Mutation spectrum of NOD2 reveals recessive inheritance as a main driver of Early Onset Crohn’s Disease

Abstract Inflammatory bowel disease (IBD), clinically defined as Crohn’s disease (CD), ulcerative colitis (UC), or IBD-unclassified, results in chronic inflammation of the gastrointestinal tract in genetically susceptible hosts. Pediatric onset IBD represents ≥ 25% of all IBD diagnoses and often pre...

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Autores principales:	Julie E. Horowitz, Neil Warner, Jeffrey Staples, Eileen Crowley, Nehal Gosalia, Ryan Murchie, Cristopher Van Hout, Karoline Fiedler, Gabriel Welch, Alejandra Klauer King, Jeffrey G. Reid, John D. Overton, Aris Baras, Alan R. Shuldiner, Anne Griffiths, Omri Gottesman, Aleixo M. Muise, Claudia Gonzaga-Jauregui
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/1f5de0d61ecd4e8a964ff8857b3099dd
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spelling	oai:doaj.org-article:1f5de0d61ecd4e8a964ff8857b3099dd2021-12-02T13:34:32ZMutation spectrum of NOD2 reveals recessive inheritance as a main driver of Early Onset Crohn’s Disease10.1038/s41598-021-84938-82045-2322https://doaj.org/article/1f5de0d61ecd4e8a964ff8857b3099dd2021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-84938-8https://doaj.org/toc/2045-2322Abstract Inflammatory bowel disease (IBD), clinically defined as Crohn’s disease (CD), ulcerative colitis (UC), or IBD-unclassified, results in chronic inflammation of the gastrointestinal tract in genetically susceptible hosts. Pediatric onset IBD represents ≥ 25% of all IBD diagnoses and often presents with intestinal stricturing, perianal disease, and failed response to conventional treatments. NOD2 was the first and is the most replicated locus associated with adult IBD, to date. However, its role in pediatric onset IBD is not well understood. We performed whole-exome sequencing on a cohort of 1,183 patients with pediatric onset IBD (ages 0–18.5 years). We identified 92 probands with biallelic rare and low frequency NOD2 variants accounting for approximately 8% of our cohort, suggesting a Mendelian inheritance pattern of disease. Additionally, we investigated the contribution of recessive inheritance of NOD2 alleles in adult IBD patients from a large clinical population cohort. We found that recessive inheritance of NOD2 variants explains ~ 7% of cases in this adult IBD cohort, including ~ 10% of CD cases, confirming the observations from our pediatric IBD cohort. Exploration of EHR data showed that several of these adult IBD patients obtained their initial IBD diagnosis before 18 years of age, consistent with early onset disease. While it has been previously reported that carriers of more than one NOD2 risk alleles have increased susceptibility to Crohn’s Disease (CD), our data formally demonstrate that recessive inheritance of NOD2 alleles is a mechanistic driver of early onset IBD, specifically CD, likely due to loss of NOD2 protein function. Collectively, our findings show that recessive inheritance of rare and low frequency deleterious NOD2 variants account for 7–10% of CD cases and implicate NOD2 as a Mendelian disease gene for early onset Crohn’s Disease.Julie E. HorowitzNeil WarnerJeffrey StaplesEileen CrowleyNehal GosaliaRyan MurchieCristopher Van HoutKaroline FiedlerGabriel WelchAlejandra Klauer KingJeffrey G. ReidJohn D. OvertonAris BarasAlan R. ShuldinerAnne GriffithsOmri GottesmanAleixo M. MuiseClaudia Gonzaga-JaureguiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Julie E. Horowitz Neil Warner Jeffrey Staples Eileen Crowley Nehal Gosalia Ryan Murchie Cristopher Van Hout Karoline Fiedler Gabriel Welch Alejandra Klauer King Jeffrey G. Reid John D. Overton Aris Baras Alan R. Shuldiner Anne Griffiths Omri Gottesman Aleixo M. Muise Claudia Gonzaga-Jauregui Mutation spectrum of NOD2 reveals recessive inheritance as a main driver of Early Onset Crohn’s Disease
description	Abstract Inflammatory bowel disease (IBD), clinically defined as Crohn’s disease (CD), ulcerative colitis (UC), or IBD-unclassified, results in chronic inflammation of the gastrointestinal tract in genetically susceptible hosts. Pediatric onset IBD represents ≥ 25% of all IBD diagnoses and often presents with intestinal stricturing, perianal disease, and failed response to conventional treatments. NOD2 was the first and is the most replicated locus associated with adult IBD, to date. However, its role in pediatric onset IBD is not well understood. We performed whole-exome sequencing on a cohort of 1,183 patients with pediatric onset IBD (ages 0–18.5 years). We identified 92 probands with biallelic rare and low frequency NOD2 variants accounting for approximately 8% of our cohort, suggesting a Mendelian inheritance pattern of disease. Additionally, we investigated the contribution of recessive inheritance of NOD2 alleles in adult IBD patients from a large clinical population cohort. We found that recessive inheritance of NOD2 variants explains ~ 7% of cases in this adult IBD cohort, including ~ 10% of CD cases, confirming the observations from our pediatric IBD cohort. Exploration of EHR data showed that several of these adult IBD patients obtained their initial IBD diagnosis before 18 years of age, consistent with early onset disease. While it has been previously reported that carriers of more than one NOD2 risk alleles have increased susceptibility to Crohn’s Disease (CD), our data formally demonstrate that recessive inheritance of NOD2 alleles is a mechanistic driver of early onset IBD, specifically CD, likely due to loss of NOD2 protein function. Collectively, our findings show that recessive inheritance of rare and low frequency deleterious NOD2 variants account for 7–10% of CD cases and implicate NOD2 as a Mendelian disease gene for early onset Crohn’s Disease.
format	article
author	Julie E. Horowitz Neil Warner Jeffrey Staples Eileen Crowley Nehal Gosalia Ryan Murchie Cristopher Van Hout Karoline Fiedler Gabriel Welch Alejandra Klauer King Jeffrey G. Reid John D. Overton Aris Baras Alan R. Shuldiner Anne Griffiths Omri Gottesman Aleixo M. Muise Claudia Gonzaga-Jauregui
author_facet	Julie E. Horowitz Neil Warner Jeffrey Staples Eileen Crowley Nehal Gosalia Ryan Murchie Cristopher Van Hout Karoline Fiedler Gabriel Welch Alejandra Klauer King Jeffrey G. Reid John D. Overton Aris Baras Alan R. Shuldiner Anne Griffiths Omri Gottesman Aleixo M. Muise Claudia Gonzaga-Jauregui
author_sort	Julie E. Horowitz
title	Mutation spectrum of NOD2 reveals recessive inheritance as a main driver of Early Onset Crohn’s Disease
title_short	Mutation spectrum of NOD2 reveals recessive inheritance as a main driver of Early Onset Crohn’s Disease
title_full	Mutation spectrum of NOD2 reveals recessive inheritance as a main driver of Early Onset Crohn’s Disease
title_fullStr	Mutation spectrum of NOD2 reveals recessive inheritance as a main driver of Early Onset Crohn’s Disease
title_full_unstemmed	Mutation spectrum of NOD2 reveals recessive inheritance as a main driver of Early Onset Crohn’s Disease
title_sort	mutation spectrum of nod2 reveals recessive inheritance as a main driver of early onset crohn’s disease
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/1f5de0d61ecd4e8a964ff8857b3099dd
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Mutation spectrum of NOD2 reveals recessive inheritance as a main driver of Early Onset Crohn’s Disease

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