Very early-onset inflammatory bowel disease: Gaining insight through focused discovery

Inflammatory Bowel Diseases

Volumn 21, Issue 5, 2015, Pages 1166-1175

  Moran, Christopher J ^a,b   Klein, Christoph ^c   Muise, Aleixo M ^d,e   Snapper, Scott B ^b,f,g  

^a MASSACHUSETTS GENERAL HOSPITAL   (United States)

^b HARVARD MEDICAL SCHOOL   (United States)

^c LUDWIG MAXIMILIANS UNIVERSITY   (Germany)

^d HOSPITAL FOR SICK CHILDREN   (Canada)

^e HOSPITAL FOR SICK CHILDREN RESEARCH INSTITUTE   (Canada)

^f BOSTON CHILDREN S HOSPITAL   (United States)

^g BRIGHAM AND WOMEN S HOSPITAL   (United States)

Author keywords

Crohn's disease; genetics; genome wide association studies; immunodeficiency; inflammatory bowel disease; pediatric; ulcerative colitis; very early onset IBD; whole exome sequencing

Indexed keywords

ARTICLE; CARBOHYDRATE METABOLISM; CELL MIGRATION; GENE FUNCTION; GENE LOCUS; GENETIC ASSOCIATION; GENETIC POLYMORPHISM; GENETIC VARIABILITY; HUMAN; IMMUNE DEFICIENCY; INFLAMMATORY BOWEL DISEASE; OXIDATIVE STRESS; PRIORITY JOURNAL; SINGLE NUCLEOTIDE POLYMORPHISM; GENETIC PREDISPOSITION; GENETICS; ONSET AGE; PHENOTYPE; PROGNOSIS; TRANSLATIONAL RESEARCH;

AGE OF ONSET; GENETIC LOCI; GENETIC PREDISPOSITION TO DISEASE; GENOME-WIDE ASSOCIATION STUDY; HUMANS; INFLAMMATORY BOWEL DISEASES; PHENOTYPE; PROGNOSIS; TRANSLATIONAL MEDICAL RESEARCH;

EID: 84929091976     PISSN: 10780998     EISSN: 15364844     Source Type: Journal    
DOI: 10.1097/MIB.0000000000000329     Document Type: Article

References (155)

1. Kaser A, Zeissig S, Blumberg RS. Inflammatory bowel disease. Annu Rev Immunol. 2010;28:573-621.
2. Tysk C, Lindberg E, Jarnerot G, et al. Ulcerative colitis and Crohn's disease in an unselected population of monozygotic and dizygotic twins. A study of heritability and the influence of smoking. Gut. 1988;29:990-996.
3. Orholm M, Binder V, Sorensen TI, et al. Concordance of inflammatory bowel disease among Danish twins. Results of a nationwide study. Scand J Gastroenterol. 2000;35:1075-1081.
4. Probert CS, Jayanthi V, Hughes AO, et al. Prevalence and family risk of ulcerative colitis and Crohn's disease: An epidemiological study among Europeans and south Asians in Leicestershire. Gut. 1993;34:1547-1551.
5. Orholm M, Munkholm P, Langholz E, et al. Familial occurrence of inflammatory bowel disease. N Engl J Med. 1991;324:84-88.
6. Colombel JF, Grandbastien B, Gower-Rousseau C, et al. Clinical characteristics of Crohn's disease in 72 families. Gastroenterology. 1996; 111:604-607.
7. Polito JM II, Childs B, Mellits ED, et al. Crohn's disease: influence of age at diagnosis on site and clinical type of disease. Gastroenterology. 1996;111:580-586.
8. Manolio TA, Collins FS, Cox NJ, et al. Finding the missing heritability of complex diseases. Nature. 2009;461:747-753.
9. Park JH, Wacholder S, Gail MH, et al. Estimation of effect size distribution from genome-wide association studies and implications for future discoveries. Nat Genet. 2010;42:570-575.
10. Loftus Jr. EV. Clinical epidemiology of inflammatory bowel disease: incidence, prevalence, and environmental influences. Gastroenterology. 2004;126:1504-1517.
11. Kim SC, Ferry GD. Inflammatory bowel diseases in pediatric and adolescent patients: clinical, therapeutic, and psychosocial considerations. Gastroenterology. 2004;126:1550-1560.
12. Sawczenko A, Sandhu BK, Logan RF, et al. Prospective survey of childhood inflammatory bowel disease in the British Isles. Lancet. 2001;357: 1093-1094.
13. Hyams J, Markowitz J, Lerer T, et al. The natural history of corticosteroid therapy for ulcerative colitis in children. Clin Gastroenterol Hepatol. 2006;4:1118-1123.
14. Henriksen M, Jahnsen J, Lygren I, et al. Ulcerative colitis and clinical course: results of a 5-year population-based follow-up study (the IBSEN study). Inflamm Bowel Dis. 2006;12:543-550.
15. Van Limbergen J, Russell RK, Drummond HE, et al. Definition of phenotypic characteristics of childhood-onset inflammatory bowel disease. Gastroenterology. 2008;135:1114-1122.
16. Gupta N, Bostrom AG, Kirschner BS, et al. Presentation and disease course in early-compared to later-onset pediatric Crohn's disease. Am J Gastroenterol. 2008;103:2092-2098.
17. Mamula P, Telega GW, Markowitz JE, et al. Inflammatory bowel disease in children 5 years of age and younger. Am J Gastroenterol. 2002;97: 2005-2010.
18. Meinzer U, Idestrom M, Alberti C, et al. Ileal involvement is age dependent in pediatric Crohn's disease. Inflamm Bowel Dis. 2005;11:639-644.
19. Abraham BP, Mehta S, El-Serag HB. Natural history of pediatric-onset inflammatory bowel disease: a systematic review. J Clin Gastroenterol. 2012;46:581-589.
20. Jakobsen C, Bartek J Jr, Wewer V, et al. Differences in phenotype and disease course in adult and paediatric inflammatory bowel disease-A population-based study. Aliment Pharmacol Ther. 2011;34:1217-1224.
21. Pigneur B, Seksik P, Viola S, et al. Natural history of Crohn's disease: comparison between childhood-And adult-onset disease. Inflamm Bowel Dis. 2010;16:953-961.
22. Silverberg MS, Satsangi J, Ahmad T, et al. Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: report of a Working Party of the 2005 Montreal World Congress of Gastroenterology. Can J Gastroenterol. 2005;19(suppl A):5-36.
23. Levine A, Griffiths A, Markowitz J, et al. Pediatric modification of the Montreal classification for inflammatory bowel disease: the Paris classification. Inflamm Bowel Dis. 2011;17:1314-1321.
24. Heyman MB, Kirschner BS, Gold BD, et al. Children with early-onset inflammatory bowel disease (IBD): analysis of a pediatric IBD consortium registry. J Pediatr. 2005;146:35-40.
25. Markowitz J, Kugathasan S, Dubinsky M, et al. Age of diagnosis influences serologic responses in children with Crohn's disease: a possible clue to etiology?. Inflamm Bowel Dis. 2009;15:714-719.
26. Griffiths AM. Specificities of inflammatory bowel disease in childhood. Best Pract Res Clin Gastroenterol. 2004;18:509-523.
27. Ruemmele FM, El Khoury MG, Talbotec C, et al. Characteristics of inflammatory bowel disease with onset during the first year of life. J Pediatr Gastroenterol Nutr. 2006;43:603-609.
28. Benchimol EI, Mack DR, Nguyen GC, et al. Incidence, outcomes, and health services burden of very early onset inflammatory bowel disease. Gastroenterology. 2014;147:803-813.
29. Paul T, Birnbaum A, Pal DK, et al. Distinct phenotype of early childhood inflammatory bowel disease. J Clin Gastroenterol. 2006;40:583-586.
30. Uhlig HH. Monogenic diseases associated with intestinal inflammation: implications for the understanding of inflammatory bowel disease. Gut. 2013;62:1795-1805.
31. Stokkers PC, Reitsma PH, Tytgat GN, et al. HLA-DR and-DQ phenotypes in inflammatory bowel disease: a meta-Analysis. Gut. 1999;45: 395-401.
32. Forcione DG, Sands B, Isselbacher KJ, et al. An increased risk of Crohn's disease in individuals who inherit the HLA class II DRB3 0301 allele. Proc Natl Acad Sci U S A. 1996;93:5094-5098.
33. Toyoda H, Wang SJ, Yang HY, et al. Distinct associations of HLA class II genes with inflammatory bowel disease. Gastroenterology. 1993;104: 741-748.
34. Asakura H, Tsuchiya M, Aiso S, et al. Association of the human lymphocyte-DR2 antigen with Japanese ulcerative colitis. Gastroenterology. 1982;82:413-418.
35. Hugot JP, Laurent-Puig P, Gower-Rousseau C, et al. Mapping of a susceptibility locus for Crohn's disease on chromosome 16. Nature. 1996; 379:821-823.
36. Rioux JD, Silverberg MS, Daly MJ, et al. Genomewide search in Canadian families with inflammatory bowel disease reveals two novel susceptibility loci. Am J Hum Genet. 2000;66:1863-1870.
37. Hugot JP, Chamaillard M, Zouali H, et al. Association of NOD2 leucinerich repeat variants with susceptibility to Crohn's disease. Nature. 2001; 411:599-603.
38. Clarke TB, Weiser JN. Intracellular sensors of extracellular bacteria. Immunol Rev. 2011;243:9-25.
39. Ogura Y, Bonen DK, Inohara N, et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature. 2001;411:603-606.
40. Economou M, Trikalinos TA, Loizou KT, et al. Differential effects of NOD2 variants on Crohn's disease risk and phenotype in diverse populations: a metaanalysis. Am J Gastroenterol. 2004; 99:2393-2404.
41. Hampe J, Cuthbert A, Croucher PJ, et al. Association between insertion mutation in NOD2 gene and Crohn's disease in German and British populations. Lancet. 2001;357:1925-1928.
42. Adler J, Rangwalla SC, Dwamena BA, et al. The prognostic power of the NOD2 genotype for complicated Crohn's disease: a meta-Analysis. Am J Gastroenterol. 2011;106:699-712.
43. Jostins L, Ripke S, Weersma RK, et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012;491:119-124.
44. Anderson CA, Boucher G, Lees CW, et al. Meta-Analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat Genet. 2011;43:246-252.
45. Imielinski M, Baldassano RN, Griffiths A, et al. Common variants at five new loci associated with early-onset inflammatory bowel disease. Nat Genet. 2009;41:1335-1340.
46. Franke A, Balschun T, Karlsen TH, et al. Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility. Nat Genet. 2008;40:1319-1323.
47. Silverberg MS, Cho JH, Rioux JD, et al. Ulcerative colitis-risk loci on chromosomes 1p36 and 12q15 found by genome-wide association study. Nat Genet. 2009;41:216-220.
48. Consortium UIG, Barrett JC, Lee JC, et al. Genome-wide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region. Nat Genet. 2009;41:1330-1334.
49. McGovern DP, Gardet A, Torkvist L, et al. Genome-wide association identifies multiple ulcerative colitis susceptibility loci. Nat Genet. 2010; 42:332-337.
50. Kugathasan S, Baldassano RN, Bradfield JP, et al. Loci on 20q13 and 21q22 are associated with pediatric-onset inflammatory bowel disease. Nat Genet. 2008;40:1211-1215.
51. Asano K, Matsushita T, Umeno J, et al. A genome-wide association study identifies three new susceptibility loci for ulcerative colitis in the Japanese population. Nat Genet. 2009;41:1325-1329.
52. Franke A, McGovern DP, Barrett JC, et al. Genome-wide meta-Analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nat Genet. 2010;42:1118-1125.
53. Wellcome Trust Case Control C. Genome-wide association study of 14, 000 cases of seven common diseases and 3, 000 shared controls. Nature. 2007;447:661-678.
54. Barrett JC, Hansoul S, Nicolae DL, et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat Genet. 2008;40:955-962.
55. Umeno J, Asano K, Matsushita T, et al. Meta-Analysis of published studies identified eight additional common susceptibility loci for Crohn's disease and ulcerative colitis. Inflamm Bowel Dis. 2011;17: 2407-2415.
56. Libioulle C, Louis E, Hansoul S, et al. Novel Crohn disease locus identified by genome-wide association maps to a gene desert on 5p13.1 and modulates expression of PTGER4. PLoS Genet. 2007;3:e58.
57. Franke A, Balschun T, Sina C, et al. Genome-wide association study for ulcerative colitis identifies risk loci at 7q22 and 22q13 (IL17REL). Nat Genet. 2010;42:292-294.
58. Hampe J, Franke A, Rosenstiel P, et al. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat Genet. 2007;39:207-211.
59. Parkes M, Barrett JC, Prescott NJ, et al. Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility. Nat Genet. 2007;39:830-832.
60. Barrett JC, Lee JC, Lees CW, et al. Genome-wide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region. Nat Genet. 2009;41:1330-1334.
61. Momozawa Y, Mni M, Nakamura K, et al. Resequencing of positional candidates identifies low frequency IL23R coding variants protecting against inflammatory bowel disease. Nat Genet. 2011;43:43-47.
62. Rivas MA, Beaudoin M, Gardet A, et al. Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease. Nat Genet. 2011;43:1066-1073.
63. Cuthbert AP, Fisher SA, Mirza MM, et al. The contribution of NOD2 gene mutations to the risk and site of disease in inflammatory bowel disease. Gastroenterology. 2002;122:867-874.
64. Li E, Hamm CM, Gulati AS, et al. Inflammatory bowel diseases phenotype, C. difficile and NOD2 genotype are associated with shifts in human ileum associated microbial composition. PloS One. 2012;7:e26284.
65. Cleynen I, Gonzalez JR, Figueroa C, et al. Genetic factors conferring an increased susceptibility to develop Crohn's disease also influence disease phenotype: results from the IBDchip European Project. Gut. 2013;62:1556-1565.
66. Duraes C, Machado JC, Portela F, et al. Phenotype-genotype profiles in Crohn's disease predicted by genetic markers in autophagy-related genes (GOIA study II). Inflamm Bowel Dis. 2013;19:230-239.
67. Prescott NJ, Fisher SA, Franke A, et al. A nonsynonymous SNP in ATG16L1 predisposes to ileal Crohn's disease and is independent of CARD15 and IBD5. Gastroenterology. 2007;132:1665-1671.
68. Ananthakrishnan AN, Huang H, Nguyen DD, et al. Differential effect of genetic Burden on disease phenotypes in Crohn's disease and ulcerative colitis: analysis of a North American cohort. Am J Gastroenterol. 2014;109:395-400.
69. Perry JR, McCarthy MI, Hattersley AT, et al. Interrogating type 2 diabetes genome-wide association data using a biological pathway-based approach. Diabetes. 2009;58:1463-1467.
70. Li D, Duell EJ, Yu K, et al. Pathway analysis of genome-wide association study data highlights pancreatic development genes as susceptibility factors for pancreatic Cancer. Carcinogenesis. 2012;33:1384-1390.
71. Menashe I, Figueroa JD, Garcia-Closas M, et al. Large-scale pathwaybased analysis of bladder cancer genome-wide association data from five studies of European background. PLoS One. 2012;7:e29396.
72. Lee YH, Choi SJ, Ji JD, et al. Genome-wide pathway analysis of a genome-wide association study on psoriasis and Behcet's disease. Mol Biol Rep. 2012;39:5953-5959.
73. Giallourakis CC, Benita Y, Molinie B, et al. Genome-wide analysis of immune system genes by expressed sequence Tag profiling. J Immunol. 2013;190:5578-5587.
74. Yang X, Deignan JL, Qi H, et al. Validation of candidate causal genes for obesity that affect shared metabolic pathways and networks. Nat Genet. 2009;41:415-423.
75. Ramanan VK, Shen L, Moore JH, et al. Pathway analysis of genomic data: concepts, methods and prospects for future development. Trends Genet. 2012;28:323-332.
76. Califano A, Butte AJ, Friend S, et al. Leveraging models of cell regulation and GWAS data in integrative network-based association studies. Nat Genet. 2012;44:841-847.
77. Ballard D, Abraham C, Cho J, et al. Pathway analysis comparison using Crohn's disease genome wide association studies. BMC Med Genomics. 2010;3:25.
78. Torkamani A, Topol EJ, Schork NJ. Pathway analysis of seven common diseases assessed by genome-wide association. Genomics. 2008;92:265-272.
79. Essers JB, Lee JJ, Kugathasan S, et al. Established genetic risk factors do not distinguish early and later onset Crohn's disease. Inflamm Bowel Dis. 2009;15:1508-1514.
80. Pot C, Apetoh L, Awasthi A, et al. Induction of regulatory Tr1 cells and inhibition of T(H)17 cells by IL-27. Semin Immunol. 2011;23:438-445.
81. Hirano Y, Hendil KB, Yashiroda H, et al. A heterodimeric complex that promotes the assembly of mammalian 20S proteasomes. Nature. 2005; 437:1381-1385.
82. Hsu TL, Chang YC, Chen SJ, et al. Modulation of dendritic cell differentiation and maturation by decoy receptor 3. J Immunol. 2002;168: 4846-4853.
83. Hsu TL, Wu YY, Chang YC, et al. Attenuation of Th1 response in decoy receptor 3 transgenic mice. J Immunol. 2005;175:5135-5145.
84. Ina K, Itoh J, Fukushima K, et al. Resistance of Crohn's disease T cells to multiple apoptotic signals is associated with a Bcl-2/Bax mucosal imbalance. J Immunol. 1999;163:1081-1090.
85. Wang K, Zhang H, Kugathasan S, et al. Diverse genome-wide association studies associate the IL12/IL23 pathway with Crohn Disease. Am J Hum Genet. 2009;84:399-405.
86. Visscher PM, Brown MA, McCarthy MI, et al. Five years of GWAS discovery. Am J Hum Genet. 2012;90:7-24.
87. Grucela AL, Patel P, Goldstein E, et al. Granulomatous enterocolitis associated with Hermansky-Pudlak syndrome. Am J Gastroenterol. 2006;101:2090-2095.
88. Yamaguchi T, Ihara K, Matsumoto T, et al. Inflammatory bowel diseaselike colitis in glycogen storage disease type 1b. Inflamm Bowel Dis. 2001;7:128-132.
89. Montalto M, D'Onofrio F, Santoro L, et al. Autoimmune enteropathy in children and adults. Scand J Gastroenterol. 2009;44:1029-1036.
90. Kang EM, Marciano BE, DeRavin S, et al. Chronic granulomatous disease: overview and hematopoietic stem cell transplantation. J Allergy Clin Immunol. 2011;127:1319-1326; quiz 27-8.
91. Ochs HD, Thrasher AJ. The Wiskott-Aldrich syndrome. J Allergy Clin Immunol. 2006;117:725-738; quiz 39.
92. Nguyen DD, Maillard MH, Cotta-de-Almeida V, et al. Lymphocyte-dependent and Th2 cytokine-Associated colitis in mice deficient in Wiskott-Aldrich syndrome protein. Gastroenterology. 2007;133:1188-1197.
93. Maillard MH, Cotta-de-Almeida V, Takeshima F, et al. The Wiskott-Aldrich syndrome protein is required for the function of CD4(+)CD25(+) Foxp3(+) regulatory T cells. J Exp Med. 2007;204:381-391.
94. Nguyen DD, Wurbel MA, Goettel JA, et al. Wiskott-Aldrich syndrome protein deficiency in innate immune cells leads to mucosal immune dysregulation and colitis in mice. Gastroenterology. 2012;143:719-729 e2.
95. Dupuis-Girod S, Medioni J, Haddad E, et al. Autoimmunity in Wiskott-Aldrich syndrome: risk factors, clinical features, and outcome in a singlecenter cohort of 55 patients. Pediatrics. 2003;111:e622-e627.
96. Jin Y, Mazza C, Christie JR, et al. Mutations of the Wiskott-Aldrich Syndrome Protein (WASP): hotspots, effect on transcription, and translation and phenotype/genotype correlation. Blood. 2004;104:4010-4019.
97. Heyworth PG, Cross AR, Curnutte JT. Chronic granulomatous disease. Curr Opin Immunol. 2003;15:578-584.
98. Rahman FZ, Marks DJ, Hayee BH, et al. Phagocyte dysfunction and inflammatory bowel disease. Inflamm Bowel Dis. 2008;14:1443-1452.
99. Goldblatt D, Thrasher AJ. Chronic granulomatous disease. Clin Exp Immunol. 2000;122:1-9.
100. Winkelstein JA, Marino MC, Johnston RB Jr, et al. Chronic granulomatous disease. Report on a national registry of 368 patients. Medicine. 2000;79:155-169.
101. Dinauer MC, Orkin SH. Chronic granulomatous disease. Annu Rev Med. 1992;43:117-124.
102. Agarwal S, Mayer L. Gastrointestinal manifestations in primary immune disorders. Inflamm Bowel Dis. 2010;16:703-711.
103. Marks DJ, Miyagi K, Rahman FZ, et al. Inflammatory bowel disease in CGD reproduces the clinicopathological features of Crohn's disease. Am J Gastroenterol. 2009;104:117-124.
104. Marciano BE, Rosenzweig SD, Kleiner DE, et al. Gastrointestinal involvement in chronic granulomatous disease. Pediatrics. 2004;114:462-468.
105. Foster CB, Lehrnbecher T, Mol F, et al. Host defense molecule polymorphisms influence the risk for immune-mediated complications in chronic granulomatous disease. J Clin Invest. 1998;102:2146-2155.
106. Segal AW, Loewi G. Neutrophil dysfunction in Crohn's disease. Lancet. 1976;2:219-221.
107. Rioux JD, Xavier RJ, Taylor KD, et al. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat Genet. 2007;39:596-604.
108. Verspaget HW, Mieremet-Ooms MA, Weterman IT, et al. Partial defect of neutrophil oxidative metabolism in Crohn's disease. Gut. 1984;25:849-853.
109. Muise AM, Xu W, Guo CH, et al. NADPH oxidase complex and IBD candidate gene studies: identification of a rare variant in NCF2 that results in reduced binding to RAC2. Gut. 2012;61:1028-1035.
110. Dhillon SS, Fattouh R, Elkadri A, et al. Variants in NADPH oxidase complex components determine susceptibility to very early onset inflammatory bowel disease. Gastroenterology. 2014;147:680-689.
111. Shouval DS, Ouahed J, Biswas A, et al. Interleukin 10 receptor signaling: master regulator of intestinal mucosal homeostasis in mice and humans. Adv Immunol. 2014;122:177-210.
112. Glocker EO, Kotlarz D, Boztug K, et al. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N Engl J Med. 2009;361: 2033-2045.
113. Moran CJ, Walters TD, Guo CH, et al. IL-10R polymorphisms are associated with very-early-onset ulcerative colitis. Inflamm Bowel Dis. 2013; 19:115-123.
114. Engelhardt KR, Shah N, Faizura-Yeop I, et al. Clinical outcome in IL-10-And IL-10 receptor-deficient patients with or without hematopoietic stem cell transplantation. J Allergy Clin Immunol. 2013;131:825-830.
115. Pigneur B, Escher J, Elawad M, et al. Phenotypic Characterization of very early-onset IBD due to mutations in the IL10, IL10 receptor alpha or Beta gene: a survey of the GENIUS working group. Inflamm Bowel Dis. 2013;19:2820-2828.
116. Begue B, Verdier J, Rieux-Laucat F, et al. Defective IL10 signaling defining a subgroup of patients with inflammatory bowel disease. Am J Gastroenterol. 2011;106:1544-1555.
117. Murugan D, Albert MH, Langemeier J, et al. Very early onset inflammatory bowel disease associated with aberrant Trafficking of IL-10R1 and Cure by T Cell Replete Haploidentical Bone Marrow transplantation. J Clin Immunol. 2014;34:331-339.
118. Glocker EO, Frede N, Perro M, et al. Infant colitis-it's in the genes. Lancet. 2010;376:1272.
119. Neven B, Mamessier E, Bruneau J, et al. AMendelian predisposition to B-cell lymphoma caused by IL-10R deficiency. Blood. 2013;122:3713-3722.
120. Blaydon DC, Biancheri P, Di WL, et al. Inflammatory skin and bowel disease linked to ADAM17 deletion. N Engl J Med. 2011;365:1502-1508.
121. Muise AM, Snapper SB, Kugathasan S. The age of gene discovery in very early onset inflammatory bowel disease. Gastroenterology. 2012; 143:285-288.
122. Bick D, Dimmock D. Whole exome and whole genome sequencing. Curr Opin Pediatr. 2011;23:594-600.
123. Antonarakis SE, Beckmann JS. Mendelian disorders deserve more attention. Nat Rev Genet. 2006;7:277-282.
124. Bamshad MJ, Ng SB, Bigham AW, et al. Exome sequencing as a tool for Mendelian disease gene discovery. Nat Rev Genet. 2011;12:745-755.
125. Tennessen JA, Bigham AW, O'Connor TD, et al. Evolution and functional impact of rare coding variation from deep sequencing of human exomes. Science. 2012;337:64-69.
126. Tsurusaki Y, Okamoto N, Ohashi H, et al. Mutations affecting components of the SWI/SNF complex cause Coffin-Siris syndrome. Nat Genet. 2012;44:376-378.
127. Ng SB, Bigham AW, Buckingham KJ, et al. Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nat Genet. 2010; 42:790-793.
128. Lines MA, Huang L, Schwartzentruber J, et al. Haploinsufficiency of a spliceosomal GTPase encoded by EFTUD2 causes mandibulofacial dysostosis with microcephaly. Am J Hum Genet. 2012;90:369-377.
129. Ramagopalan SV, Dyment DA, Cader MZ, et al. Rare variants in the CYP27B1 gene are associated with multiple sclerosis. Ann Neurol. 2011; 70:881-886.
130. Guerreiro RJ, Lohmann E, Kinsella E, et al. Exome sequencing reveals an unexpected genetic cause of disease: NOTCH3 mutation in a Turkish family with Alzheimer's disease. Neurobiol Aging. 2012;33:1008 e17-e23.
131. Musunuru K, Pirruccello JP, Do R, et al. Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia. N Engl J Med. 2010; 363:2220-2227.
132. Dyment DA, Cader MZ, Chao MJ, et al. Exome sequencing identifies a novel multiple sclerosis susceptibility variant in the TYK2 gene. Neurology. 2012;79:406-411.
133. Worthey EA, Mayer AN, Syverson GD, et al. Making a definitive diagnosis: successful clinical application of whole exome sequencing in a child with intractable inflammatory bowel disease. Genet Med. 2011; 13:255-262.
134. Filipovich AH, Zhang K, Snow AL, et al. X-linked lymphoproliferative syndromes: brothers or distant cousins?. Blood. 2010;116:3398-3408.
135. Rezaei N, Mahmoudi E, Aghamohammadi A, et al. X-linked lymphoproliferative syndrome: a genetic condition typified by the triad of infection, immunodeficiency and lymphoma. Br J Haematol. 2011; 152:13-30.
136. Rigaud S, Fondaneche MC, Lambert N, et al. XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome. Nature. 2006; 444:110-114.
137. Pachlopnik Schmid J, Canioni D, Moshous D, et al. Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1/SAP deficiency) versus type 2 (XLP-2/XIAP deficiency). Blood. 2011;117:1522-1529.
138. Speckmann C, Lehmberg K, Albert MH, et al. X-linked inhibitor of apoptosis (XIAP) deficiency: the spectrum of presenting manifestations beyond hemophagocytic lymphohistiocytosis. Clin Immunol. 2013;149:133-141.
139. Zeissig Y, Petersen BS, Milutinovic S, et al. XIAP variants in male Crohn's disease. Gut. 2015;64:66-76.
140. Conley ME, Dobbs AK, Quintana AM, et al. Agammaglobulinemia and absent B lineage cells in a patient lacking the p85alpha subunit of PI3K. J Exp Med. 2012;209:463-470.
141. de la Morena M, Haire RN, Ohta Y, et al. Predominance of sterile immunoglobulin transcripts in a female phenotypically resembling Bruton's agammaglobulinemia. Eur J Immunol. 1995;25:809-815.
142. Alangari A, Alsultan A, Adly N, et al. LPS-responsive beige-like anchor (LRBA) gene mutation in a family with inflammatory bowel disease and combined immunodeficiency. J Allergy Clin Immunol. 2012;130:481-488.
143. Avitzur Y, Guo C, Mastropaolo LA, et al. Mutations in tetratricopeptide repeat domain 7A result in a severe form of very early onset inflammatory bowel disease. Gastroenterology. 2014;146:1028-1039.
144. Chen R, Giliani S, Lanzi G, et al. Whole-exome sequencing identifies tetratricopeptide repeat domain 7A (TTC7A) mutations for combined immunodeficiency with intestinal atresias. J Allergy Clin Immunol. 2013;132:656-664.
145. Samuels ME, Majewski J, Alirezaie N, et al. Exome sequencing identifies mutations in the gene TTC7A in French-Canadian cases with hereditary multiple intestinal atresia. J Med Genet. 2013;50: 324-329.
146. Bigorgne AE, Farin HF, Lemoine R, et al. TTC7A mutations disrupt intestinal epithelial apicobasal polarity. J Clin Invest. 2014; 124:328-337.
147. Mao H, Yang W, Lee PP, et al. Exome sequencing identifies novel compound heterozygous mutations of IL-10 receptor 1 in neonatalonset Crohn's disease. Genes Immun. 2012;13:437-442.
148. Ellinghaus D, Zhang H, Zeissig S, et al. Association between variants of PRDM1 and NDP52 and Crohns disease, based on exome sequencing and functional studies. Gastroenterology. 2013;145:339-347.
149. Christodoulou K, Wiskin AE, Gibson J, et al. Next generation exome sequencing of paediatric inflammatory bowel disease patients identifies rare and novel variants in candidate genes. Gut. 2013;62:977-984.
150. Berger MF, Hodis E, Heffernan TP, et al. Melanoma genome sequencing reveals frequent PREX2 mutations. Nature. 2012;485:502-506.
151. Fujimoto A, Totoki Y, Abe T, et al. Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators. Nat Genet. 2012;44:760-764.
152. Egan JB, Shi CX, Tembe W, et al. Whole genome sequencing of multiple myeloma from diagnosis to plasma cell leukemia reveals genomic initiating events, evolution and clonal tides. Blood. 2012;120: 1060-1066.
153. Sobreira NL, Cirulli ET, Avramopoulos D, et al. Whole-genome sequencing of a single proband together with linkage analysis identifies a Mendelian disease gene. PLoS Genet. 2010;6:e1000991.
154. Talkowski ME, Ordulu Z, Pillalamarri V, et al. Clinical diagnosis by whole-genome sequencing of a prenatal sample. N Engl J Med. 2012; 367:2226-2232.
155. Ashley EA, Butte AJ, Wheeler MT, et al. Clinical assessment incorporating a personal genome. Lancet. 2010;375:1525-1535.