Exome Sequencing Identifies a Novel <i>FOXP3</i> Mutation in a 2‐Generation Family With Inflammatory Bowel Disease

Okou, David T.; Mondal, Kajari; Faubion, William A.; Kobrynski, Lisa; Denson, Lee A.; Mullé, Jennifer G.; Ramachandran, Dhanya; Xiong, Yuning; Svingen, Phyllis A.; Patel, Viren; Bose, Promita; Waters, Jon; Prahalad, Sampath; Cutler, David J.; Zwick, Michael E.; Kugathasan, Subra

doi:10.1097/mpg.0000000000000302

Cited by 48 publications

(31 citation statements)

References 44 publications

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“…The specific VEO phenotypes often include manifestation of known monogenic diseases and the first case of the Mendelian form of VEO IBD was confirmed as a mutation in the IL10R gene (30) that underlined an association of IBD with primary immunodeficiency. Recently, a novel FOXP3 mutation was also identified in a two-generation family with early onset phenotypes similar to IBD (67), thus lending support to the manifestation of Mendelian disease in IBD cases. Many monogenic disease genes have been shown to confer overlapping pathology with IBD (known as IBD-like pathogenesis) and are seen more frequently in VEO cases (69).…”

Section: Monogenetic Disorders and Association With Very Early Onset Ibdmentioning

confidence: 93%

“…Since then, WES has successfully identified rare functional variants in novel genes implicated in the pathogenesis of VEO ( FOXP3 (67), IL10RB (30, 56) and XIAP (66) genes) or even adult ( GSDMB (54) and NDP5 2 genes (61)) IBD. WES is therefore the most current cost effective technology capable of exposing low to intermediate frequency variants that may have higher effect size than the weaker associations reported by common GWAS variants.…”

Section: Sequencing In Ibd Genetic Studies: Progressmentioning

confidence: 99%

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Role of Genetics in Pediatric Inflammatory Bowel Disease

Okou¹,

Kugathasan²

2014

Inflammatory Bowel Diseases

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Inflammatory bowel disease (IBD), encompassing Crohn’s disease (CD), ulcerative colitis (UC) and unclassified IBD (IBDU), is characterized by chronic intestinal inflammation, and has a multi-factorial etiology with complex interactions between genetic and environmental factors. The genetics of IBD are believed to be common and complex with over 163 associated genetic loci. However, the genetic contribution of the majority of these common loci is small and the effect sizes are low. Although childhood onset IBD represents only 10–25% of all IBD cases, in depth research into the genetic networks of pediatric IBD has revealed exciting new developments and unsuspected pathways. Recent pediatric studies have revealed an increasing spectrum of human monogenic diseases with high effect sizes/penetrance that can present with IBD or IBD-like intestinal inflammation. A substantial proportion of patients with these genetic defects present with very early onset of intestinal inflammation, with onset of IBD at less than 10 years of age. There is also considerable overlap with primary immunodeficiencies and very early onset IBD. This review summarizes the current understanding of the genetics of pediatric inflammatory bowel disease with a focus on the very early onset population, and discusses the promising results from the effort of finding missing heritability of IBD from studying pediatric population.

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Section: Monogenetic Disorders and Association With Very Early Onset Ibdmentioning

confidence: 93%

Section: Sequencing In Ibd Genetic Studies: Progressmentioning

confidence: 99%

Role of Genetics in Pediatric Inflammatory Bowel Disease

Okou¹,

Kugathasan²

2014

Inflammatory Bowel Diseases

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“…Importantly, XIAP is a positive regulator of NOD2 function 60 , and so therefore, loss-of-function mutations in XIAP would result in similar functional effects as those observed with NOD2 mutations. Subsequent successful application of WES has identified more rare functional variants in novel genes implicated in the pathogenesis of VEO ( FOXP3 61 , IL10RB 62 ; 63 and adult onset ( GSDMB 64 and NDP5 2 genes 65 ) IBD.…”

Section: Common and Rare Ibd Genetic Variation: Sequencing Studies Inmentioning

confidence: 99%

Genetics of Inflammatory Bowel Diseases

2015

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In this Review, we provide an update on genome-wide association studies (GWAS) in inflammatory bowel disease (IBD). In addition, we summarize progress in defining the functional consequences of associated alleles for coding and non-coding genetic variation. In the small minority of loci where major association signals correspond to non-synonymous variation, we summarize studies defining their functional effects and implications for therapeutic targeting. Importantly, the large majority of GWAS-associated loci involve non-coding variation, many of which modulate levels of gene expression. Recent expression quantitative trait loci (eQTL) studies have established that expression of the large majority of human genes is regulated by non-coding genetic variation. Significant advances in defining the epigenetic landscape have demonstrated that IBD GWAS signals are highly enriched within cell-specific active enhancer marks. Studies in European ancestry populations have dominated the landscape of IBD genetics studies, but increasingly, studies in Asian and African-American populations are being reported. Common variation accounts for only a modest fraction of the predicted heritability and the role of rare genetic variation of higher effects (i.e. odds ratios markedly deviating from one) is increasingly being identified through sequencing efforts. These sequencing studies have been particularly productive in very-early onset, more severe cases. A major challenge in IBD genetics will be harnessing the vast array of genetic discovery for clinical utility, through emerging precision medicine initiatives. We discuss the rapidly evolving area of direct to consumer genetic testing, as well as the current utility of clinical exome sequencing, especially in very early onset, severe IBD cases. We summarize recent progress in the pharmacogenetics of IBD with respect of partitioning patient responses to anti-TNF and thiopurine therapies. Highly collaborative studies across research centers and across subspecialties and disciplines will be required to fully realize the promise of genetic discovery in IBD.

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“…81 One example of successful exome sequencing is the discovery of a novel A-to-C missense variant (c.694A>C) in exon 6 of the FOXP3 gene on chromosome X in VEO IBD. 82 Interestingly, GWAS-based studies have shown that a substantial proportion of IBD-associated loci are located in non-coding regions, suggesting rare variants regulating gene expression may also be important in IBD pathogenesis. 8 The roles of non-coding regions on their pathogenic effects through modulation of gene expression are being identified by expression quantitative trait loci (eQTL)-GWAS mapping analysis.…”

Section: Current Status Of Genetic Research For Ibdmentioning

confidence: 99%

Genetic variation in IBD: progress, clues to pathogenesis and possible clinical utility

McGovern

2016

Expert Review of Clinical Immunology

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Epidemiological and clinical studies have suggested that the pathogenesis of inflammatory bowel disease (IBD) is strongly influenced by genetic predisposition. Beyond the limitations of linkage analysis, multiple genome-wide association studies, their meta-analyses, and targeted genotyping array techniques have broadened our understanding of the genetic architecture of IBD. Currently, over 200 single nucleotide polymorphisms are known to be associated with susceptibility to IBD and through functional analysis of genes and loci, a substantial proportion of pathophysiologic mechanisms have been revealed. However, because only a modest fraction of predicted heritability can be explained by known genes/loci, additional strategies are needed including the identification of rare variants with large effect sizes to help explain the missing heritability. Considerable progress is also being made on applying outcomes of genetic research in diagnostics, classification, prognostics, and the development of new therapeutics of IBD.

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Exome Sequencing Identifies a Novel FOXP3 Mutation in a 2‐Generation Family With Inflammatory Bowel Disease

Cited by 48 publications

References 44 publications

Role of Genetics in Pediatric Inflammatory Bowel Disease

Role of Genetics in Pediatric Inflammatory Bowel Disease

Genetics of Inflammatory Bowel Diseases

Genetic variation in IBD: progress, clues to pathogenesis and possible clinical utility

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