Familial dysbetalipoproteinemia (FD) is a highly atherogenic, prevalent genetically based lipid disorder. About 10% of FD patients have rare APOE variants associated with autosomal dominant FD. However, there are insufficient data on the relationship between rare APOE variants and FD. Genetic data from 4720 subjects were used to identify rare APOE variants and investigate their pathogenicity for autosomal dominant FD. We observed 24 variants in 86 unrelated probands. Most variants were unique (66.7%). Five identified APOE variants (p.Glu63ArgfsTer15, p.Gly145AlafsTer97, p.Lys164SerfsTer87, p.Arg154Cys, and p.Glu230Lys) are causal for autosomal dominant FD. One of them (p.Lys164SerfsTer87) was described for the first time. When we compared clinical data, it was found that carriers of pathogenic or likely pathogenic APOE variants had significantly higher triglyceride levels (median 5.01 mmol/L) than carriers of benign or likely benign variants (median 1.70 mmol/L, p = 0.034) and variants of uncertain significance (median 1.38 mmol/L, p = 0.036). For the first time, we estimated the expected prevalence of causal variants for autosomal dominant FD in the population sample: 0.27% (one in 619). Investigating the spectrum of APOE variants may advance our understanding of the genetic basis of FD and underscore the importance of APOE gene sequencing in patients with lipid metabolism disorders.

Aim. To evaluate the information content of genetic risk scores (GRSs) for coronary artery disease (CAD), previously developed on European populations, in representatives of the Russian population. Material and methods . The work involved 1685 people from the ESSE-Ivanovo epidemiological study. CAD was verified in 3,1% of individuals. The coronary composite endpoint was assessed annually during 8-year follow-up. Next generation sequencing was performed using a targeted panel. Logistic regression analysis and area under the ROC curve (AUC) were used. Age, sex, and smoking status were taken into account in the multivariate model. Results. Of the 16 GRSs included in the analysis, only 2 GRSs demonstrated significance in the univariate analysis of association with CAD (highest AUC — 0,577). In a multivariate model, with an increase by 1 standard deviation (SD) for the 6 studied GRSs, a significant association with CAD was obtained — the odds ratio varied in the range of 1,31-1,47. The two GRSs demonstrated significant differences in the incidence of CAD between the groups corresponding to the upper and lower quintiles. Forty-five endpoints were registered. The risk ratio for the end point with an increase in GRS by 1 SD, taking into account cofactors, exceeded statistical significance for the 9 analyzed GRS and was in the range of 1,36-1,54. Conclusion. For the first time in Russia, 16 CAD GRSs, previously developed on European samples, was validated. The results were reproduced only for a few of the studied CAD SGRs.

In connection with the development of genetic and other types of research in translational medicine, collections containing a significant number of biospecimens and large data sets are required. Since in-depth examination of patients is most often carried out during hospitalization, the creation of collections based on electronic medical records (EMR) data is promising. In this regard, the project "Total biobanking in the hospital of the National Medical Research Center for Therapy and Preventive Medicine" was initiated, aimed at total biobanking of blood and related products from patients in inpatient departments and the creation of a unified system that combines information on biosamples, clinical and other types of data. Aim. To describe the collection of biospecimens collected within the project "Total biobanking in the hospital of the National Medical Research Center for Therapy and Preventive Medicine" for August 2023, and to analyze the process of biospecimen description. Material and methods . Recruitment of patients is carried out on the basis of inpatient departments of the National Medical Research Center for Therapy and Preventive Medicine, only if the patient signs informed consent. After blood is taken, the biomaterial enters the biobank, where sample preparation and storage is carried out, as well as data about each biosample is entered into a special FreezerPRO system. At the same time, clinical data about the patient is collected using EMR, which are combined in the Medialog medical information system. Results. A special software for data exchange between the medical information system and the biobank has been developed, which combines information about patients entering the Medialog medical information system and the FreezerPro biospecimen management system, which contains detailed information about biospecimens. As of August 25, 2023, biomaterial from 3996 patients was collected, which was accompanied by a detailed clinical summary. In particular, data is available on diagnoses (for 100% of patients), laboratory test data (100%), paraclinical data, in particular, electrocardiography (100%), echocardiography (76,8%), 24-hour Holter monitoring (59,8%), esophagogastroduodenoscopy (27,3%), etc. The most common diseases were hypertension (76,0%), atherosclerosis (69,9%), coronary artery disease (52,9%), arrhythmias (50,6%), diabetes (19,2%). In addition, 25,0% of patients had prior stenting. Conclusion. Total biobanking within the hospital of a multidisciplinary research medical center allows for the rapid and high-quality collection of biomaterial and related data. A collection of biospecimens with comprehensive and detailed clinical annotations has been collected. A primary analysis of the collection was carried, which showed that it can be used for a wide range of studies.

Genetic overdiagnosis of long QT syndrome (LQTS) becomes a critical concern due to the high clinical significance of DNA diagnosis. Current guidelines for LQTS genetic testing recommend a limited scope and strict referral based on the Schwartz score. Nevertheless, LQTS may be underdiagnosed in patients with borderline phenotypes. We aimed to evaluate the total yield of rare variants in cardiac genes in LQTS patients. The cohort of 82 patients with LQTS referral diagnosis underwent phenotyping, Schwartz score counting, and exome sequencing. We assessed known LQTS genes for diagnostics, as per guidelines, and a broader set of genes for research. Diagnostic testing yield reached 75% in index patients; all causal variants were found in KCNQ1, KCNH2, and SCN5A genes. Research testing of 248 heart-related genes achieved a 50% yield of molecular diagnosis in patients with a low Schwartz score (<3.5). In patients with LQTS-causing variants, each additional rare variant in heart-related genes added 0.94 points to the Schwartz score (p value = 0.04), reflecting the more severe disease in such patients than in those with causal variants but without additional findings. We conclude that the current LQTS genetic diagnosis framework is highly specific but may lack sensitivity for patients with a Schwartz score <3.5. Improving referral criteria for these patients could enhance DNA diagnosis. Also, our results suggest that additional variants in cardiac genes may affect the severity of the disease in the carriers of LQTS-causing variants, which may aid in identifying new modifier genes.

Background: Genetic testing for long QT syndrome (LQTS) is straightforward in many families; however, in severe and complex cases, a single disease-causing variant may not be enough to explain all clinical features. In such cases, the search for genetic modifiers may be beneficial for precise diagnosis and management. Case presentation: We describe a three-generational family affected with clinically heterogeneous LQTS type 3 and bradycardia in which a novel missense variant p.V642M in HCN4 was identified in addition to the known pathogenic variant p.E1784K in SCN5A. We performed the detailed clinical investigation of the family and a deep in silico analysis of the discovered variants, showing the causal role of a new HCN4 variant in sinus bradycardia and its possible contribution to the phenotypic heterogeneity of LQTS type 3. Conclusions: This case is the first description of a functional variant in HCN4 as a candidate modifier in LQTS type 3 and demonstrates the importance of analyzing additional genetic variations in families with complex LQTS phenotypes.

Заседание Совета по терапевтическим наукам Отделения медицинских наук РАН: Марафон научных проектов терапевтических кафедр России "От инновационных технологий и образования к практике здравоохранения. Дисплазии соединительной ткани: проблемы диагностики и ведения пациентов"