Recent exome sequencing studies identified filamin C (
) as a candidate gene for hypertrophic cardiomyopathy (HCM). Our aim was to determine the rate of
candidate variants in a large cohort of HCM ...patients who were also sequenced for the main sarcomere genes.
A total of 448 HCM patients were next generation-sequenced (semiconductor chip technology) for the
,
,
,
,
,
,
,
, and
genes. We also sequenced 450 healthy controls from the same population. Based on the reported population frequencies, bioinformatic criteria, and familial segregation, we identified 20
candidate variants (13 new; 1 nonsense; and 19 missense) in 22 patients. Compared with the patients, only 1 of the control's missense variants was nonreported (
=0.007; Fisher exact probability test). Based on the familial segregation and the reported functional studies, 6 of the candidate variants (in 7 patients) were finally classified as likely pathogenic, 10 as variants of uncertain significance, and 4 as likely benign.
We provide a compelling evidence of the involvement of
in the development of HCM. Most of the
variants were associated with mild forms of HCM and a reduced penetrance, with few affected in the families to confirm the segregation. Our work, together with others who found
variants among patients with dilated and restrictive cardiomyopathies, pointed to this gene as an important cause of structural cardiomyopathies.
(1)
: Dilated cardiomyopathy (DCM) mainly affects young individuals and is the main indication of heart transplantation. The variant
of the gene coding for emerin
in chromosome
has been catalogued as ...a pathogenic variant for the development of DCM, exhibiting an X-linked inheritance pattern. (2)
: A retrospective study was conducted covering the period 2015-2023 in patients with DCM of genetic origin. The primary endpoint was patient age at onset of the first composite major cardiac event, in the form of a first episode of heart failure, malignant ventricular arrhythmia, or end-stage heart failure, according to the presence of truncating variant in titin gene
versus the
mutation in the
protein. (3)
: A total of 31 and 22 patients were included in the
group and
group, respectively. The primary endpoint was significantly higher in the
group, with a hazard ratio of 4.16 (95% confidence interval: 1.83-9.46;
= 0.001). At 55 years of age, all the patients in the
group had already presented heart failure, nine presented malignant ventricular arrhythmia (29%), and 13 required heart transplantation (42%). (4)
: DCM secondary to the
mutation in the
gene is associated to an increased risk of major cardiac events compared to patients with DCM due to
, with a large proportion of transplanted patients in the fifth decade of life.
Basal cardiovascular risk assessment in cardio-oncology is essential. Integrating clinical information, ECG and transthoracic echocardiogram can identify concealed inherited cardiomyopathies (ICMPs) ...with potential added risk of cardiotoxicity. We aimed to evaluate the impact of our Cardio-Oncology Unit design in detecting concealed ICMPs.
We carried out a retrospective study of all consecutive breast cancer patients referred to the Cardio-Oncology Unit for cardiac evaluation (2020-2022). ICMPs diagnosis was provided according to ESC guidelines and underwent genetic testing. ICMPs prevalence in this cohort was compared to the highest and lowest frequency reported in the general population.
Among 591 breast cancer patients, we identified eight patients with ICMPs: one arrhythmogenic cardiomyopathy (ACM), three familial non-ischemic dilated cardiomyopathy (DCM), three hypertrophic cardiomyopathy (HCM) and one left ventricular non-compaction cardiomyopathy (LVNC), which has now been reclassified as non-dilated left ventricular cardiomyopathy. The number of ICMPs identified was within the expected range (neither overdiagnosed nor overlooked): ACM 0.0017 vs. 0.0002-0.001 (
0.01-0.593); DCM 0.0051 vs. 0.002-0.0051 (
0.094-0.676); HCM 0.005 vs. 0.0002-0.002 (
< 0.001-0.099); LVCN 0.0017 vs. 0.00014-0.013 (
0.011-0.015). Genetic testing identified a pathogenic
variant and two pathogenic
variants.
Opportunistic screening of ICMPs during basal cardiovascular risk assessment can identify high-risk cancer patients who benefit from personalized medicine and enables extension of prevention strategies to all available relatives at concealed high cardiovascular risk.
Heart transplantation remains the gold standard for the treatment of advanced heart failure (HF). Identification of the etiology of HF is mandatory, as the specific pathology can determine subsequent ...treatment. Early identification of familial hypercholesterolemia (FH), the most common genetic disorder associated with premature cardiovascular disease, has a potential important impact on clinical management and public health. We evaluated the genetic information in the genes associated with FH in a cohort of 140 heart-transplanted patients. All patients underwent NGS genetic testing including
, and
. We identified four carriers of rare pathogenic variants in
and
. Although all four identified carriers had dyslipidemia, only the one carrying the pathogenic variant
c.676T>C was transplanted due to CAD. Another patient with heart valvular disease was carrier of the controversial
c.2096C>T. Two additional patients with non-ischemic dilated cardiomyopathy were carriers of variants in
(c.4672A>G and c.5600G>A). In our cohort, we identified the genetic cause of FH in patients that otherwise would not have been diagnosed. Opportunistic genetic testing for FH provides important information to perform personalized medicine and risk stratification not only for patients but also for relatives at concealed high cardiovascular risk. Including the
gene in standard NGS cardiovascular diagnostics panels should be considered.
Cardiovascular disease (CVD) is the leading cause of death worldwide, with coronary artery disease (CAD) being one of its main manifestations. Both environmental and genetic factors are widely known ...to be related to CAD, such as smoking, diabetes mellitus, dyslipidemia, and a family history of CAD. However, there is still a lack of information about other risk factors, especially those related to genetic mutations. Sex represents a classic CAD risk factor, as men are more likely to suffer CAD, but there is lack of evidence with regard to sex-specific genetic factors. We evaluated the Y chromosome haplogroups in a cohort of young Spanish male patients who suffered from STEMI. In this cohort, haplogroup R was significantly more frequent in STEMI patients.
Long QT syndrome (LQTS) is an inherited (autosomal dominant) channelopathy associated with susceptibility to ventricular arrhythmias due to malfunction of ion channels in cardiomyocytes, that could ...lead to sudden death (SD). Most pathogenic variants are in the main 3 genes:
,
and
. Efforts to improve the understanding of the genotype-phenotype relationship are essential to improve the medical clinical practice. In this study, we identified all index patients referred for NGS genetic sequencing due to LQTS, in a Spanish cohort, who were carriers of a new pathogenic variant (
p.Gly262AlafsTer98). Genetic and clinical family screening was performed in order to describe its phenotypic characteristics. We identified 22 relatives of Romani ethnicity, who were carriers of the variant. Penetrance reached a 100% and adherence to medical treatment was low. There was a high rate of clinical events, particularly arrhythmic events and SD (1 in every 4 patients presented syncope, 1 presented an aborted SD, 2 obligated carriers suffered SD before the age of 40 and 4 out of 6 carriers of an implantable cardioverter-defibrillator (ICD) had appropriate ICD therapies. Correct adherence to medical treatment in all carriers should be specially encouraged in this population. ICD implantation decision in non-compliant patients, and refusing left cardiac sympathetic denervation, should be carefully outweighed.
Hypertrophic cardiomyopathy (HCM) is a monogenic disease with autosomal dominant inheritance. Genotype−phenotype relationships are complex, with variable penetrance even within the same family. The ...involvement of other modulating genetic and environmental factors is unknown. We aimed to analyze the HCM in monozygotic twins, carriers of the same founder pathogenic variant MYBPC3 p.G263*. The relationship was verified using the PowerPlex 16 HS System kit. Phenotypic differences and environmental differences (overloading conditions, coexistence and location, lifestyle, sport, and intensity) were analyzed. Three pairs of twins genetically identical for all markers and carriers of MYBPC3 G263* were identified. No environmental differences were identified. One of the 89-year-old twins had symptomatic severe obstructive HCM that required septal ablation, while her twin has remained asymptomatic with mild phenotype >80 years. A 49-year-old twin had a severe phenotype of obstructive HCM and pending myectomy, while his twin had a mild asymptomatic phenotype. In the last pair of twins, one presented a much larger left ventricular hypertrophy than his identical twin. In summary, we present three pairs of HCM twin patients sharing not only the genetic cause of the inherited disease but the entire genetic background. Despite identical genetic information and the absence of other known clinical, environmental, or lifestyle differences, the severity of the HCM phenotype is strikingly different. These unexplained differences should prompt the study of other unknown modulating factors, either epigenetic or environmental.
Background: In around 40−60% of Hypertrophic Cardiomyopathy (HCM) cases pathogenic variants are not identified. Our aim was to evaluate the possible association of lncRNAs with the risk of developing ...HCM. Methods: We sequenced 10 lncRNAs coding genes that have been associated with cardiovascular disease in a discovery cohort (238 HCM patients and 212 controls) by NGS, and genotyped rs74035787 G>A and rs1424019 A>G polymorphism in a validation cohort (962 HCM patients and 923 controls). Finally, we sequenced the FENDRR promoter by Sanger sequencing. Results: We observed by NGS that FENDRR rs39527, rs39529 and rs40384 polymorphisms were significantly associated with HCM in our cohort (p = 0.0284; OR: 0.24, 95%CI: 0.07−0.86). NGS results were confirmed by genotyping rs74035787 polymorphism (p = 0.001; OR:0.38, 95%CI: 0.21−0.66). Moreover, it is also associated when stratification by sex (p = 0.003; OR:0.20, 95%CI: 0.06−0.53), and age (≥50 years old p = 0.001, OR:0.33, 95%CI: 0.16−0.63) Moreover, the risk of HCM in the carriers of the GG genotype of the rs1424019 polymorphism was significantly higher than that of the AA/AG genotypes carriers in the elderly subjects (p = 0.045, OR:1.24, 95%CI: 1.01−1.53). On the other hand, we observed significant differences in the rs74035787 A/rs1424019 G haplotype frequency (p = 0.0035; OR: 0.20, 95%CI: 0.07−0.59). Conclusions: Our study suggested a significant association between FENDRR gene variants and HCM.
PDF
