Hypertrophic cardiomyopathy (HCM), caused by mutations in thin filament proteins, manifests as moderate cardiac hypertrophy and is associated with sudden cardiac death (SCD). We identified a new de novo variant, c.656A>T (p.D219V), in the TPM1 gene encoding cardiac tropomyosin 1.1 (Tpm) in a young SCD victim with post-mortem-diagnosed HCM. We produced recombinant D219V Tpm1.1 and studied its structural and functional properties using various biochemical and biophysical methods. The D219V mutation did not affect the Tpm affinity for F-actin but increased the thermal stability of the Tpm molecule and Tpm-F-actin complex. The D219V mutation significantly increased the Ca²⁺ sensitivity of the sliding velocity of thin filaments over cardiac myosin in an in vitro motility assay and impaired the inhibition of the filament sliding at low Ca²⁺ concentration. The molecular dynamics (MD) simulation provided insight into a possible molecular mechanism of the effect of the mutation that is most likely a cause of the weakening of the Tpm interaction with actin in the "closed" state and so makes it an easier transition to the “open” state. The changes in the Ca²⁺ regulation of the actin-myosin interaction characteristic of genetic HCM suggest that the mutation is likely pathogenic.

НЕКОМПАКТНЫЙ МИОКАРД ЛЕВОГО ЖЕЛУДОЧКА: СИМПТОМ, СИНДРОМ ИЛИ ВАРИАНТ РАЗВИТИЯ?

Andersen-Tawil syndrome (ATS) is a rare channelopathy, sometimes referred to as long QT syndrome type 7. ATS is an autosomal dominant disease predominantly caused by mutations in the KCNJ2 gene. Patients with ATS present with episodes of muscle weakness, arrythmias, including prolonged QT intervals, and various skeletal abnormalities. Unlike other channelopathies, ATS has a relatively mild clinical course and low risk of sudden cardiac death. In this study, we describe a female patient with typical symptoms of ATS with the addition of unusually severe arrhythmias. Extensive DNA testing was performed to find the possible cause of this unique presentation. In addition to a known mutation in KCNJ2, the patient carried a variant in KCNH2. The combination of genetic variants may lead to the severe clinical manifestation of ATS. Additional genetic information allowed accurate genetic counselling to be provided to the patient.

Background: Inherited deficiency of the antithrombin (hereditary antithrombin deficiency, AT deficiency, OMIM #613118) is a relatively rare (1:2000–3000) autosomal-dominant disorder with high risk of venous thromboembolism. Mutations in the serpin family C member 1 gene (SERPINC1) can lead to Quantitative (type I) and Qualitative (type II) types of antithrombin deficiency. We describe a new genetic variant in the SERPINC1 gene and our approach to variant interpretation. Case presentation: We observed a 29 y.o. female proband with the episode of venous thrombosis at the age of 18 and family history of thrombosis. The antithrombin level in our patient was low, 44–48% (AT deficiency type I). A new genetic variant c.662G > C (p.W221S) in the SERPINC1 gene was detected in proband and affected father but was absent in healthy sister. We used in silico tools to evaluate the possible impact of p.W221S variant on protein structure and function. In mutated SERPINC1 protein a new N-linked glycosylation site is formed, however, it is unclear if the glycosylation at 219–221 site is possible. Conclusion: The proband was provided with appropriate genetic counseling and referred to a hematologist. Based on all the evidence we classify the p.W221S variant as variant of unknown clinical significance. In this paper we discuss some aspects of genetic counseling, variant interpretation and thromboembolic prophilaxis.

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.

Регистр взрослых больных с некомпактным миокардом левого желудочка: классификация клинических форм и проспективная оценка их прогрессирования