α-actinin (ACTN) is a pivotal member of the actin-binding protein family, crucial for the anchoring and organization of actin filaments within the cytoskeleton. Four isoforms of α-actinin exist: two non-muscle isoforms (ACTN1 and ACTN4) primarily associated with actin stress fibers and focal adhesions, and two muscle-specific isoforms (ACTN2 and ACTN3) localized to the Z-disk of the striated muscle. Although these isoforms share structural similarities, they exhibit distinct functional characteristics that reflect their specialized roles in various tissues. Genetic variants in α-actinin isoforms have been implicated in a range of pathologies, including cardiomyopathies, thrombocytopenia, and non-cardiovascular diseases, such as nephropathy. However, the precise impact of these genetic variants on the α-actinin structure and their contribution to disease pathogenesis remains poorly understood. This review provides a comprehensive overview of the structural and functional attributes of the four α-actinin isoforms, emphasizing their roles in actin crosslinking and sarcomere stabilization. Furthermore, we present detailed structural modeling of select ACTN1 and ACTN2 variants to elucidate mechanisms underlying disease pathogenesis, with a particular focus on macrothrombocytopenia and hypertrophic cardiomyopathy. By advancing our understanding of α-actinin's role in both normal cellular function and disease states, this review lays the groundwork for future research and the development of targeted therapeutic interventions.

Hypertrophic cardiomyopathy (HCM) is an inherited cardiac condition affecting ∼1 in 500 and exhibits marked genetic heterogeneity. Previously published in 2019, 57 HCM-associated genes were curated providing the first systematic evaluation of gene-disease validity.

The authors report work by the Clinical Genome Resource Hereditary Cardiovascular Disease (HCVD) Gene Curation Expert Panel (GCEP) to reappraise the clinical validity of previously curated and new putative HCM genes.

The Clinical Genome Resource systematic gene curation framework was used to reclassify the gene-disease relationships for HCM and related syndromic entities involving left ventricular hypertrophy. Genes previously curated were included if their classification was not definitive, and if the time since curation was >2 to 3 years. New genes with literature assertions for HCM were included for initial evaluation. Existing genes were curated for new inheritance patterns where evidence existed. Curations were presented on twice monthly calls, with the HCVD GCEP composed of 29 individuals from 21 institutions across 6 countries.

Thirty-one genes were recurated and an additional 5 new potential HCM-associated genes were curated. Among the recurated genes, 17 (55%) genes changed classification: 1 limited and 4 disputed (from no known disease relationship), 9 disputed (from limited), and 3 definitive (from moderate). Among these, 3 (10%) genes had a clinically relevant upgrade, including TNNC1, a 9th sarcomere gene with definitive HCM association. With new evidence, 2 genes were curated for multiple inheritance patterns (TRIM63, disputed for autosomal dominant but moderate for autosomal recessive; ALPK3, strong for autosomal dominant and definitive for recessive). CSRP3 was curated for a semidominant mode of inheritance (definitive). Nine (29%) genes were downgraded to disputed, further discouraging clinical reporting of variants in these genes. Five genes recently reported to cause HCM were curated: RPS6KB1 and RBM20 (limited), KLHL24 and MT-TI (moderate), and FHOD3 (definitive).

We report 29 genes with definitive, strong, or moderate evidence of causation for HCM or isolated left ventricular hypertrophy, including sarcomere, sarcomere-associated, and syndromic conditions.

Hypertrophic cardiomyopathy (HCM) is an inherited cardiac condition affecting ~1 in 500 and exhibits marked genetic heterogeneity. Previously published in 2019, 57 HCM-associated genes were curated providing the first systematic evaluation of gene-disease validity. Here we report work by the ClinGen Hereditary Cardiovascular Disorders Gene Curation Expert Panel (HCVD-GCEP) to reappraise the clinical validity of previously curated and new putative HCM genes.

The ClinGen systematic gene curation framework was used to re-classify the gene-disease relationships for HCM and related syndromic entities involving left ventricular hypertrophy. Genes previously curated were included if their classification was not definitive, and if the time since curation was >2-3 years. New genes with literature assertions for HCM were included for initial evaluation. Existing genes were curated for new inheritance patterns where evidence existed. Curations were presented on twice monthly calls, with the HCVD-GCEP composed of 29 individuals from 21 institutions across 6 countries.

Thirty-one genes were re-curated and an additional 5 new potential HCM-associated genes were curated. Among the re-curated genes, 17 (55%) genes changed classification: 1 limited and 4 disputed (from no known disease relationship), 9 disputed (from limited), and 3 definitive (from moderate). Among these, 3 (10%) genes had a clinically relevant upgrade, including TNNC1, a 9th sarcomere gene with definitive HCM association. With new evidence, two genes were curated for multiple inheritance patterns (TRIM63, disputed for autosomal dominant but moderate for autosomal recessive; ALPK3, strong for autosomal dominant and definitive for recessive). CSRP3 was curated for a semi-dominant mode of inheritance (definitive). Nine (29%) genes were downgraded to disputed, further discouraging clinical reporting of variants in these genes. Five genes recently reported to cause HCM were curated: RPS6KB1 and RBM20 (limited), KLHL24 and MT-TI (moderate), and FHOD3 (definitive).

We report 29 genes with definitive, strong or moderate evidence of causation for HCM or isolated LVH, including sarcomere, sarcomere-associated and syndromic conditions.

Atrial fibrillation (AFib) is characterized by a complex genetic component. We aimed to investigate the association between variations in genes related to cardiac ion handling and AFib in a cohort of Romanian patients with hypertrophic cardiomyopathy (HCM). Forty-five unrelated probands with HCM were genotyped by targeted next-generation sequencing (NGS) for 24 genes associated with cardiac ion homeostasis. Subsequently, the study cohort was divided into two groups based on the presence (AFib+) or absence (AFiB-) of AFib detected during ECG monitoring. We identified two polymorphisms (rs1805127 located in KCNE1 and rs55742440 located in SCN1B) linked to AFib susceptibility. In AFib+, rs1805127 was associated with increased indexed left atrial (LA) maximal volume (LAVmax) (58.42 ± 21 mL/m2 vs. 32.54 ± 6.47 mL/m2, p < 0.001) and impaired LA strain reservoir (LASr) (13.3 ± 7.5% vs. 24.4 ± 6.8%, p < 0.05) compared to those without respective variants. The rs55742440 allele was less frequent in patients with AFib+ (12 out of 25, 48%) compared to those without arrhythmia (15 out of 20, 75%, p = 0.05). Also, AFib+ rs55742440 carriers had significantly lower LAVmax compared to those who were genotype negative. Among patients with HCM and AFib+, the rs1805127 variant was accompanied by pronounced LA remodeling, whereas rs55742440's presence was related to a milder LA enlargement.

Founder variants in sarcomere protein genes account for a significant proportion of disease-causing variants in patients with hypertrophic cardiomyopathy (HCM). However, information on founder variants in non-sarcomeric protein genes, such as FHOD3, which have only recently been associated with HCM, remains scarce. In this study, we conducted a retrospective analysis of exome sequencing data of 134 probands with HCM for recurrent pathogenic variants. We discovered a novel likely pathogenic variant c.1646+2T>C in FHOD3 in heterozygous state in eight probands with HCM and confirmed its presence in seven additional relatives. Individuals with this variant had a wide range of ages at onset of the disease (4-63 years). No adverse cardiac events were observed. Haplotype analysis revealed that the individuals with this variant shared a genomic region of approximately 5 Mbp surrounding the variant, confirming the founder effect of the variant. FHOD3 c.1646+2T>C is estimated to have arisen 58 generations ago (95% CI: 45-81) in a common ancestor living on the Balkans. A founder FHOD3 c.1646+2T>C variant is the second most common genetic variant in our cohort of patients with HCM, occurring in 16% of probands with a known genetic cause of HCM, which represents a substantially higher proportion than the currently estimated 0.5-2% for causal FHOD3 variants. Our study broadens the understanding of the genetic causes of HCM and may improve the diagnosis of this condition, particularly in patients from the Balkans.

Anomalies of the mitral apparatus have been shown to contribute to left ventricular outflow obstruction in patients with hypertrophic cardiomyopathy (HCM). We report our 5-year single-center experience with a shallow myectomy procedure associated with transaortic mitral valve repair in a cohort of HCM patients.

We studied 83 consecutive patients who underwent surgical treatment of symptomatic left ventricular outflow obstruction. In all study patients, a transaortic shallow septal myectomy was performed. Fibrous or muscular structures connecting the papillary muscles to the septum or free wall were resected, and fibrotic secondary chordae of the anterior mitral valve were cut selectively.

We report one death (1.2%) during hospitalization, no iatrogenic ventricular septal defects, and two (2.4%) mitral valve replacements. At discharge, no patients were in New York Heart Association (NYHA) Class III/IV, from 49 (59%) preoperatively. Mean maximal septal thickness decreased from 24 ± 6 to 16 ± 3 mm. Mean outflow gradient decreased from 93 ± 33 to 13 ± 11 mmHg. Grade 3 or 4 mitral regurgitation was noticed in one patient postoperatively, from 32 (39%) before surgery.

Shallow septal myectomy associated with secondary mitral valve chordal cutting and papillary muscle mobilization provided excellent results offering adequate treatment of outflow obstruction.

Hypertrophic cardiomyopathy (HCM) is a primary disease of the myocardium most commonly caused by mutations in sarcomeric genes. We aimed to perform a nationwide large-scale genetic analysis of a previously unreported, representative HCM cohort in Hungary. A total of 242 consecutive HCM index patients (127 men, 44 ± 11 years) were studied with next generation sequencing using a custom-designed gene-panel comprising 98 cardiomyopathy-related genes. A total of 90 patients (37%) carried pathogenic/likely pathogenic (P/LP) variants. The percentage of patients with P/LP variants in genes with definitive evidence for HCM association was 93%. Most of the patients with P/LP variants had mutations in MYBPC3 (55 pts, 61%) and in MYH7 (21 pts, 23%). Double P/LP variants were present in four patients (1.7%). P/LP variants in other genes could be detected in ≤3% of patients. Of the patients without P/LP variants, 46 patients (19%) carried a variant of unknown significance. Non-HCM P/LP variants were identified in six patients (2.5%), with two in RAF1 (p.Leu633Val, p.Ser257Leu) and one in DES (p.Arg406Trp), FHL1 (p.Glu96Ter), TTN (p.Lys23480fs), and in the mitochondrial genome (m.3243A>G). Frameshift, nonsense, and splice-variants made up 82% of all P/LP MYBPC3 variants. In all the other genes, missense mutations were the dominant form of variants. The MYBPC3 p.Gln1233Ter, the MYBPC3 p.Pro955ArgfsTer95, and the MYBPC3 p.Ser593ProfsTer11 variants were identified in 12, 7, and 13 patients, respectively. These three variants made up 36% of all patients with identified P/LP variants, raising the possibility of a possible founder effect for these mutations. Similar to other HCM populations, the MYBPC3 and the MYH7 genes seemed to be the most frequently affected genes in Hungarian HCM patients. The high prevalence of three MYBPC3 mutations raises the possibility of a founder effect in our HCM cohort.

Drosophila melanogaster (the fruit fly) is arguably a superstar of genetics, an astonishing versatile experimental model which fueled no less than six Nobel prizes in medicine. Nowadays, an evolving research endeavor is to simulate and investigate human genetic diseases in the powerful D. melanogaster platform. Such a translational experimental strategy is expected to allow scientists not only to understand the molecular mechanisms of the respective disorders but also to alleviate or even cure them. In this regard, functional gene orthology should be initially confirmed in vivo by transferring human or vertebrate orthologous transgenes in specific mutant backgrounds of D. melanogaster. If such a transgene rescues, at least partially, the mutant phenotype, then it qualifies as a strong candidate for modeling the respective genetic disorder in the fruit fly. Herein, we review various examples of inter-species rescue of relevant mutant phenotypes of the fruit fly and discuss how these results recommend several human genes as candidates to study and validate genetic variants associated with human diseases. We also consider that a wider implementation of this evolutionist exploratory approach as a standard for the medicine of genetic disorders would allow this particular field of human health to advance at a faster pace.

Hypertrophic cardiomyopathy (HCM) and arterial hypertension (HTN) are conditions with different pathophysiology, but both can result in left-ventricular hypertrophy (LVH). The role of left-atrial (LA) functional changes detected by two-dimensional speckle-tracking echocardiography (STE) in indicating LVH etiology is unknown.

We aimed to characterize LA mechanics using STE in LVH patients with HCM and HTN. LA 2D volumetric and STE parameters were analyzed in 86 LVH patients (43 HCM and 43 isolated HTN subjects) and 33 age- and sex-matched controls.

The volumetric study showed that LA reservoir and conduit function were impaired in the HCM group compared to controls, while, in the HTN group, only LA conduit function was deteriorated. The HCM group had all three STE-derived LA functions impaired compared to controls. The HTN group, consistently with volumetric analysis, had solely LA conduit function reduced compared to controls. Ratios of LA booster-pump strain (S) and strain rate (SR) to interventricular septum (IVS) thickness were the most accurate parameters to discriminate between HCM and HTN. The subgroup harboring sarcomeric pathogenic (P)/likely pathogenic (LP) variants had reduced LA booster-pump S and SR compared with the genotype-negative subgroup.

LA reservoir, conduit, and pump functions are decreased in HCM compared to HTN patients with similar LVH. We report the ratios between LA contraction S/SR and IVS thickness as novel parameters with high accuracy in discriminating LVH due to HCM. The presence of P/LP variants in sarcomeric or sarcomeric-associated genes could be associated with more severe LA dysfunction.

Among inherited cardiac conditions, a special place is kept by cardiomyopathies (CMPs) and channelopathies (CNPs), which pose a substantial healthcare burden due to the complexity of the therapeutic management and cause early mortality. Like other inherited cardiac conditions, genetic CMPs and CNPs exhibit incomplete penetrance and variable expressivity even within carriers of the same pathogenic deoxyribonucleic acid variant, challenging our understanding of the underlying pathogenic mechanisms. Until recently, the lack of accurate physiological preclinical models hindered the investigation of fundamental cellular and molecular mechanisms. The advent of induced pluripotent stem cell (iPSC) technology, along with advances in gene editing, offered unprecedented opportunities to explore hereditary CMPs and CNPs. Hallmark features of iPSCs include the ability to differentiate into unlimited numbers of cells from any of the three germ layers, genetic identity with the subject from whom they were derived, and ease of gene editing, all of which were used to generate "disease-in-a-dish" models of monogenic cardiac conditions. Functionally, iPSC-derived cardiomyocytes that faithfully recapitulate the patient-specific phenotype, allowed the study of disease mechanisms in an individual-/allele-specific manner, as well as the customization of therapeutic regimen. This review provides a synopsis of the most important iPSC-based models of CMPs and CNPs and the potential use for modeling disease mechanisms, personalized therapy and deoxyribonucleic acid variant functional annotation.