Exome Sequencing Identifies the Extremely Rare ITGAV and FN1 Variants in Early Onset Inflammatory Bowel Disease Patients

Abstract

BackgroundMolecular diagnosis of early onset inflammatory bowel disease (IBD) is very important for adopting suitable treatment strategies. Owing to the sparse data available, this study aims to identify the molecular basis of early onset IBD in Arab patients.MethodsA consanguineous Arab family with monozygotic twins presenting early onset IBD was screened by whole exome sequencing (WES). The variants functional characterization was performed by a series of computational biology methods. The IBD variants were further screened in in-house whole exome data of 100 Saudi cohorts ensure their rare prevalence in the population.ResultsGenetic screening has identified the digenic autosomal recessive mode of inheritance of ITGAV (G58V) and FN1 (G313V) variants in IBD twins with early onset IBD. Findings from pathogenicity predictions, stability and molecular dynamics have confirmed the deleterious nature of both variants on structural features of the corresponding proteins. Functional biology data suggested that both genes show abundant expression in gastrointestinal tract and immune organs, involved in immune cell restriction, regulation of different immune related pathways. Data from knockout mouse models for ITGAV gene has revealed that the dysregulated expression of this gene impacts intestinal immune homeostasis. The defective ITGAV and FN1 involved in integrin pathway, are likely to induce intestinal inflammation by disturbing immune homeostasis.ConclusionsOur findings provide novel insights into the molecular etiology of pediatric onset IBD and may likely pave way in developing genomic medicine.

Gene Identification in Inflammatory Bowel Disease via a Machine Learning Approach

“…Song et al [ 65 ] showed that ADH1C is downregulated in UC. FN1 was suggested by Al-Numan [ 66 ] to be related to the early onset of IBD. SPINT2 plays a role in epithelial adhesion [ 17 ].…”

Rare variant burden analysis from exomes of three consanguineous families reveals LILRB1 and PRSS3 as potential key proteins in inflammatory bowel disease pathogenesis

“…Although, studying the familial cases may uncover rare causal variants, their heritability of disease in unrelated patient cohorts is still uncertain (23). Unlike VEO-IBD, which has a causal monogenic factor, late-onset is a complex and multifactorial disorder that cannot be explained by classical genetic segregation methods (16,24,25). Large-scale sporadic case-control studies on WES-based rare variant burden analysis (RVB) have previously identified several strong risk loci for complex diseases, such as Schizophrenia ( 26), Alzheimer's disease (27), epilepsy (2019), autism (28), and Crohn's disease (12).…”

“…Thus, to better understand the pathogenesis of complex diseases, application of next-generation sequencing technologies is having a greater impact, especially in consanguineous societies (15)(16)(17). They will provide an excellent opportunity to identify rare variants with intermediate to high effect ranges more efficiently.…”

Structural Protein Effects Underpinning Cognitive Developmental Delay of the PURA p.Phe233del Mutation Modelled by Artificial Intelligence and the Hybrid Quantum Mechanics–Molecular Mechanics Framework

“…These results will pave the way for future prediction/validation of DNA and RNA binding proteins affected in human disorders through AlphaFold-predicted structures modeling and refined stereochemistry experiments at atomic resolution [ 18 , 19 ]. This article represents the first report of a de novo mutation underpinning a PURA syndrome in a Latin American patient and highlights the importance of predicting the molecular effects on protein structure with artificial intelligence and advanced molecular chemistry algorithms.…”