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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.

Successful therapy in a cohort with early onset Danon disease (DD) highlights the potential importance of earlier disease recognition. We present experience from the largest National Pediatric Center in Russia for cardiomyopathy patients. This report focuses on identification of early clinical features of DD in the pediatric population by detailed pedigree analysis and review of medical records. RESULTS: Nine patients (3 females) were identified with DD at the Russian National Medical Research Center of Children's Health ("National Pediatric Center") aged birth to 16 years. At presentation/evaluation: all patients had left ventricular hypertrophy (LVH), ECG features of Wolff-Parkinson-White (WPW), and an increase in hepatic enzymes (particularly lactate dehydrogenase (LDH)); three had marked increase in NT-proBNP; two had HCM with impaired LV function; one had LVH with LV noncompaction; five had arrhythmia with paroxysmal supraventricular and/or ventricular tachycardia. Two teenagers died at ages 16-17 from refractory heart failure and two underwent heart transplantation. All patients were found to have a pathogenic/likely pathogenic variant in the LAMP2 gene, six patients had no family history and a de novo evolvement was documented in 4/6 of those available for genetic tested. Retrospective review related to family background and earlier clinical evaluations revealed a definitive or highly suspicious family history of DD in 3, early clinical presentation with cardiac abnormalities (ECG, echo) in 3, and cerebral, hepatic and/or neuromuscular symptoms in 5. Abnormalities were detected 9,5 months to 5,8 years, median 3,5 years prior to referral to the National Pediatric Center. CONCLUSION: The earliest clinical manifestations of Danon disease occur in the first 12 years of life with symptoms of skeletal muscle and cerebral disease, raised hepatic enzymes, and evidence of cardiac disease on ECG/echo., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results., (Copyright © 2023 Elsevier B.V. All rights reserved.)

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.

Left ventricular non-compaction cardiomyopathy (LVNC) is a rare heart disease, with or without left ventricular dysfunction, which is characterized by a two-layer structure of the myocardium and an increased number of trabeculae. The study of familial forms of LVNC is helpful for risk prediction and genetic counseling of relatives. Here, we present a family consisting of three members with LVNC. Using a next-generation sequencing approach a combination of two (likely) pathogenic nonsense mutations DSG2 -p.S363X and TBX20 -p.D278X was identified in all three patients. TBX20 encodes the cardiac T-box transcription factor 20. DSG2 encodes desmoglein-2, which is part of the cardiac desmosomes and belongs to the cadherin family. Since the identified nonsense variant ( DSG2 -p.S363X) is localized in the extracellular domain of DSG2 , we performed in vitro cell transfection experiments. These experiments revealed the absence of truncated DSG2 at the plasma membrane, supporting the pathogenic relevance of DSG2 -p.S363X. In conclusion, we suggest that in the future, these findings might be helpful for genetic screening and counseling of patients with LVNC.

Aim: To analyze and demonstrate various phenotypes in patients with familial left ventricular noncompaction (LVNC)., Materials and Methods: In 2013 was created a multicenter registry of LVNC patients. On its basis 30 families with a familial LVNC were selected., Results: 30 LVNC families were selected from the register. From a total of 115 people (probands and relatives) in 71 (61.7%) LVNC was diagnosed (30 probands and 41 relatives with non-compact myocardial criteria). The most common type of remodeling in patients was the dilated type (DT) (n=30), the isolated LVNC with preserved ejection fraction (EF) was slightly less common (n=23), and the hypertrophic type (GT) was detected in 8 patients. 4 patients were diagnosed with the isolated LVNC with a reduced EF. 3 patients were with a combination of non-compact myocardium with congenital heart disease and with a combination of DT and GT (DT+GT). During the analysis of cases a combination of different phenotypes in the same family was observed. The largest number of families was diagnosed with a combination of DT and the isolated LVNC with preserved EF. The development of cardiovascular complications was associated with DT., Conclusion: Family cases of LVNC had different types of myocardial remodeling and variants of clinical course. In one family a combination of different types of left ventricular remodeling is possible. DT is associated with the most severe clinical manifestations. The clinical picture of the isolated LVNC with preserved EF, is the most favorable, but in rare cases, serious clinical manifestations were observed.

About 50% of patients with arrhythmogenic cardiomyopathy (ACM) carry a pathogenic or likely pathogenic mutation in the desmosomal genes. However, there is a significant number of patients without positive familial anamnesis. Therefore, the molecular reasons for ACM in these patients are frequently unknown and a genetic contribution might be underestimated. Here, we used a next-generation sequencing (NGS) approach and in addition single nucleotide polymor-phism (SNP) arrays for the genetic analysis of two independent index patients without familial medical history. Of note, this genetic strategy revealed a homozygous splice site mutation (DSG2-c.378+1G>T) in the first patient and a nonsense mutation (DSG2-p.L772X) in combination with a large deletion in DSG2 in the second one. In conclusion, a recessive inheritance pattern is likely for both cases, which might contribute to the hidden medical history in both families. This is the first report about these novel loss-of-function mutations in DSG2 that have not been previously identi-fied. Therefore, we suggest performing deep genetic analyses using NGS in combination with SNP arrays also for ACM index patients without obvious familial medical history. In the future, this finding might has relevance for the genetic counseling of similar cases.

Here, we present a small Russian family, where the index patient received a diagnosis of left-ventricular non-compaction cardiomyopathy (LVNC) in combination with a skeletal myopathy. Clinical follow-up analysis revealed a LVNC phenotype also in her son. Therefore, we applied a broad next-generation sequencing gene panel approach for the identification of the underlying mutation. Interestingly, DES -p.A337P was identified in the genomes of both patients, whereas only the index patient carried DSP -p.L1348X. DES encodes the muscle-specific intermediate filament protein desmin and DSP encodes desmoplakin, which is a cytolinker protein connecting desmosomes with the intermediate filaments. Because the majority of DES mutations cause severe filament assembly defects and because this mutation was found in both affected patients, we analyzed this DES mutation in vitro by cell transfection experiments in combination with confocal microscopy. Of note, desmin-p.A337P forms cytoplasmic aggregates in transfected SW-13 cells and in cardiomyocytes derived from induced pluripotent stem cells underlining its pathogenicity. In conclusion, we suggest including the DES gene in the genetic analysis for LVNC patients in the future, especially if clinical involvement of the skeletal muscle is present.

Purpose of the Study: The study of the diagnostic value of biochemical markers of myocardial stress and inflammation in chronic heart failure (CHF) with different values of the ejection fraction (EF) of the left ventricle (LV)., Material and Methods: The cross-sectional study included 105 patients aged 24 to 84 years (mean 58+/-14 years) with stable chronic heart failure I-II NYHA functional class classification. The causes of CHF were ischemic heart disease (IHD) in 33% of patients and arterial hypertension (AH) - 67%. All patients received medical treatment: angiotensin-converting enzyme (ACE) - 76%, -blockers - 72%, diuretics - 100%, statins - 80%. The control group consisted of 35 healthy volunteers. All subjects identified blood natriuretic peptide (NT-proBNP, ANP), adiponectin, galectin-3, pentraxins-3 and growth differentiation factor-15 (GDF-15) by enzyme immunoassay (ELISA). All surveyed performed transthoracic echocardiography (Echo)., Results: The blood NT-proBNP, ANP, galectin-3, pentraxins and GDF-3-15 in patients with chronic heart failure was significantly higher than in the control group (p<0.001 in all cases). In contrast, the level of adiponectin was significantly higher than in healthy individuals - 11.90 (11.39; 12.65) vs 7.73 (3.58; 8.86) ng/ml in patients with chronic heart failure (p<0.001). LVEF ranged from 30 to 55%, in 33% of patients it was >50%. Correlation analysis Spearman found strong correlations (p<0.001 for all markers) between LVEF and the content of all the biomarkers, while between the PV and the level of adiponectin is a positive correlation was found (r=0.862), and between the PV and the other biomarkers - reverse (r from -0.858 to -0.901). Multivariate linear regression analysis found the strongest correlation with the value of LVEF at pentraxin 3 and adiponectin. Subsequent ROC-analysis confirmed the diagnostic value of adiponectin in patients with heart failure and preserved ejection fraction. Thus, the level of adiponectin more than 8.3 ng/ml served as a prognostic factor for the presence of heart failure in patients with LVEF >50% with a sensitivity of 94.3% and a specificity of 92.9% (area under the curve 0.977; 95% confidence interval from 0.954 to 0.999; p<0.001)., Conclusions: Among the 6 studied biomarkers of myocardial stress and inflammation only adiponectin has diagnostic significance in patients with heart failure and preserved ejection fraction.