Familial hypercholesterolemia (FH) is a common autosomal codominant disorder, characterized by elevated low-density lipoprotein cholesterol levels causing premature atherosclerotic cardiovascular disease. About 2900 variants of LDLR, APOB, and PCSK9 genes potentially associated with FH have been described earlier. Nevertheless, the genetics of FH in a Russian population is poorly understood. The aim of this study is to present data on the spectrum of LDLR, APOB, and PCSK9 gene variants in a cohort of 595 index Russian patients with FH, as well as an additional systematic analysis of the literature for the period of 1995–2020 on LDLR, APOB and PCSK9 gene variants described in Russian patients with FH. We used targeted and whole genome sequencing to search for variants. Accordingly, when combining our novel data and the data of a systematic literature review, we described 224 variants: 187 variants in LDLR, 14 variants in APOB, and 23 variants in PCSK9. A significant proportion of variants, 81 of 224 (36.1%), were not described earlier in FH patients in other populations and may be specific for Russia. Thus, this study significantly supplements knowledge about the spectrum of variants causing FH in Russia and may contribute to a wider implementation of genetic diagnostics in FH patients in Russia.

Heterozygous familial hypercholesterolemia (HeFH) is one of the most common genetic conditions but remains substantially underdiagnosed. The aim of our study was to investigate the prevalence of HeFH in the population of 11 different regions of Russia. Individuals were selected from the Epidemiology of Cardiovascular Risk Factors and Diseases in Regions of the Russian Federation Study. All participants who had low-density lipoprotein cholesterol (LDL-C) higher than 4.9 mmol/L, or LDL-C lower than 4.9 mmol/L, but had statin therapy, were additionally examined by FH experts. FH was diagnosed using the Dutch Lipid Clinic Network criteria, incorporating genetic testing. HeFH prevalence was assessed for 18,142 participants. The prevalence of patients with definite or probable HeFH combined was 0.58% (1 in 173). A total of 16.1% of patients with definite or probable HeFH had tendon xanthomas; 36.2% had mutations in one of the three genes; 45.6% of FH patients had coronary artery disease; 63% of HeFH patients received statins; one patient received an additional PCSK9 inhibitor; no patients received ezetimibe. Only 3% of patients reached the LDL-C goal based on 2019 ESC/EAS guidelines. Underdiagnosis and undertreatment of FH in Russia underline the need for the intensification of FH detection with early and aggressive cholesterol-lowering treatment.

РАСПРЕДЕЛЕНИЕ ПОКАЗАТЕЛЕЙ ЛИПИДНОГО СПЕКТРА У МУЖЧИН И ЖЕНЩИН ТРУДОСПОСОБНОГО ВОЗРАСТА В РОССИЙСКОЙ ФЕДЕРАЦИИ: РЕЗУЛЬТАТЫ ИССЛЕДОВАНИЯ ЭССЕ-РФ ЗА 2012-2014ГГ

Here, we present a small Russian family, where the index patient received a diagnosis of left-ventricular non-compaction cardiomyopathy (LVNC) in combination with a skeletal myopathy. Clinical follow-up analysis revealed a LVNC phenotype also in her son. Therefore, we applied a broad next-generation sequencing gene panel approach for the identification of the underlying mutation. Interestingly, DES-p.A337P was identified in the genomes of both patients, whereas only the index patient carried DSP-p.L1348X. DES encodes the muscle-specific intermediate filament protein desmin and DSP encodes desmoplakin, which is a cytolinker protein connecting desmosomes with the intermediate filaments. Because the majority of DES mutations cause severe filament assembly defects and because this mutation was found in both affected patients, we analyzed this DES mutation in vitro by cell transfection experiments in combination with confocal microscopy. Of note, desmin-p.A337P forms cytoplasmic aggregates in transfected SW-13 cells and in cardiomyocytes derived from induced pluripotent stem cells underlining its pathogenicity. In conclusion, we suggest including the DES gene in the genetic analysis for LVNC patients in the future, especially if clinical involvement of the skeletal muscle is present.

The prevalence of familial hypercholesterolemia (FH) in Russia has not previously been evaluated. The aim of our study was to investigate the prevalence of FH in the population of the West Siberian region of Russia, and then estimate the frequency of coronary artery disease (CAD) and treatment with cholesterol-lowering medication in FH patients. The sample of our study consisted of participants from the population-based cohort of The Epidemiology of Cardiovascular Risk Factors and Diseases in Regions of the Russian Federation Study (ESSE-RF), conducted in the Tyumen and Kemerovo regions (1,630 and 1,622 people, respectively, aged 25–64). All participants who had LDL-cholesterol higher than 4.9 mmol/l and who had LDL-cholesterol less than or equal to 4.9 mmol/l but had statin therapy were examined and interviewed by experts in FH. The prevalence of patients with definite FH was 0.24% (one in 407) (95% confidence interval [CI]: 0.06%–0.42%), with probable FH was 0.68% (one in 148) (95% CI: 0.38%–0.98%), and with definite or probable FH combined was 0.92% (one in 108) (95% CI: 0.58%–1.26%). 40% (95% CI: 20.8%–59.2%) of patients with definite or probable FH had CAD. However, only 23% (95% CI: 6.3%–39.7%) of patients with definite or probable FH were on statins. The odds ratios for CAD and myocardial infarction (MI), adjusted for age, gender, region, smoking, hypertension, and diabetes mellitus, were 3.71 (95% CI: 1.58–8.72) (p = 0.003) and 4.06 (95% CI: 0.89–18.55) (р = 0.070) respectively for individuals with definite or probable FH relative to those who were unlikely to have FH. The prevalence of FH in Russia may be significantly higher than previously estimated. There is underdiagnosis and undertreatment of FH in Russia.

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