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.

Left ventricular noncompaction (LVNC) is a highly heterogeneous primary disorder of the myocardium. Its clinical features and genetic spectrum strongly overlap with other types of primary cardiomyopathies, in particular, hypertrophic cardiomyopathy. Study and the accumulation of genotype–phenotype correlations are the way to improve the precision of our diagnostics. We present a familial case of LVNC with arrhythmic and thrombotic complications, myocardial fibrosis and heart failure, cosegregating with the splicing variant in the FHOD3 gene. This is the first description of FHOD3-dependent LVNC to our knowledge. We also revise the assumed mechanism of pathogenesis in the case of FHOD3 splicing alterations.

Triple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer (BC), comprising approximately 20% of newly diagnosed BC cases. The poor prognosis, high recurrence rates, and inefficacy of hormone-based therapies make TNBC one of the greatest challenges in contemporary oncology. The unique immunological features of TNBC, including relatively high tumor mutational burden, abundance of tumor-infiltrating lymphocytes, and elevated PD-L1 expression, offer a wide range of opportunities for immunotherapeutic approaches, of which the most progressive and promising are neoantigen-driven ones. This review examines the current landscape of neoantigen-based therapeutic approaches in TNBC treatment, spanning from discovery methodologies to clinical applications. We provide a critical analysis of the tumor microenvironment (TME) in TNBC, highlighting the balance between its immunoactivating (CD8+ T-cells, dendritic cells) and immunosuppressive (regulatory T-cells, M2 macrophages) components as the key determinant of therapeutic success, as well as reviewing the emerging approaches to TME reprogramming and recruiting in favor of better outcomes. We also present state-of the-art methods in neoantigen identification and prioritization, covering the landscape of technological platforms and prediction algorithms, addressing the existing accuracy limitations along with emerging computational solutions, and comprehensively discussing the TNBC neoantigen spectrum. Our analysis shows the strong domination of patient-specific (“private”) neoantigens over shared variants in the TNBC, with TP53 as the only gene with recurrent variants. Finally, we extensively cover neoantigen-recruiting therapeutic modalities including adoptive cell therapies, personalized vaccine platforms (peptide-based, mRNA/DNA vaccines, dendritic cell vaccines), and oncolytic viruses-based approaches. Our study of current clinical trials demonstrates the substantial gap between early proof-of-concept experiments and further applicability of neoantigen-driven therapies. The major challenges hampering the success of such methods include neoantigen prediction inaccuracy rates, high manufacturing costs, and time consumption. Promising ways to overcome these difficulties include the development of combinational strategies, TME modeling and modifying, and improvement of the therapy delivery properties, along with the optimization of production workflows and cost-effectiveness of vaccine development.

A genetic diagnosis of primary cardiomyopathies can be a long-unmet need in patients with complex phenotypes. We investigated a three-generation family with cardiomyopathy and various extracardiac abnormalities that had long sought a precise diagnosis. The 41-year-old proband had hypertrophic cardiomyopathy (HCM), left ventricular noncompaction, myocardial fibrosis, arrhythmias, and a short stature. His sister showed HCM, myocardial hypertrabeculation and fibrosis, sensorineural deafness, and congenital genitourinary malformations. Their father had left ventricular hypertrophy (LVH). The proband’s eldest daughter demonstrated developmental delay and seizures. We performed a clinical examination and whole-exome sequencing for all available family members. All patients with HCM/LVH shared a c.4411-2A>C variant in ALPK3, a recently known HCM-causative gene. Functional studies confirmed that this variant alters ALPK3 canonical splicing. Due to extracardiac symptoms in the female patients, we continued the search and found two additional single-gene disorders. The proband’s sister had a p.Trp329Gly missense in GATA3, linked to hypoparathyroidism, sensorineural deafness, and renal dysplasia; his daughter had a p.Ser251del in WDR45, associated with beta-propeller protein-associated neurodegeneration. This unique case of three monogenic disorders in one family shows how a comprehensive approach with thorough phenotyping and extensive genetic testing of all symptomatic individuals provides precise diagnoses and appropriate follow-up, embodying the concept of personalized medicine. We also present the first example of a splicing functional study for ALPK3 and describe the genotype–phenotype correlations in cardiomyopathy.

Variants of the MYH7 gene have been associated with a number of primary cardiac conditions, including left ventricular noncompaction cardiomyopathy (LVNC). Most cases of MYH7-related diseases are associated with such variant types as missense substitutions and in-frame indels. Thus, truncating variants in MYH7 (MYH7tv) and associated mechanism of haploinsufficiency are usually considered not pathogenic in these disorders. However, recent large-scale studies demonstrated evidence of the significance of MYH7tv for LVNC and gave rise to an assumption that haploinsufficiency may be the causal mechanism for LVNC. In this article, we present a family with isolated LVNC and a heterozygous splice variant of the MYH7 gene, analyze possible consequences of this variant and conclude that not all variants that are predicted truncating really act through haploinsufficiency. This study can highlight the importance of a precise assessment of MYH7 splicing variants and their participation in the development of LVNC.

Background. A few cases of combination of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) with left ventricular noncompaction (LVNC) have been described. Aims to study the genetics, diagnostical features and clinical course of the combination of ARVC with LVNC. Methods. 58 patients with ARVC diagnosis (26 men; mean age 39.1 14.2 years; mean follow-up period 21.5 [6; 60] months) and 125 patients with LVNC (74 men; mean age 46.4 15.1 years; mean follow-up period 14 [3; 40] months). All patients underwent electrocardiogram (ECG), echocardiography, 24-h ECG monitoring. Heart MRI was performed in 53 (91.4%) patients with ARVC and 60 (48%) with LVNC, heart CT in 18 (31%) patients with ARVC and 89 (71.2%) with LVNC. For all patients with combination of ARVC and LVNC DNA-diagnostic was performed using both ARVC (PKP2, DSG2, DSP, DSC2, JUP, TMEM43, TGFB3, PLN, LMNA, DES, CTTNA3, EMD, SCN5A, LDB3, CRYAB, FLNC) and LVNC (MYH7, MYBPC3, TAZ, TPM1, LDB3, MYL2, MYL3, ACTC1, TNNT2, TNI3) gene panels. Results. Combination of ARVC and LVNC was found in 9 patients (15.5% of patients form ARVC cohort and 7.2% from LVNC cohort). These patients were distinguished from patients with isolated ARVC or LVNC by aggressive ventricular arrhythmias (frequent premature ventricular beats, sustained ventricular tachycardia, significantly worse antiarrhythmic therapy effect, appropriate shocks of implanted cardioverter-defibrillators (ICD) in all patients with ICD). Patients with combination of ARVC + LVNC were also distinguished from patients with isolated LVNC by the dilatation of RV, low QRS voltage on ECG, presence of AV block, absence of signs of LV hypertrophy on ECG. LV dilatation with reduction of its ejection fraction distinguished patients with mixed cardiomyopathy from patients with isolated ARVC. Potentially pathogenic variants (IVV classes of pathogenicity) and variants of unclear clinical significance (III class of pathogenicity) were found in both desmosomal and non-desmosomal genes in 78% of patients, including 3 (33%) in DSP gene. Conclusions. The combination of ARVC and LVNC can be caused by mutations in both desmosomal and non-desmosomal genes and has typical features: aggressive, resistant ventricular rhythm abnormalities leading to appropriate ICD shocks and a high risk of sudden cardiac death.