Different Phenotypes of Sarcomeric MyBPC3-Cardiomyopathy in the Same Family: Hypertrophic, Left Ventricular Noncompaction and Restrictive Phenotypes (in Association with Sarcoidosis).

The same variants in sarcomeric genes can lead to different cardiomyopathies within the same family. This gave rise to the concept of a continuum of sarcomeric cardiomyopathies. However, the manifestations and evolution of these cardiomyopathies in pathogenic variant carriers, including members of the same family, remains poorly understood. We present a case of familial sarcomeric cardiomyopathy caused by heterozygous truncating pathogenic variant p.Q1233* in cardiac myosin-binding protein C (MyBPC3) gene. The proband was first diagnosed with restrictive cardiomyopathy combined with left ventricular noncompaction (LVNC) and sarcoidosis at the age of 64. The predominantly restrictive phenotype of cardiomyopathy is considered to be a result of interaction between LVNC and sarcoid myocarditis. His 39-year-old son and 35-year-old daughter have identical non-obstructive asymmetric hypertrophic cardiomyopathy. The risk of sudden cardiac death in the son is high due to myocardial fibrosis, ischemia and nonsustained VT. We assume that both phenotypes in the family may have originally been different or there may have been a gradual transformation of the hypertrophic phenotype into LVNC. Myocarditis is regarded as an important epigenomic modifier of sarcomeric cardiomyopathy. In the proband and his son, cardioverter-defibrillators were implanted, and the proband experienced appropriate shocks due to ventricular tachycardia/fibrillation. The proband was also treated with corticosteroids. His death at the age of 69 years occurred due to acute gastric hemorrhage accompanied by progressive heart failure. This report confirms the concept of the phenotypic continuum of sarcomeric cardiomyopathies and describes possible phenotypic patterns and their transformation over time.

Variable Clinical Appearance of the Kir2.1 Rare Variants in Russian Patients with Long QT Syndrome.

BACKGROUND: The KCNJ2 gene encodes inward rectifier Kir2.1 channels, maintaining resting potential and cell excitability. Presumably, clinical phenotypes of mutation carriers correlate with ion permeability defects. Loss-of-function mutations lead to QTc prolongation with variable dysmorphic features, whereas gain-of-function mutations cause short QT syndrome and/or atrial fibrillation. METHODS: We screened 210 probands with Long QT syndrome for mutations in the KCNJ2 gene. The electrophysiological study was performed for the p.Val93Ile variant in the transfected CHO-K1 cells. RESULTS: We found three rare genetic variants, p.Arg67Trp, p.Val93Ile, and p.R218Q, in three unrelated LQTS probands. Probands with p.Arg67Trp and p.R218Q had a phenotype typical for Andersen-Tawil (ATS), and the p.Val93Ile carrier had lone QTc prolongation. Variant p.Val93Ile was initially described as a gain-of-function pathogenic mutation causing familial atrial fibrillation. We validated electrophysiological features of this variant in CHO-K1 cells, but no family members of these patients had atrial fibrillation. Using ACMG (2015) criteria, we re-assessed this variant as a variant of unknown significance (class III). CONCLUSIONS: LQT7 is a rare form of LQTS in Russia, and accounts for 1% of the LQTS cohort. Variant p.Val93Ile leads to a gain-of-function effect in the different cell lines, but its clinical appearance is not so consistent. The clinical significance of this variant might be overestimated.

De Novo Asp219Val Mutation in Cardiac Tropomyosin Associated with Hypertrophic Cardiomyopathy.

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.

Compound heterozygous mutations in KCNJ2 and KCNH2 in a patient with severe Andersen-Tawil syndrome.

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.

New genetic variant in the SERPINC1 gene: hereditary Antithrombin deficiency case report, familial thrombosis and considerations on genetic counseling.

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.

Common pathogenic mechanism in patients with dropped head syndrome caused by different mutations in the MYH7 gene.

Mutations in the MYH7 gene are the source of an allelic series of diseases, including various cardiomyopathies and skeletal myopathies that usually manifest in adulthood. We observed a 1.5 y.o. male patient with congenital weaknesses of the axial muscles, "dropped head" syndrome, and dilated cardiomyopathy. The clinical evaluation included medical history, an echocardiogram, electromyography, and a histopathological study. The genetic evaluation included whole exome sequencing. Muscle biopsy samples from the proband were used for mRNA extraction. We revealed a novel genetic variant c.5655 + 5G > C in the MYH7 gene. The analysis of the cDNA showed an in-frame skipping of exon 38 (p.1854_1885del). This variant and two previously published mutations (c.5655G > A and c.5655 + 1G > A), also presumably leading to exon 38 skipping, were studied by expression analysis in the HEK293T cell line transfected with 4 plasmids containing the MYH7 minigene (wt, c.5655G > C, c.5655 + 1G > A and c.5655 + 5G > A). A quantitative difference in expression was shown for cell lines with each of the three mutant plasmids. All mutation carriers had a similar phenotype and included congenital axial myopathy and variable cardiac involvement. Prominent dropped head syndrome was mentioned in all patients. Early-onset axial myopathy with a dropped head syndrome is a distinct clinical entity within MYH7-related disorders. We suggest that mutations in the MYH7 gene affecting the C-terminal domain of beta-myosin heavy chain should also be considered as a possible cause in cases of early-onset myopathy with "dropped head" syndrome.