Characterization of Von Hippel Lindau gene variants by race.

Abstract

e15158 Background: Autosomal dominant (AD) pathogenic/ likely pathogenic (P/LP) variants in the VHL gene cause Von Hippel Lindau syndrome, historically studied in White populations. We aimed to characterize VHL variants and disease phenotypes in both Non-White (NW) patients, which include Asian and African-American (AA), and in Non-Hispanic White (NHW) patients. Methods: Patients undergoing germline genetic testing (GGT) at Invitae Corporation from November 2014 to March 2022, carrying a P/LP AD variant in VHL gene were identified. Demographic and clinical data were obtained from Test requisition forms. Fisher's exact test and Wilcoxon rank-sum tests were performed for categorical and continuous variables, respectively, to compare groups. Results: The final analysis included 363 patients (NW=27%). Hemangioblastoma was predominant in all groups (NHW=13%, NW=27%, p=0.004). Breast cancer exclusively occurred in NHW patients (7%, p=0.019). NHW and NW patients had a higher family history of breast cancer (NHW=7%, NW=1%, p=0.046) and hemangioblastoma (NHW=3%, NW=8%, p=0.037), respectively. Distribution of VHL variants between NW and NHW patients varied significantly (p<0.001, Indels p=0.009, substitution variants p<0.001). Deletion exon 2 was predominant in all groups (NHW=15%, NW=35%) P.Leu188Val was exclusive to NHW patients (26%)while p.Arg167Trp (NHW=6%, NW=11%) and p.Arg167Gln (NHW=2%, NW=10%) were more common in NW patients. Several unique variants in AA and Hispanic patients were seen. Conclusions: This study reveals differences in P/LP VHL variant distribution and disease phenotype between NHW and NW races. Ethnicity-specific characterization uncovers unique variants in AA and Hispanic patients. This dataset informs future research on VHL disease and treatment in diverse populations.