Whole-genome sequencing identifies novel candidate pathogenic variants associated with left ventricular non-compaction in a three-generation family.
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ABSTRACT:
SUBMITTER: Zhang Z
PROVIDER: S-EPMC8351521 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Left ventricular non-compaction (LVNC) is a rare cardiomyopathy. Many genetic variants have been associated with LVNC. However, the number of the previous LVNC-associated variants that are common in the background population remains unknown. The aim of this study was to provide an updated list of previously reported LVNC-associated variants with biologic description and investigate the prevalence of LVNC variants in healthy general population to find false-positive LVNC-associated variants.The Human Gene Mutation Database and PubMed were systematically searched to identify all previously reported LVNC-associated variants. Thereafter, the Exome Sequencing Project (ESP) and the Exome Aggregation Consortium (ExAC), that both represent the background population, was searched for all variants. Four in silico prediction tools were assessed to determine the functional effects of these variants. The prediction results of those identified in the ESP and ExAC and those not identified in the ESP and ExAC were compared. In 12 genes, 60 LVNC-associated missense/nonsense variants were identified. MYH7 was the predominant gene, encompassing 24 of the 60 LVNC-associated variants. The ESP only harbored nine and ExAC harbored 18 of the 60 LVNC-associated variants. In total, eight out of nine ESP-positive variants overlapped with the 18 variants identified in ExAC database.In this article, we identified 9 ESP-positive and 18 ExAC-positive variants of 60 previously reported LVNC-associated variants, suggesting that these variants are not necessarily the monogenic cause of LVNC.
| S-EPMC4799875 | biostudies-other
Project description: Not available
| S-EPMC7316563 | biostudies-literature
Project description:Left ventricular non-compaction (LVNC) is a congenital cardiomyopathy characterized by deep ventricular trabeculations thought to be due to an arrest of myocardial morphogenesis. Integration of various cardiac imaging modalities such as echocardiography, cardiac computed tomography and cardiac magnetic resonance imaging help in the diagnosis of this rare clinical entity. We describe a child with rare variant of LVNC with predominant involvement of interventricular septum resulting in multiple ventricular septal defects.
| S-EPMC4590191 | biostudies-literature
Project description:Left ventricle non-compaction cardiomyopathy (LVNC) has gained great interest in recent years, being one of the most controversial cardiomyopathies. There are several open debates, not only about its genetic heterogeneity, or about the possibility to be an acquired cardiomyopathy, but also about its possible overdiagnosis based on imaging techniques. In order to better understand this entity, we identified 38 LVNC patients diagnosed by cardiac MRI (CMRI) or anatomopathological study that could underwent NGS-sequencing and clinical study. Anatomopathological exam was performed in eight available LVNC hearts. The genetic yield was 34.2%. Patients with negative genetic testing had better left ventricular ejection fraction (LVEF) or it showed a tendency to improve in follow-up, and a possible trigger factor for LVNC was identified in 1/3 of them. Nonetheless, cerebrovascular accidents occurred in similar proportions in both groups. We conclude that in LVNC there seem to be different ways to achieve the same final phenotype. Genetic testing has a good genetic yield and provides valuable information. LVNC without an underlying genetic cause may have a better prognosis in terms of LVEF evolution. However, anticoagulation to prevent cerebrovascular accident (CVA) should be carefully evaluated in all patients. Larger series with pathologic examination are needed to help better understand this entity.
| S-EPMC7464545 | biostudies-literature
Project description:Mitochondrial presequence proteases perform fundamental functions as they process about 70 % of all mitochondrial preproteins that are encoded in the nucleus and imported posttranslationally. The mitochondrial intermediate presequence protease MIP/Oct1, which carries out precursor processing, has not yet been established to have a role in human disease.Whole exome sequencing was performed on four unrelated probands with left ventricular non-compaction (LVNC), developmental delay (DD), seizures, and severe hypotonia. Proposed pathogenic variants were confirmed by Sanger sequencing or array comparative genomic hybridization. Functional analysis of the identified MIP variants was performed using the model organism Saccharomyces cerevisiae as the protein and its functions are highly conserved from yeast to human.Biallelic single nucleotide variants (SNVs) or copy number variants (CNVs) in MIPEP, which encodes MIP, were present in all four probands, three of whom had infantile/childhood death. Two patients had compound heterozygous SNVs (p.L582R/p.L71Q and p.E602*/p.L306F) and one patient from a consanguineous family had a homozygous SNV (p.K343E). The fourth patient, identified through the GeneMatcher tool, a part of the Matchmaker Exchange Project, was found to have inherited a paternal SNV (p.H512D) and a maternal CNV (1.4-Mb deletion of 13q12.12) that includes MIPEP. All amino acids affected in the patients' missense variants are highly conserved from yeast to human and therefore S. cerevisiae was employed for functional analysis (for p.L71Q, p.L306F, and p.K343E). The mutations p.L339F (human p.L306F) and p.K376E (human p.K343E) resulted in a severe decrease of Oct1 protease activity and accumulation of non-processed Oct1 substrates and consequently impaired viability under respiratory growth conditions. The p.L83Q (human p.L71Q) failed to localize to the mitochondria.Our findings reveal for the first time the role of the mitochondrial intermediate peptidase in human disease. Loss of MIP function results in a syndrome which consists of LVNC, DD, seizures, hypotonia, and cataracts. Our approach highlights the power of data exchange and the importance of an interrelationship between clinical and research efforts for disease gene discovery.
| S-EPMC5088683 | biostudies-literature
Project description:BackgroundLeft ventricular noncompaction (LVNC) is a genetically and phenotypically heterogeneous cardiomyopathy in which myocardium consists of two, distinct compacted and noncompacted layers, and prominent ventricular trabeculations and deep intertrabecular recesses are present. LVNC is associated with an increased risk of heart failure, atrial and ventricular arrhythmias and thromboembolic events. Familial forms of primary sinus bradycardia have been attributed to alterations in HCN4. There are very few reports about the association between HCN4 and LVNC. The aim of our study was to characterize the clinical phenotype of families with LVNC and sinus bradycardia caused by pathogenic variants of the HCN4 gene.MethodsFrom March 2008 to July 2021, we enrolled six patients from four families with diagnosed isolated LVNC based on the clinical presentation, family history and echocardiographic and cardiovascular magnetic resonance (CMR) evidence of LVNC. Next generation sequencing (NGS) analysis was undertaken for the evaluation of the molecular basis of the disease in each family.ResultsA total of six children (median age 11 years) were recruited and followed prospectively for the median of 12 years. All six patients were diagnosed with LVNC by echocardiography, and five participants additionally by CMR. The presence of late gadolinium enhancement (LGE) was found in three children. Sinus bradycardia and dilation of the ascending aorta occurred in five studied patients. In four patients from three families, the molecular studies demonstrated the presence of rare heterozygous HCN4 variants.Conclusion(1) The HCN4 molecular variants influence the presence of a complex LVNC phenotype, sinus bradycardia and dilation of the ascending aorta. (2) The HCN4 alteration may be associated with the early presentation of clinical symptoms and the severe course of the disease. (3) It is particularly important to assess myocardial fibrosis not only within the ventricles, but also in the atria in patients with LVNC and sinus bradycardia.
| S-EPMC8949387 | biostudies-literature
Project description:BackgroundAs the paucity of data focusing on evaluating cardiac structure and function in patients with or without gene mutation, this study was sought to investigate the correlation between genotype and cardiac magnetic resonance (CMR) phenotype in patients with left ventricular non-compaction cardiomyopathy (LVNC) and to explore prognostic relevance in this cohort if possible.MethodsPatients with LVNC who underwent CMR and targeted gene sequencing between 2006 and 2016 were retrospectively evaluated. Demographic data, clinical presentation, genetic analysis, CMR data and follow-up data of all participants were collected.ResultsCompared to negative genotype (G-) group, patients with positive genotype (G+) had larger left atrial volume (LAV), and carriers of multiple variants had lower left ventricular (LV) ejection fraction and cardiac index, increased LV fibrosis, larger LA volume, reduced LV global circumferential strain, LA reservoir strain and booster pump strain (all p < 0.05). LA volume was able to discriminate patients with G + (all p < 0.05), as well as those with multiple genetic mutation (all p < 0.01). During a median follow-up of 5.1 years, Kaplan-Meier survival analysis revealed worse primary endpoint-free survival among carriers of multiple variants compared to G- group.ConclusionsCMR feature tracking is a remarkable tool to evaluate implication, genetics cascade screen and predict outcome in LVNC population. LA volume is a sensitive and robust indicator for genetic mutational condition, of which facilities to guide clinical management and intensity of follow-up for patients and their relatives.
| S-EPMC8665949 | biostudies-literature
Project description:A 58 years old male with a long-standing history of HLA-B27 positive ankylosing spondylitis presented with increasing fatigue and dyspnea on exertion. He had left ventricular dysfunction and enlargement, flail right coronary leaflet of aortic valve with severe eccentric aortic insufficiency along with left ventricular non-compaction in echocardiography. The most common cardiac manifestations of ankylosing spondylitis are aortic insufficiency and conduction disturbances. Involvement of myocardium, in the form of dilated cardiomyopathy and restrictive cardiomyopathy, has also been reported. This case presents a very rare association of ankylosing spondylitis with non-compaction cardiomyopathy.
| S-EPMC5304103 | biostudies-literature
Project description:BackgroundTitin-truncating variants (TTNtv) have been recognized as the most prevalent genetic cause of dilated cardiomyopathy. However, their effects on phenotypes of left ventricular non-compaction cardiomyopathy (LVNC) remain largely unknown.HypothesisThe presence of TTNtv may have an effect on the phenotype of LVNC.MethodsTTN was comprehensively screened by targeted sequencing in a cohort of 83 adult patients with LVNC. Baseline and follow-up data of all participants were collected. The primary endpoint was a composite of death and heart transplantation. The secondary endpoint was heart failure (HF) events, a composite of HF-related death, heart transplantation, and HF hospitalization.ResultsOverall, 13 TTNtv were identified in 13 patients, with 9 TTNtv located in the A-band of titin. There was no significant difference in baseline characteristics between patients with and without TTNtv. During a median follow-up of 4.4 years, no significant difference in death and heart transplantation between the two groups was observed. However, more HF events occurred in TTNtv carriers than in non-carriers (P = 0.006). Multivariable analyses showed that TTNtv were associated with an increased risk of HF events independent of sex, age, and baseline cardiac function (hazard ratio: 3.25, 95% confidence interval: 1.50-7.01, P = 0.003). Sensitivity analysis excluding non-A-band TTNtv yielded similar results, but with less strength.ConclusionsThe presence of TTNtv may be a genetic modifier of LVNC and confer a higher risk of HF events among adult patients. Studies of larger cohorts are needed to confirm our findings.
| S-EPMC6523007 | biostudies-literature
Project description:Left ventricular non-compaction cardiomyopathy (LVNC) is one of the most common inherited cardiovascular diseases. The genetic backgrounds of most LVNC patients are not fully understood. We collected clinical data, family histories, and blood samples and performed genetic analysis using next-generation sequencing (NGS) from a Chinese family of 15 subjects. Clinically LVNC affected subjects showed marked cardiac phenotype heterogeneity. We found that these subjects with LVNC carried a missense heterozygous genetic mutation c.905G>A (p.R302Q) in γ2 subunit of AMP-activated protein kinase (PRKAG2) gene through NGS. Individuals without this mutation showed no symptoms or cardiac structural abnormalities related to LVNC. One subject was the victim of sudden cardiac death. To sum up, PRKAG2 mutation c.905G>A (p.R302Q) caused familial LVNC. Our results described a potentially pathogenic mutation associated with LVNC, which may further extend the spectrum of LVNC phenotypes related to PRKAG2 gene mutations.
| S-EPMC9552423 | biostudies-literature