Introduction: Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) is a chronic pain disorder causing symptoms of urinary frequency, urgency and bladder discomfort. Methods: We performed genetic analyses of whole exome sequencing (ES) on a total of 109 individuals with IC/BPS (93 female and 16 male). Each individual had a cystoscopy, physical exam, urinalysis, and completed questionnaires including the O’Leary- Sant for women, and the NIH-CPSI for men. Our study urologist confirmed the IC/BPS diagnosis. Data was analyzed in Codified Genomics for Mendelian variants. SKAT analysis was performed in Genuity Science for a small list of candidate genes, based on the results of the Mendelian analysis. Results: One family had a previously reported SIX5 variant (ENST00000317578.6:c.472G>A, p.Ala158Thr), consistent with Branchiootorenal syndrome 2 (BOR2). A likely pathogenic heterozygous variant in ATP2A2 (ENST00000539276.2:c.235G>A, p.Glu79Lys) was identified in two probands, indicating possible Darier-White disease. Two private heterozygous variants were identified in ATP2C1 (ENST00000393221.4:c.2358A>T, p.Glu786Asp (VUS/Likely Pathogenic) and ENST00000393221.4:c.989C>G, p.Thr330Ser (Likely Pathogenic)), indicative of Hailey-Hailey Disease. SKAT analysis found a trend towards increased burden of rare ATP2C1 variants in the IC/BPS cases vs a control cohort (p=0.03, OR=6.76), though did not survive Bonferroni correction. Conclusions: Our data suggest that some individuals with IC/BPS may have unrecognized Mendelian syndromes, and ATP2C1, ATP2A2, and SIX5 may be candidate genes for IC/BPS. Impairment of ATP2C1 leads to a dysfunction in the Golgi-associated human secretory pathway Ca2+/Mn2+ ATPase (hSPCA1) that results in recurrent blisters and erosions in intertriginous sites. Studies show that knockdown of SPCA1 results in disruption of Golgi morphology in HeLa cells, and reduction of the amount of Ca2+ stored in the Golgi lumen. The Golgi complex is tightly integrated into the urothelial cellular system, where it is crucial for the health of the blood–urine barrier, mainly through its association with uroplakins. One can hypothesize that mutations of ATP2C1 may also result in a disruption of Golgi morphology in urothelial tissue, impairing the formation of the blood-urine barrier, a hallmark of IC/BPS. Genetically screening individuals with IC/BPS may be useful in diagnosing and treating this painful disorder due to its heterogeneous nature. SOURCE OF Funding: This work was funded by NIH 5U54DK104309-07, CDC 1U01DP006634-01-00, P50HD105351, and the Broad Institute BCH Collaborative Grant Award.
