A Rare Coincidence of Three Inherited Diseases in a Family with Cardiomyopathy and Multiple Extracardiac Abnormalities.

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.

A Splice Variant of the MYH7 Gene Is Causative in a Family with Isolated Left Ventricular Noncompaction 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.

A Case of Severe Left-Ventricular Noncompaction Associated with Splicing Altering Variant in the FHOD3 Gene.

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.

The LDLR, APOB, and PCSK9 Variants of Index Patients with Familial Hypercholesterolemia in Russia.

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.

Temperature-controlled magnetic nanoparticles hyperthermia inhibits primary tumor growth and metastases dissemination.

Magnetic hyperthermia (MHT) is a promising approach for cancer therapy. However, a systematic MHT characterization as function of temperature on the therapeutic efficiency is barely analyzed. Here, we first perform comparative temperature-dependent analysis of the cobalt ferrite nanoparticles-mediated MHT effectiveness in two murine tumors models - breast (4T1) and colon (CT26) cancer in vitro and in vivo. The overall MHT killing capacity in vitro increased with the temperature and CT26 cells were more sensitive than 4T1 when heated to 43 °C. Well in line with the in vitro data, such heating cured non-metastatic CT26 tumors in vivo, while only inhibiting metastatic 4T1 tumor growth without improving the overall survival. High-temperature MHT (>47 °C) resulted in complete 4T1 primary tumor clearance, 25-40% long-term survival rates, and, importantly, more effective prevention of metastasis comparing to surgical extraction. Thus, the specific MHT temperature must be defined for each tumor individually to ensure a successful antitumor therapy.

Trained Circulating Monocytes in Atherosclerosis: Ex Vivo Model Approach.

Inflammation is one of the key processes in the pathogenesis of atherosclerosis. Numerous studies are focused on the local inflammatory processes associated with atherosclerotic plaque initiation and progression. However, changes in the activation state of circulating monocytes, the main components of the innate immunity, may precede the local events. In this article, we discuss tolerance, which results in decreased ability of monocytes to be activated by pathogens and other stimuli, and training, the ability of monocyte to potentiate the response to pathological stimuli, and their relation to atherosclerosis. We also present previously unpublished results of the experiments that our group performed with monocytes/macrophages isolated from atherosclerosis patients. Our data allow assuming the existence of relationship between the formation of monocyte training and the degree of atherosclerosis progression. The suppression of trained immunity ex vivo seems to be a perspective model for searching anti-atherogenic drugs.