Background/Purpose: Behcet’s disease (BD) is a systemic inflammatory disease characterized by recurrent oral and genital ulcers, skin lesions, uveitis, and other organ complications such as vascular, central nervous system, and gastrointestinal involvement. The etiology and pathogenesis of BD are poorly understood. Despite the identification of multiple common genetic variants associated with BD, rare genetic variants have been less explored. We performed whole exome sequencing (WES) in a European-derived cohort of BD patients to investigate the role of rare protein-coding variants in this disease.

Methods: Whole exome sequencing was initially performed in 14 BD patients of European descent. Exome enrichment was performed using the TrueSeq Exome Enrichment Kit (Illumina), then paired-end 100bp reads were sequenced on an Illumina HiSeq 2000 instrument. Sequence alignment, quality assurance measures, and data analysis were performed using the DNA-Seq Analysis Package (SVS 7) implemented in Golden Helix. Sanger sequencing and Sequenom technology genotyping were performed in the original patient set and two additional independent European-derived sets for validation and replication. Protein damaging potential for non-synonymous coding variants was assessed using SIFT, Polyphen, Mutation Taser, Mutation Assessor, and FATHMM. 

Results: We identified 77 protein-coding non-synonymous variants in 74 genes detected in at least 2 out of 14 re-sequenced BD patients, with a minor allele frequency (MAF)<0.01 in 6,500 control individuals included in the NHLBI Exome Sequencing Project, and predicted to have protein damaging effect. Sanger sequencing in selected variants confirmed our exome sequencing results. Genotyping was successfully performed and passed quality control measures in 61 variants in two additional sets of 49 and 129 European-derived BD patients from Germany and Italy, respectively. Genetic analysis was performed in BD cases compared to 503 European-derived controls included in the 1000 Genomes Project. Two rare protein-coding non-synonymous genetic variants were significantly associated with BD with a Bonferroni-corrected P value of <8X10^-4. We detected an association with non-synonymous potentially damaging variants in LIMK2 which is involved in actin cytoskeleton organization, and the DNA repair gene NEIL1. 

Conclusion: We used whole exome sequencing in BD for the first time, and identified rare non-synonymous protein-coding variants associated with this disease.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/whole-exome-sequencing-identifies-rare-protein-coding-variants-in-behcets-disease/