Polygenic Risk Score Predicts Modified Risk in BRCA1 Pathogenic Variant c.4035del and c.5266dup Carriers in Breast Cancer Patients

Funding Information: This research has been developed with financing from the European Social Fund and Latvian state budget within the project no. 8.2.2.0/20/I/004 “Support for involving doctoral students in scientific research and studies” at Rīga Stradiņš University. Publisher Copyright: © 2023 by the authors.The aim of this study was to assess the power of the polygenic risk score (PRS) in estimating the overall genetic risk of women carrying germline BRCA1 pathogenic variants (PVs) c.4035del or c.5266dup to develop breast (BC) or ovarian cancer (OC) due to additional genetic variations. In this study, PRSs previously developed from two joint models using summary statistics of age-at-onset (BayesW model) and case–control data (BayesRR-RC model) from a genome-wide association analysis (GWAS) were applied to 406 germline BRCA1 PV (c.4035del or c.5266dup) carriers affected by BC or OC, compared with unaffected individuals. A binomial logistic regression model was used to assess the association of PRS with BC or OC development risk. We observed that the best-fitting BayesW PRS model effectively predicted the individual’s BC risk (OR = 1.37; 95% CI = 1.03–1.81, p = 0.02905 with AUC = 0.759). However, none of the applied PRS models was a good predictor of OC risk. The best-fitted PRS model (BayesW) contributed to assessing the risk of developing BC for germline BRCA1 PV (c.4035del or c.5266dup) carriers and may facilitate more precise and timely patient stratification and decision-making to improve the current BC treatment or even prevention strategies.Peer reviewe

Hypercalcemia and CYP24A1 Gene Mutation Diagnosed in the 2nd Trimester of a Twin Pregnancy : A Case Report

Publisher Copyright: © Am J Case Rep, 2021.Objective: Rare disease Background: Loss-of-function mutations of the CYP24A1 gene cause a deficiency of the CYP24A1 enzyme, which is involved in the catabolism of 1,25-dihydroxyvitamin D3. Patients who are CYP24A1 enzyme deficient are at increased risk of developing hypercalcemia during pregnancy and should avoid additional vitamin D supplementation. This case report provides additional information for managing and diagnosing patients with a CYP24A1 gene mutation. Case Report: A primipara woman with a twin pregnancy was admitted to our hospital for frequent hypertensive crises. She had no history of hypercalcemia-associated signs and symptoms except nephrocalcinosis, and reported no oth-er abnormalities or discomfort at presentation. Laboratory tests revealed that the parathyroid hormone level was suppressed and the serum calcium level was markedly increased. The 25-hydroxyvitamin D level was at the upper limit of the reference range while the 1,25-dihydroxyvitamin D3 level was elevated, suggesting a vitamin D catabolism disorder. A genetic test was performed and a homozygous likely pathogenic variant (based on the American College of Medical Genetics and Genomics guidelines) c.964G>A (p.Glu322Lys) was detected in the CYP24A1 gene (NM_000782.5). A cesarean section delivery was performed due to a single intrauterine demise at 33 weeks of gestation. The preterm newborn was diagnosed with transitional hypercalcemia and hyperphosphatemia; however, he was not treated, as he was asymptomatic. Conclusions: Patients with a CYP24A1 gene mutation are at increased risk of hypercalcemia and fetal demise; therefore, 25-hy-droxyvitamin D and calcium levels should be monitored in routine blood tests during pregnancy. Hypercalcemia in a newborn should be carefully evaluated and treated, as hypercalciuria can lead to nephrocalcinosis.Peer reviewe