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Reverse Cascade Genetic Screening for Revealing New Cases of Familial Hypercholesterolemia in Russia: Pilot Project
Valentina V Miroshnikova1,2, Artem D Izyumchenko1,2, Nataliia N Smirnova3
1Department of Molecular and Radiation Biophysics, Petersburg Nuclear Physics Institute named by B.P. Konstantinov of National Research Centre «Kurchatov Institute», 188300 Gatchina, Russia.
Background:
Reverse cascade genetic screening, following initial lipid testing, is an effective strategy for the early diagnosis of familial hypercholesterolemia (FH) and related hereditary dyslipidemias. In this study, we present the results of a pilot project in Russia.
Methods:
This was a hybrid retrospective-prospective cross-sectional study. Analysis of 1897 lipid screenings of children referred to the main pediatric centers in St. Petersburg, Russia, demonstrated that 60 (3.2%) met the Simon Broome criteria for FH, defined as total cholesterol (TC) ≥6.5 mmol/L or low-density lipoprotein cholesterol (LDL-C) ≥4 mmol/L. All families were invited to undergo genetic testing, regardless of their history, with 35 (58%) families participating in the second stage of the study. Targeted sequencing was performed for children, and Sanger sequencing was performed for variant validation in children and their family members.
Results:
Sixteen children were shown to have causal variants in dyslipidemia-associated genes, including fourteen (40% of 35 tested children) with hereditary dyslipidemias: twelve FH cases (linked to LDLR and APOB genetic variants), one dysbetalipoproteinemia case (APOE), and one sitosterolemia case (ABCG8). Two children were heterozygous for sitosterolemia variants (one case with ABCG5, one case with ABCG8). Family history of FH or atherosclerotic cardiovascular disease (ASCVD) was reported in only 50% of cases, regardless of whether a causal variant was present. TC and LDL-C were higher in the causal variant-positive subgroup. Receiver operating characteristic curve analysis revealed that LDL-C >4.8 mmol/L acted as a diagnostic indicator of disease causing variant with 84% accuracy, 93% sensitivity, and 73% specificity.
Conclusions:
Reverse cascade genetic screening following selective lipid testing in children is an effective strategy to reveal new FH and other hereditary dyslipidemia cases, helping to mitigate future ASCVD risks and early mortality.
