Ankylosing spondylitis (AS) is a common complex inflammatory disease; however, up to now distinct genes with monogenic pattern have not been reported for this disease. In the present study, we report a large Iranian family with several affected members with AS. DNAs of the three affected and two healthy cases were chosen for performing whole-exome sequencing (WES). After several filtering steps, candidate variants in the following genes were detected: RELN, DNMT1, TAF4β, MUC16, DLG2, and FAM208. However, segregation analysis confirmed the association of only one variant, c.7456A>G; p.(Ser2486Gly) in the RELN gene with AS in this family. In addition, in silico predictions supported the probable pathogenicity of this variant. In this study, for the first time, we report a novel variant in the RELN gene, c.7456A>G; p.(Ser2486Gly), which completely co-segregates with AS. This association suggests potential insights into the pathophysiological bases of AS and it could broaden horizons toward new therapeutic strategies.
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Human variant and phenotypes have been reported to ClinVar (Accession number: SCV000930629; www.ncbi.nlm.nih.gov/clinvar) and LOVD (Individual ID: 00250194). Whole-exome sequencing data produced in the current study have been deposited in the NCBI Sequence Read Archive (SRA) with accession numbers SAMN12565062, SAMN12565063, SAMN12565064, SAMN12565065, and SAMN12565066 and URL: https://dataview.ncbi.nlm.nih.gov/object/PRJNA558631. Also, bioproject is accessible by PRJNA558631 as an accession number and the following URL: https://www.ncbi.nlm.nih.gov/bioproject/PRJNA558631.
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We thank the family for their valuable contributions. We are also grateful for Corinna Jensen, Helmholtz-Zentrum Geesthacht, University of Hamburg, and Christian Sperling for their excellent technical help and Robert Weissmann and Dr Farveh Ehya for their supports in bioinformatics analysis.
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Garshasbi, M., Mahmoudi, M., Razmara, E. et al. Identification of RELN variant p.(Ser2486Gly) in an Iranian family with ankylosing spondylitis; the first association of RELN and AS. Eur J Hum Genet (2020). https://doi.org/10.1038/s41431-020-0573-4