alejo N, Seeleuthner Y, Yang R, Ogishi M et al. 2019. Homozygosity for TYK2 P1104A underlies tuberculosis in about 1% of patients in a cohort of European ancestry. PNAS 116:10430–34
    [Google Scholar]
  146. 146. 
    Bolze A, Boisson B, Bosch B, Antipenko A, Bouaziz M et al. 2018. Incomplete penetrance for isolated congenital asplenia in humans with mutations in translated and untranslated RPSA exons. PNAS 115:E8007–16
    [Google Scholar]
  147. 147. 
    Bolze A, Mahlaoui N, Byun M, Turner B, Trede N et al. 2013. Ribosomal protein SA haploinsufficiency in humans with isolated congenital asplenia. Science 340:976–78
    [Google Scholar]
  148. 148. 
    Boisson B, Honda Y, Ajiro M, Bustamante J, Bendavid M et al. 2019. Rescue of recurrent deep intronic mutation underlying cell type–dependent quantitative NEMO deficiency. J. Clin. Investig. 129:583–97
    [Google Scholar]
  149. 149. 
    Courtois G, Smahi A, Reichenbach J, Doffinger R, Cancrini C et al. 2003. A hypermorphic IκBα mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency. J. Clin. Investig. 112:1108–15
    [Google Scholar]
  150. 150. 
    Doffinger R, Smahi A, Bessia C, Geissmann F, Feinberg J et al. 2001. X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-κB signaling. Nat. Genet. 27:277–85
    [Google Scholar]
  151. 151. 
    Picard C, Puel A, Bonnet M, Ku CL, Bustamante J et al. 2003. Pyogenic bacterial infections in humans with IRAK-4 deficiency. Science 299:2076–79
    [Google Scholar]
  152. 152. 
    von Bernuth H, Picard C, Jin Z, Pankla R, Xiao H et al. 2008. Pyogenic bacterial infections in humans with MyD88 deficiency. Science 321:691–96
    [Google Scholar]
  153. 153. 
    Israel L, Wang Y, Bulek K, Della Mina E, Zhang Z et al. 2017. Human adaptive immunity rescues an inborn error of innate immunity. Cell 168:789–800.e10
    [Google Scholar]
  154. 154. 
    Casrouge A, Zhang SY, Eidenschenk C, Jouanguy E, Puel A et al. 2006. Herpes simplex virus encephalitis in human UNC-93B deficiency. Science 314:308–12
    [Google Scholar]
  155. 155. 
    Zhang SY, Jouanguy E, Ugolini S, Smahi A, Elain G et al. 2007. TLR3 deficiency in patients with herpes simplex encephalitis. Science 317:1522–27
    [Google Scholar]
  156. 156. 
    Zhang SY. 2020. Herpes simplex virus encephalitis of childhood: inborn errors of central nervous system cell-intrinsic immunity. Hum. Genet. 139:91118
    [Google Scholar]
  157. 157. 
    Abel L, Plancoulaine S, Jouanguy E, Zhang SY, Mahfoufi N et al. 2010. Age-dependent Mendelian predisposition to herpes simplex virus type 1 encephalitis in childhood. J. Pediatr. 157:623–29.e1
    [Google Scholar]
  158. 158. 
    Andersen LL, Mork N, Reinert LS, Kofod-Olsen E, Narita R et al. 2015. Functional IRF3 deficiency in a patient with herpes simplex encephalitis. J. Exp. Med. 212:1371–79
    [Google Scholar]
  159. 159. 
    Guo Y, Audry M, Ciancanelli M, Alsina L, Azevedo J et al. 2011. Herpes simplex virus encephalitis in a patient with complete TLR3 deficiency: TLR3 is otherwise redundant in protective immunity. J. Exp. Med. 208:2083–98
    [Google Scholar]
  160. 160. 
    Herman M, Ciancanelli M, Ou YH, Lorenzo L, Klaudel-Dreszler M et al. 2012. Heterozygous TBK1 mutations impair TLR3 immunity and underlie herpes simplex encephalitis of childhood. J. Exp. Med. 209:1567–82
    [Google Scholar]
  161. 161. 
    Pérez de Diego R, Sancho-Shimizu V, Lorenzo L, Puel A, Plancoulaine S et al. 2010. Human TRAF3 adaptor molecule deficiency leads to impaired Toll-like receptor 3 response and susceptibility to herpes simplex encephalitis. Immunity 33:400–11
    [Google Scholar]
  162. 162. 
    Sancho-Shimizu V, Pérez de Diego R, Lorenzo L, Halwani R, Alangari A et al. 2011. Herpes simplex encephalitis in children with autosomal recessive and dominant TRIF deficiency. J. Clin. Investig. 121:4889–902
    [Google Scholar]
  163. 163. 
    Lafaille FG, Pessach IM, Zhang SY, Ciancanelli MJ, Herman M et al. 2012. Impaired intrinsic immunity to HSV-1 in human iPSC-derived TLR3-deficient CNS cells. Nature 491:769–73
    [Google Scholar]
  164. 164. 
    Zimmer B, Ewaleifoh O, Harschnitz O, Lee YS, Peneau C et al. 2018. Human iPSC-derived trigeminal neurons lack constitutive TLR3-dependent immunity that protects cortical neurons from HSV-1 infection. PNAS 115:E8775–82
    [Google Scholar]
  165. 165. 
    Lafaille FG, Harschnitz O, Lee YS, Zhang P, Hasek ML et al. 2019. Human SNORA31 variations impair cortical neuron-intrinsic immunity to HSV-1 and underlie herpes simplex encephalitis. Nat. Med. 25:1873–84
    [Google Scholar]
  166. 166. 
    Zhang SY, Clark NE, Freije CA, Pauwels E, Taggart AJ et al. 2018. Inborn errors of RNA lariat metabolism in humans with brainstem viral infection. Cell 172:952–65.e18
    [Google Scholar]
  167. 167. 
    Zhang Q. 2020. Human genetics of life-threatening influenza pneumonitis. Hum. Genet. 139:941–48
    [Google Scholar]
  168. 168. 
    Ciancanelli MJ, Huang SX, Luthra P, Garner H, Itan Y et al. 2015. Life-threatening influenza and impaired interferon amplification in human IRF7 deficiency. Science 348:448–53
    [Google Scholar]
  169. 169. 
    Sologuren I, Martinez-Saavedra MT, Sole-Violan J, de Borges de Oliveira E Jr, Betancor E et al. 2018. Lethal influenza in two related adults with inherited GATA2 deficiency. J. Clin. Immunol. 38:513–26
    [Google Scholar]
  170. 170. 
    Hernandez N, Melki I, Jing H, Habib T, Huang SSY et al. 2018. Life-threatening influenza pneumonitis in a child with inherited IRF9 deficiency. J. Exp. Med. 215:2567–85
    [Google Scholar]
  171. 171. 
    Bravo García-Morato M, Calvo Apalategi A, Bravo-Gallego LY, Blázquez Moreno A, Simón-Fuentes M et al. 2019. Impaired control of multiple viral infections in a family with complete IRF9 deficiency. J. Allergy Clin. Immunol. 144:309–12.e10
    [Google Scholar]
  172. 172. 
    Hambleton S, Goodbourn S, Young DF, Dickinson P, Mohamad SM et al. 2013. STAT2 deficiency and susceptibility to viral illness in humans. PNAS 110:3053–58
    [Google Scholar]
  173. 173. 
    Lim HK, Huang SXL, Chen J, Kerner G, Gilliaux O et al. 2019. Severe influenza pneumonitis in children with inherited TLR3 deficiency. J. Exp. Med. 216:2038–56
    [Google Scholar]
  174. 174. 
    Jackson CC, Dickson MA, Sadjadi M, Gessain A, Abel L et al. 2016. Kaposi sarcoma of childhood: inborn or acquired immunodeficiency to oncogenic HHV-8. Pediatr. Blood Cancer 63:392–97
    [Google Scholar]
  175. 175. 
    Camcioglu Y, Picard C, Lacoste V, Dupuis S, Akcakaya N et al. 2004. HHV-8-associated Kaposi sarcoma in a child with IFNγR1 deficiency. J. Pediatr. 144:519–23
    [Google Scholar]
  176. 176. 
    Picard C, Mellouli F, Duprez R, Chedeville G, Neven B et al. 2006. Kaposi's sarcoma in a child with Wiskott-Aldrich syndrome. Eur. J. Pediatr. 165:453–57
    [Google Scholar]
  177. 177. 
    Byun M, Abhyankar A, Lelarge V, Plancoulaine S, Palanduz A et al. 2010. Whole-exome sequencing-based discovery of STIM1 deficiency in a child with fatal classic Kaposi sarcoma. J. Exp. Med. 207:2307–12
    [Google Scholar]
  178. 178. 
    Byun M, Ma CS, Akcay A, Pedergnana V, Palendira U et al. 2013. Inherited human OX40 deficiency underlying classic Kaposi sarcoma of childhood. J. Exp. Med. 210:1743–59
    [Google Scholar]
  179. 179. 
    Drutman SB, Haerynck F, Zhong FL, Hum D, Hernandez NJ et al. 2019. Homozygous NLRP1 gain-of-function mutation in siblings with a syndromic form of recurrent respiratory papillomatosis. PNAS 116:19055–63
    [Google Scholar]
  180. 180. 
    Belkaya S, Michailidis E, Korol CB, Kabbani M, Cobat A et al. 2019. Inherited IL-18BP deficiency in human fulminant viral hepatitis. J. Exp. Med. 216:1777–90
    [Google Scholar]
  181. 181. 
    Drutman SB, Mansouri D, Mahdaviani SA, Neehus AL, Hum D et al. 2020. Fatal cytomegalovirus infection in an adult with inherited NOS2 deficiency. N. Engl. J. Med. 382:437–45
    [Google Scholar]
  182. 182. 
    Vanhollebeke B, Truc P, Poelvoorde P, Pays A, Joshi PP et al. 2006. Human Trypanosoma evansi infection linked to a lack of apolipoprotein L-I. N. Engl. J. Med. 355:2752–56
    [Google Scholar]
  183. 183. 
    Lamborn IT, Jing H, Zhang Y, Drutman SB, Abbott JK et al. 2017. Recurrent rhinovirus infections in a child with inherited MDA5 deficiency. J. Exp. Med. 214:1949–72
    [Google Scholar]
  184. 184. 
    Asgari S, Schlapbach LJ, Anchisi S, Hammer C, Bartha I et al. 2017. Severe viral respiratory infections in children with IFIH1 loss-of-function mutations. PNAS 114:8342–47
    [Google Scholar]
  185. 185. 
    Ogunjimi B, Zhang SY, Sørensen KB, Skipper KA, Carter-Timofte M et al. 2017. Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections. J. Clin. Investig. 127:3543–56
    [Google Scholar]
  186. 186. 
    Guérin A, Kerner G, Marr N, Markle JG, Fenollar F et al. 2018. IRF4 haploinsufficiency in a family with Whipple's disease. eLife 7:e32340
    [Google Scholar]
  187. 187. 
    Poyhonen L, Bustamante J, Casanova JL, Jouanguy E, Zhang Q 2019. Life-threatening infections due to live-attenuated vaccines: early manifestations of inborn errors of immunity. J. Clin. Immunol. 39:376–90
    [Google Scholar]
  188. 188. 
    Dorman SE, Picard C, Lammas D, Heyne K, van Dissel JT et al. 2004. Clinical features of dominant and recessive interferon γ receptor 1 deficiencies. Lancet 364:2113–21
    [Google Scholar]
  189. 189. 
    Boisson-Dupuis S, Kong XF, Okada S, Cypowyj S, Puel A et al. 2012. Inborn errors of human STAT1: allelic heterogeneity governs the diversity of immunological and infectious phenotypes. Curr. Opin. Immunol. 24:364–78
    [Google Scholar]
  190. 190. 
    Dupuis S, Dargemont C, Fieschi C, Thomassin N, Rosenzweig S et al. 2001. Impairment of mycobacterial but not viral immunity by a germline human STAT1 mutation. Science 293:300–3
    [Google Scholar]
  191. 191. 
    Gruber C, Bogunovic D. 2020. Incomplete penetrance in primary immunodeficiency: a skeleton in the closet. Hum. Genet. 139:74557
    [Google Scholar]
  192. 192. 
    Quintana-Murci L. 2019. Human immunology through the lens of evolutionary genetics. Cell 177:184–99
    [Google Scholar]
  193. 193. 
    Brodin P, Jojic V, Gao T, Bhattacharya S, Angel CJ et al. 2015. Variation in the human immune system is largely driven by non-heritable influences. Cell 160:37–47
    [Google Scholar]
  194. 194. 
    Delmonte OM, Castagnoli R, Calzoni E, Notarangelo LD 2019. Inborn errors of immunity with immune dysregulation: from bench to bedside. Front. Pediatr. 7:353
    [Google Scholar]
  195. 195. 
    Zhang Y, Su HC, Lenardo MJ 2015. Genomics is rapidly advancing precision medicine for immunological disorders. Nat. Immunol. 16:1001–4
    [Google Scholar]
  196. 196. 
    Garrod AE. 1931. The Inborn Factors in Disease Oxford, UK: Clarendon
  197. 197. 
    Armstrong ME, Thomas CP. 2019. Diagnosis of monogenic chronic kidney diseases. Curr. Opin. Nephrol. Hypertens. 28:183–94
    [Google Scholar]
  198. 198. 
    Chakravarti A, Clark AG, Mootha VK 2013. Distilling pathophysiology from complex disease genetics. Cell 155:21–26
    [Google Scholar]
  199. 199. 
    Chong JX, Buckingham KJ, Jhangiani SN, Boehm C, Sobreira N et al. 2015. The genetic basis of Mendelian phenotypes: discoveries, challenges, and opportunities. Am. J. Hum. Genet. 97:199–215
    [Google Scholar]
  200. 200. 
    Cirino AL, Harris S, Lakdawala NK, Michels M, Olivotto I et al. 2017. Role of genetic testing in inherited cardiovascular disease: a review. JAMA Cardiol 2:1153–60
    [Google Scholar]
  201. 201. 
    McGovern DP, Kugathasan S, Cho JH 2015. Genetics of inflammatory bowel diseases. Gastroenterology 149:1163–76.e2
    [Google Scholar]
  202. 202. 
    Rexach J, Lee H, Martinez-Agosto JA, Nemeth AH, Fogel BL 2019. Clinical application of next-generation sequencing to the practice of neurology. Lancet Neurol 18:492–503
    [Google Scholar]
  203. 203. 
    Blau N, van Spronsen FJ, Levy HL 2010. Phenylketonuria. Lancet 376:1417–27
    [Google Scholar]
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