Background Ankylosing spondylitis (AS) exhibits a strong genetic predisposition which is only partially accounted for with SNP-based genome-wide associations. To date no structural variations such as copy number variations (CNVs) have been reported to be associated with AS.

Objectives To identify highly penetrant, novel CNVs associated with familial AS by employing a custom genome-wide microarray.

Methods Our custom microarray which was comprised of 2 X 1 million probes targeting the rearrangement hotspots (mean spacing of 280 bp) was applied on a large multiplex three generational Caucasian AS family of North European ancestry. This multiplex family was consisted of five (5) individuals affected with AS, two (2) members with Systemic lupus erythematosus (SLE) and three (3) unaffected individuals. An ethnically-matched control was used for hybridization. A minimum of five (5) probes were required to call an aberration with an average intensity >0.25 and <-0.25 for a duplication and deletion, respectively. Independent validation was performed for CNV’s identified by the custom microarray using taqman-based quantitative polymerase chain reaction (qPCR).

Results Microarray analysis revealed complex rearrangements within AS patients in multiple regions not present within the unaffected family members. The most compelling evidence for structural variation was excessive genomic gains observed for the UGT2B17 gene. Duplication of the UGT2B17 gene was present in all five (5) patients with AS (i.e., two males and three females) and in a patient with SLE. No genomic gain was detected in unaffected family members. Validation using qPCR demonstrated complete concordance with the microarray results with all five (5) AS individuals contained ≥2 copies of the UGT2B17 gene, whereas unaffected individuals had only a single copy. The population frequency of the UGT2B17 CNV among Caucasians is 0.15 for a deletion, 0.45 for one copy, and 0.25 for two or more copies. The UGT2B17 gene encodes a key enzyme responsible for glucuronidation of androgens which stimulate bone formation. Interestingly, deletion of the UGT2B17 gene has been associated with osteoporosis (Yang TL et al., 2008); however, this association was not replicated in an independent study (Chew S et al., 2011).

Conclusions This is the first report of structural variants (i.e., CNVs) being associated with familial AS. Given the proposed function of this gene in stimulating bone formation, it should be considered a high priority susceptibility gene in familial AS. Replication studies and further functional studies are warranted.

Disclosure of Interest None Declared