Unexpected High Frequency of Novel and Known Pathogenic Germline Variant of the Lgr4 Gene in the Ethnic Group of West Siberia

Background : Hereditary breast cancer (BC) is an autosomal dominant disease caused by mutations in genes such as BRCA1/2, BRAD1, RAD54L, RAD51, ATM, BRIP1 , and others. The prevalence and range of mutations can differ among various regions and ethnic groups. In a previous study using whole exome sequencing, we identified a germline pathogenic variant of the LGR4 gene (rs34804482, NM_018490.3: c.2531A>G) in a young Tuvan BC patient (belonging to the Turkic-speaking tribes of Central Asia). The aim of this study was to determine the frequency of the germinal pathogenic variant rs34804482 of the LGR4 gene (NM_018490.3: c.2531A>G) in ethnic groups of West Siberia (comparing BC patients and healthy subjects) using the PCR-RT method. Methods : The study involved 735 BC patients from various ethnic groups in Siberia, including Russians, Buryats, Tuvans, Yakuts, Altaians, and Khakassians, with a median age at diagnosis of 43±15.6 years. The control group consisted of 727 healthy women from the same ethnic groups in Siberia, with a median age of 43.05±13.5 years. Results : In a general group of BC patients, the frequency of the pathogenic variant of the LGR4 gene (rs34804482) was 0.027. Specifically, the frequency of this variant was 0.015 in Russian BC patients, 0.022 in Buryat BC patients, and 0.069 in Tuvan BC patients. This variant was not detected in Khakassian and Yakut BC patients. In Tuvan women with BC, the frequency of the pathogenic variant of the LGR4 gene was significantly higher than in Russian BC patients (X ² = 8.153, p = 0.005). The frequency of the pathogenic variant of the LGR4 gene (rs34804482) in healthy Tuvan women was significantly higher than in healthy Russian women (0.066 versus 0.016, X ² =6.368, p=0.012). The mutation frequency in healthy Russians was close to that in Europeans (0.016 versus 0.0219). The highest frequency of this pathogenic variant was found among healthy Tuvans (0.066), significantly higher compared to Americans (0.0000) and other ethnic groups (according to ExAc). Conclusions : Our study was the first to investigate the frequency of the pathogenic variant of the LGR4 gene (rs34804482) in different ethnic groups of Siberia, comparing BC patients with healthy individuals. We found no statistically significant differences in the mutation frequency between BC patients and healthy individuals in the ethnic groups studied. The highest frequency of this pathogenic variant was observed among healthy Tuvans (0.066), which was significantly higher compared to other ethnic groups.