1. Introduction
Cardiomyopathies are considered as myocardial diseases with abnormal structure or function of the heart. Cardiomyopathy is a heterogeneous disease due to abnormalities in the function of the heart muscle, and is divided into dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), arrhythmogenic cardiomyopathy (ACM), and left ventricular non-compaction (LVNC) cardiomyopathy [1].
DCM has a prevalence ranging from 1:250 to 1:2500 and is the most common cause of heart failure (HF) leading to heart transplantation worldwide [2,3]. DCM is characterized by dilatation, leading to a loss of contractility and systolic dysfunction in one or both ventricles, but this usually takes the form of left ventricular (LV) dilatation in the absence of hypertension, valvular heart disease, or coronary artery disease [4,5]. DCM is found in 60% of cases of cardiomyopathy in children, with a peak incidence in the first year of life [6]. DCM seriously affects health and often leads to HF or sudden cardiac death in patients [4]. The imaging diagnosis of DCM via echocardiogram is defined by the presence of fractional shortening <25%, left ventricular ejection fraction (LVEF) <45%, and left ventricular end-diastolic diameter >2.7 cm/m2 or >117% predicted [7,8]. Among DCM patients, an estimated 20–50% have a genetic cause [2,9], and emerging data suggest that genotype has an important impact on prognosis and treatment [9]. Echocardiography is an important imaging test in the evaluation of patients with DCM. It provides information that helps in the diagnosis, risk stratification, treatment guidance, and screening of family members [10]. In addition, genetic diagnosis is of increasing importance as it can help predict prognosis, treatment, and prevention. Genetic testing in DCM cases has provided insights into the genetic basis of DCM and improved the knowledge on pathogenesis and genetic counseling for families. DCM is characterized by the inheritance of an autosomal dominant with incomplete penetrance leading to variable expressions of disease in terms of symptom severity and complication risk [2,11]. To date, more than 250 genes have been reported to be associated with the development of DCM, the majority of which are genes encodings proteins important for mitochondrial function and cellular integrity [12], including the genes coding for sarcomeric proteins, Z-disk-associated proteins, cytoskeletal proteins, and nuclear envelope proteins [2,8,11,13,14].
HCM has an estimated prevalence of 1:500 and is characterized by LV wall thickening with an increased number of cardiomyocytes [15]. HCM is usually inherited in an autosomal dominant pattern with variable penetrance [16]. Clinical presentation can vary from patient to patient, even within the same family, ranging from asymptomatic to severe symptoms such as HF or sudden cardiac death (SCD) [17]. The disease can remain clinically asymptomatic for many years, but is also the most common cause of SCD in young people [18]. More than 50 genes have been associated with HCM [19], and most of these genes involve encoded proteins of the sarcomere; the contractile unit of cardiomyocytes [20] explains the cause of disease in 35–60% of HCM patients.
In this study, whole-exome sequencing (WES) was performed to detect variants in disease-related genes in Vietnamese patients with cardiomyopathy. Information on variants in patients will provide a scientific insight on pathogenesis for physicians, resulting in definitive diagnosis, treatment, prevention, and genetic counseling for patients.
2. Materials and Methods
2.1. Patients and Clinical Information
Patients were recruited from nine unrelated families at the Cardiovascular Center, E Hospital, Hanoi, Vietnam. The patients included five girls and four boys, aged 1 to 10 years (mean age 5.33 years), with no family history of cardiomyopathy. Patients had no history of congenital heart disease detected before birth. Based on Doppler ultrasound results and the detailed clinical information listed in Table 1, eight patients were identified as having DCM and one patient as having HCM.
2.2. Exome Sequencing
DNA was extracted from patient blood samples using the Qiagen DNA Blood Mini kit (QIAGEN, Hilden, Germany). WES was performed using the SureSelect Human All Exon V7 kit with a library enriched using the SureselectXT Reagent kit (Agilent, Santa Clara, CA, USA). Data were aligned and compared with the human reference genome sequence version Hg19 using BWA 0.7.17 software (
2.3. Sanger Sequencing
Sanger sequencing was performed to confirm variants identified by WES in the sample against samples from the patients’ families. Primer pairs for polymerase chain reaction and Sanger sequencing were designed using Priemer3 Plus software (
2.4. Prediction Analysis
The influence of any nucleotide changes was evaluated with the following in silico analysis tools: CADD (
A comparison of the protein sequences was performed using Clustal X2.1 software (
3. Results
In our study, nine patients from unrelated Vietnamese families were collected for investigation. Patients had no family history of cardiomyopathy and were diagnosed based on echocardiography (Table 1). The earliest-diagnosed patient was diagnosed at 12 days of age (patient P8) and the latest at nine years of age (patient P1). Among the studied patients, eight were diagnosed with DCM and one with HCM. WES was performed on patient samples and nine heterozygous variants were identified in the following genes: ANK2 (c.9161C>G, p.Ala3054Gly), MYL2 (c.284C>G, p.Pro95Arg), MYOZ2 (c.326C>G, p.Pro109Arg), MYH7 (c.602T>C, p.Ile201Thr and c.2356A>G, p.Thr786Ala), PTPN11 (c.1391G>C, p.Gly464Ala), ACTA2 (c.623G>A, p.Arg208His), PRKAG2 (c.83A>C, p.His28Pro), and DES (c.1223T>A, p.Leu408Gln) (Table 2). Three novel variants (c.284C>G, p.Pro95Arg in the MYL2 gene, c.2356A>G, p.Thr786Ala in the MYH7 gene, and c.1223T>A, p.Leu408Gln in the DES gene) were found in the patients. The variants in the MYH7 gene (c.602T>C, p.Ile201Thr, rs397516258) and in the PTPN11 gene (c.1391G>C, p.Gly464Ala, rs121918469) are identified as a pathogenic variants on the ClinVar database (under accession numbers VCV000043093.22 and VCV000013343.48, respectively). Four rare variants (with MAF<0.001) in the ANK2, MYOZ2, ACTA2, and PRKAG2 genes have been reported in dbSNP data under accession numbers rs139007578, rs546999011, rs1057521703, and rs138051386, respectively, but are not evaluated on the ClinVar database. The Sanger sequencing results showed that the variants were either de novo in patients P2 and P5 or inherited from the asymptomatic father in patients P6 and P7 (Figure 1).
The evaluation results for the variants using the prediction software (Table 3) showed that the novel variants were pathogenic, so these variants were considered to be the cause of disease in the patients. For the variants not yet evaluated in the ClinVar database, the variants in the ANK2 and ACTA2 genes were also considered pathogenic by the software. Variant c.326C>G, p.Pro109Arg in the MYOZ2 gene is considered pathogenic by FATHMM MKL, MCAP, Mutation Taster, PolyPhen 2, and CADD, but as neutral by FATHMM, Meta, PROVEAN, SIFT, and SNP&GO. Likewise, variant c.83A>C, p.His28Pro in the PRKAG2 gene was evaluated as pathogenic by almost all software (FATHMM, MCAP, Mutation taster, SIFT, and CADD), but on the contrary as neutral by Meta and PROVEAN, and benign by PolyPhen2.
A similarity analysis of the protein sequences also showed that the variants were located in regions that were highly conserved between species (Figure 2). Therefore, changes in amino acids in these regions can lead to changes in the structure and function of the protein. Moreover, 3D structure analysis showed that the substitution of the amino acid Proline with Arginine at position 95 in the MYL2 protein also resulted in the formation of an additional hydrogen bond between this amino acid and Threonine at position 98 (Figure 3A). Figure 3B showed that the replacement of the amino acid Glycine with Alanine at position 464 in the PTPN11 protein resulted in the formation of an additional hydrogen bond between this amino acid and Glycine at position 467. Meanwhile, the replacement of the amino acid Arginine with Histidine at position 208 in the ACTA2 protein only resulted in the formation of an additional weak bond between this amino acid and the amino acid Threonine at position 204 (Figure 3C). This was also observed in the case of the substitution of Leucine with Glutamine at position 408 in the DES protein, which resulted in the formation of a weak bond between this amino acid and Tyrosine at position 405 (Figure 3E). In contrast, substituting the amino acid Threonine with Alanine at position 786 in the MYH7 protein resulted in the loss of two hydrogen bonds between this amino acid and the amino acids Arginine and Serine at positions 783 and 782, respectively (Figure 3D).
4. Discussion
In this study, the patients were diagnosed with DCM or HCM by cardiac Doppler ultrasound. The patients included five girls and four boys, aged from 1 to 10 years old (mean age was 5.33 years old), and had no family history of cardiomyopathy. WES identified nine heterozygous variants in related genes (ANK2, MYL2, MYOZ2, MYH7, PTPN11, ACTA2, PRKAG2, and DES) that were the cause of disease in patients. Among them, two variants (c.602T>C, p.Ile201Thr in the MYH7 gene (patient P4) and c.1391G>C, p.Gly464Ala in the PTPN11 gene (patient P5)) are reported as pathogenic in the ClinVar database. The results of assessing the harmfulness of the found variants (Table 3) showed that three novel variants (MYL2 (c.284C>G, p.Pro95Arg) (patient P2), MYH7 (c.2356A>G, p.Thr786Ala) (patient P7), and DES (c.1223T>A, p.Leu408Gln) (patient P9)) were pathogenic variants. Of the five unevaluated variants, two variants (ANK2 (c.0161C>G, p.Ala3054Gly) (patient P1) and ACTA2 (c.623G>A, p.Arg208His) (patient P6)) were evaluated as pathogenic variants by in silico prediction software. Two variants (MYOZ2 (c.326C>G, p.Pro109Arg) (patient P3) and PRKAG2 (c.83A>C, p.His28Pro) (patient P8)) were also considered as pathogenic by most of the software.
The role of the ANK2 gene has also been reported in patients with DCM [21]. However, variants in the MYOZ2 and PRKAG2 genes are commonly reported in patients with HCM [22,23]. Several recent studies have shown that variants in the MYL2 gene are also detected in patients with DCM [24]. The MYL2, MYOZ2, and PRKAG2 genes were also included in a 111-gene panel to screen for variants associated with DCM in the study by McNally and Mestroni [8]. It is noteworthy that the ACTA2 gene encodes specific α-smooth muscle actin, which is an isoform of vascular smooth muscle actin. This mutation mainly leads to aortic pathologies, but it also presents multisystemic smooth muscle dysfunction [25]. The ACTA2 variant is the main cause of familial thoracic aortic aneurysms and dissection [26]. However, a variant (c.623G>A, p.Arg208His) in the ACTA2 gene was found in one patient in our study. This result may be due to variations in the ACTA2 gene that present multisystemic smooth muscle dysfunction, and these findings in our study may provide new insights into the role of these genes in the pathogenesis of DCM.
Molecular and genetic studies have established that at least 40% of DCM cases are due to genetic variants [8,26]. Various genes, particularly genes for myocyte membrane factors, contractile factors, Z-disc factors, myofibrillar factors, and nuclear membrane factors, can contain pathogenic variants contributing to the pathogenesis of hereditary DCM. These effects have subsequently been demonstrated in various DCM-causing variants in actin, troponin, and tropomyosin, and appear to be a general property of muscle proteins [27]. Most DCM genes are inherited in an autosomal dominant manner and have incomplete penetrance [2]. Notably, genetic causes are identified more commonly in pediatric patients than in adults (54% versus 27%) [28]. DCM is characterized by different disease manifestations in terms of time of disease onset, severity of symptoms, and risk of complications, which creates disease heterogeneity in patients [26]. Although there is a correlation between genotype and phenotype, there are large differences between people carrying the same genetic variant, even within families [29]. A significant proportion of DCM patients (20–38%) may have an oligogenic basis due to carrying multiple rare variants from unlinked loci with varying penetrance, resulting in a similar phenotype [14]. In recent years, studies have shown that the incomplete penetrance of different variants leads to differences in clinical manifestations in patients, especially in cardiomyopathy [30,31,32]. Genetic testing for cardiomyopathy has a diagnostic yield of up to 40%, but is challenging due to genetic heterogeneity, variable expressivity, and incomplete penetrance. Genotype-positive and phenotype-negative relatives are candidates for serial evaluation, with frequency varying with age [33]. McGurk et al. [34] pointed out that understanding the penetrance of pathogenic variants as secondary findings (SFs) will be important as genetic testing becomes more widespread. The authors estimated that the penetrance in late adulthood of rare pathogenic variants (23% for HCM and 35% for DCM) and likely pathogenic variants (7% for HCM, 10% for DCM) is significant in dominant cardiomyopathy. The penetrance of variants in genes associated with HCM is significantly higher for loss-of-function or rare variants and higher in males than females. Similarly, Cabrera-Romero et al. [35] evaluated penetrance and disease risk in 779 patients who carried variants of TTN but did not present with DCM. The authors also point out that the relationship between age and incomplete penetrance in disease expression leads to major challenges in disease management. This may also explain the cause of disease in the patients in our study, especially the two cases (patient P6 and P7) where the Sanger sequencing results showed that the patients’ fathers also carried the variant but did not show symptoms of the disease.
In our study, patient P5 was diagnosed with HCM, and genetic analysis showed that the patient carried a pathogenic variant in the PTPN11 gene. Variants in the PTPN11 gene, which encodes protein–tyrosine phosphatase, nonreceptor type 11, have also been reported to cause HCM in patients [36]. Although HCM is generally a relatively benign disease that may remain asymptomatic for many years, HCM carries a high risk of leading to SCD, with a leading mortality rate in the young [37]. The most devastating complication of HCM is that it is the cause of SCD in young people when the disease first appears [38]. A current challenge is the incomplete understanding of genetic variations in genes associated with HCM; thus, genetic testing is of great significance in identifying at-risk individuals early before clinical disease onset. Understanding the pathogenesis of HCM allows for the development of treatments, possible prevention, clinical management, and genetic counseling for patients.
5. Conclusions
In this study, nine pathogenic variants, including three novel variants, were identified in the genes ANK2, MYL2, MYOZ2, MYH7, PTPN11, ACTA2, PRKAG2, and DES, which were considered the cause of disease in patients with DCM and HCM. Our results contribute to understanding the pathogenesis of cardiomyopathy and provide a basis for diagnosis, prevention, and the development of treatments.
Conceptual framework design, D.D.T. and N.T.K.L.; writing—original draft preparation, N.T.K.L.; writing—review and editing, D.D.T., N.T.K.L., N.C.H., P.T.N., L.T.T., N.M.D. and N.H.H.; data curation, investigation, D.D.T., D.A.T., D.T.H.T., B.Q.H., T.T.K.O., N.T.P.L., N.T.H. and N.N.L.; methodology, software, N.T.K.L. and N.V.T. All authors have read and agreed to the published version of the manuscript.
This study was conducted in accordance with the Declaration of Helsinki and ved by the Ethics Committee of the Institute of Genome Research (Approval No. 02-2021/NCHG-HDDD. Approval date: 29 October 2021).
Written informed consent was obtained from the patients’ parents for the publication of any potentially identifiable images or data included in the article.
Data is contained within the article or
We would like to thank the patients and their families who participated in this study.
The authors declare no conflicts of interest.
Footnotes
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.
Figure 1. Sanger sequencing result confirms p.Pro95Arg in the MYL2 gene in family members of patient P2 (A); p.Gly464Ala variant in the PTPN11 gene in family members of patient P5 (B); p.Arg208His in the ACTA2 gene in family members of patient P6 (C); and p.Thr786Ala in the MYH7 gene in family members of patient P7 (D).
Figure 2. Multiple alignment of the proteins from human and other species by Clustal-X2. Multiple alignments of the MYL2, MYOZ2, MYH7, PTPN11, ACTA2, PRKAG2, and DES proteins at the positions of variants based on amino acid sequences from different species, including Homo sapiens, Cricetulus griseus, Sus scrofa, Canis lupus, Equus caballus, Bos taurus, Mus musculus, Gallus gallus, and Rattus norvegicus.
Figure 3. Three-dimensional structure of the proteins predicted by Swiss-Pdb Viewer. (A) Mutant type of MYL2 protein with the formation of one more strong H bond (in green color) between Arg95 and Thr98. (B) Mutant type of PTPN11 protein with the formation of one more strong H bond (in green color) between Ala464 and Gly467. (C) Mutant type of ACTA2 protein with the formation of one more weak H bond (in pink color) between His208 and Thr204. (D) Mutant type of MYH7 protein with the loss of two strong H bonds (in green color) between Ala786 with Ser782 and Arg783. (E) Mutant type of DES protein with the formation of one more weak H bond (in pink color) between Gln408 and Tyr405.
Clinical information of patients in the study.
Patient | Sex/Age | Rapid Heart Rate (bpm) | Sp02 (%) | EF (%) | Dd (mm) | NT-ProBNP | Right Ventricular TAPSE (mm) | Diagnosed |
---|---|---|---|---|---|---|---|---|
P1 | Female | 60 | 94 | 18 | 59 | 7260 | 20 | DCM at 9 years old |
P2 | Female | 178 | 97 | 30 | 37 | - | - | DCM at 2 months of age |
P3 | Male | 150 | 97 | 30 | 32 | - | 12 | DCM at 5 years old |
P4 | Female | 132 | 98 | 16 | 58 | 854 | - | DCM at 8 months of age |
P5 | Female | 130 | 98 | 90 | 17 | - | - | HCM at 20 days old |
P6 | Female | 120 | 98 | 23 | 46 | - | - | DCM at 1 year old |
P7 | Male | 100 | 98 | 23 | 54 | 9496 | - | DCM at 6 years old |
P8 | Male | 132 | 98 | 85 | 29 | - | - | DCM at 12 days old |
P9 | Male | 100 | 98 | 14 | 57 | 28,835 | 8 | DCM at 8 years old |
Variants identified in the patients.
Patient | Gene | cDNA | Protein | dbSNP/MAF | ClinVar |
---|---|---|---|---|---|
P1 | ANK2 | c.9161C>G | p.Ala3054Gly | rs139007578 | Uncertain significance |
P2 | MYL2 | c.284C>G | p.Pro95Arg | novel | |
P3 | MYOZ2 | c.326C>G | p.Pro109Arg | rs546999011 | Uncertain significance |
P4 | MYH7 | c.602T>C | p.Ile201Thr | rs397516258 | Pathogenic |
P5 | PTPN11 | c.1391G>C | p.Gly464Ala | rs121918469 | Pathogenic |
P6 | ACTA2 | c.623G>A | p.Arg208His | rs1057521703 | Uncertain significance |
P7 | MYH7 | c.2356A>G | p.Thr786Ala | novel | |
P8 | PRKAG2 | c.83A>C | p.His28Pro | rs138051386 | Uncertain significance |
P9 | DES | c.1223T>A | p.Leu408Gln | novel |
Prediction results using in silico prediction software.
Gene/Variants | ANK2 | MYL2 | MYOZ2 | ACTA2 | MYH7 | PRKAG2 | DES |
---|---|---|---|---|---|---|---|
dbSNP | rs139007578 | Novel | rs546999011 | rs1057521703 | Novel | rs138051386 | Novel |
FATHMM | −4.18 | −1.20 | −0.02 | −3.50 | −3.14 | −2.30 | −3.82 |
FATHMM MKL | 0.911 | 0.964 | 0.994 | 0.987 | 0.979 | 0.616 | 0.985 |
MCAP | 0.393 | - | 0.060 | 0.558 | 0.690 | 0.061 | 0.298 |
Meta | 1.061 | - | −0.171 | 0.989 | 0.526 | −0.639 | 1.086 |
Meta LR | 0.939 | - | 0.446 | 0.909 | 0.764 | 0.433 | 0.959 |
Mutation assess | 2.515 | - | 3.205 | 2.030 | 3.160 | - | 4.920 |
Mutation taster | 0.863 | 1.000 | 1.000 | 0.999 | 0.999 | 0.999 | |
PolyPhen 2 | 1.000 | 0.993 | 0.988 | 0.992 | 0.096 | 0.118 | 0.999 |
PROVEAN | −1.68 | −6.38 | −2.100 | −3.550 | −3.760 | 0.760 | −5.110 |
SIFT | 0.017 | 0.000 | 0.063 | - | 0.001 | 0.044 | 0.000 |
SNP&GO | - | R10 | R5 | R2 | R10 | - | R9 |
CADD | 24.8 | 26.1 | 27.6 | 33.0 | 23.8 | 16.9 | 31.0 |
Supplementary Materials
The following supporting information can be downloaded at:
References
1. Maron, B.J.; Towbin, J.A.; Thiene, G.; Antzelevitch, C.; Corrado, D.; Arnett, D.; Moss, A.J.; Seidman, C.E.; Young, J.B. Contemporary definitions and classification of the cardiomyopathies: An American heart association scientific statement from the council on clinical cardiology, heart failure and transplantation committee; quality of care and outcomes research and functional genomics and translational biology interdisciplinary working groups; and council on epidemiology and prevention. Circulation; 2006; 113, pp. 1807-1816. [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/16567565]
2. Hershberger, R.E.; Hedges, D.J.; Morales, A. Dilated cardiomyopathy: The complexity of a diverse genetic architecture. Nat. Rev. Cardiol.; 2013; 10, pp. 531-547. [DOI: https://dx.doi.org/10.1038/nrcardio.2013.105] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23900355]
3. Reichart, D.; Magnussen, C.; Zeller, T.; Blankenberg, S. Dilated cardiomyopathy: From epidemiologic to genetic phenotypes: A translational review of current literature. J. Intern. Med.; 2019; 286, pp. 362-372. [DOI: https://dx.doi.org/10.1111/joim.12944] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31132311]
4. Elliott, P.; Andersson, B.; Arbustini, E.; Bilinska, Z.; Cecchi, F.; Charron, P.; Dubourg, O.; Kühl, U.; Maisch, B.; McKenna, W.J. Classification of the cardiomyopathies: A position statement from the European Society Of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur. Heart J.; 2008; 29, pp. 270-276. [DOI: https://dx.doi.org/10.1093/eurheartj/ehm342]
5. Pinto, Y.M.; Elliott, P.M.; Arbustini, E.; Adler, Y.; Anastasakis, A.; Böhm, M.; Duboc, D.; Gimeno, J.; de Groote, P.; Imazio, M. et al. Proposal for a revised definition of dilated cardiomyopathy, hypokinetic non-dilated cardiomyopathy, and its implications for clinical practice: A position statement of the ESC working group on myocardial and pericardial diseases. Eur. Heart J.; 2016; 37, pp. 1850-1858. [DOI: https://dx.doi.org/10.1093/eurheartj/ehv727]
6. Towbin, J.A.; Lowe, A.M.; Colan, S.D.; Sleeper, L.A.; Orav, E.J.; Clunie, S.; Messere, J.; Cox, G.F.; Lurie, P.R.; Hsu, D. et al. Incidence, causes, and outcomes of dilated cardiomyopathy in children. JAMA; 2006; 296, pp. 1867-1876. [DOI: https://dx.doi.org/10.1001/jama.296.15.1867]
7. Mestroni, L.; Maisch, B.; McKenna, W.; Schwartz, K.; Charron, P.; Rocco, C.; Tesson, F.; Richter, R.; Wilke, A.; Komajda, M. et al. Guidelines for the study of familial dilated cardiomyopathies. Eur. Heart J.; 1999; 20, pp. 93-102. [DOI: https://dx.doi.org/10.1053/euhj.1998.1145]
8. McNally, E.M.; Mestroni, L. Dilated cardiomyopathy genetic determinants and mechanisms. Circ. Res.; 2017; 121, pp. 731-748. [DOI: https://dx.doi.org/10.1161/CIRCRESAHA.116.309396]
9. de Gonzalo-Calvo, D.; Quezada, M.; Campuzano, O.; Perez-Serra, A.; Broncano, J.; Ayala, R.; Ramos, M.; Llorente-Cortes, V.; Blasco-Turrión, S.; Morales, F.J. et al. Familial dilated cardiomyopathy: A multidisciplinary entity, from basic screening to novel circulating biomarkers. Int. J. Cardiol.; 2017; 228, pp. 870-880. [DOI: https://dx.doi.org/10.1016/j.ijcard.2016.11.045]
10. Fatkin, D.; Yeoh, T.; Hayward, C.S.; Benson, V.; Sheu, A.; Richmond, Z.; Feneley, M.P.; Keogh, A.M.; Macdonald, P.S. Evaluation of left ventricular enlargement as a marker of early disease in familial dilated cardiomyopathy. Circ. Cardiovasc. Genet.; 2011; 4, pp. 342-348. [DOI: https://dx.doi.org/10.1161/CIRCGENETICS.110.958918]
11. McNally, E.M.; Golbus, J.R.; Puckelwartz, M.J. Genetic mutations and mechanisms in dilated cardiomyopathy. J. Clin. Investig.; 2013; 123, pp. 19-26. [DOI: https://dx.doi.org/10.1172/JCI62862] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23281406]
12. Gu, J.N.; Yang, C.X.; Ding, Y.Y.; Qiao, Q.; Di, R.M.; Sun, Y.M.; Wang, J.; Yang, L.; Xu, Y.J.; Yang, Y.Q. Identification of BMP10 as a novel gene contributing to dilated cardiomyopathy. Diagnostics; 2023; 13, 242. [DOI: https://dx.doi.org/10.3390/diagnostics13020242] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/36673052]
13. Bucic, D.; Bakos, M.; Ramadza, D.P.; Bartonicek, D.; Dilber, D.; Rubic, F.; Belina, D.; Rako, I.; Jercic, K.G.; Borovecki, F. et al. De novo mutation in desmin gene causing dilated cardiomyopathy requiring ECMO treatment: A clinical report. Hum. Gene; 2024; 39, 201265. [DOI: https://dx.doi.org/10.1016/j.humgen.2024.201265]
14. Eldemine, R.; Mestroni, L.; Taylor, M.R.G. Genetics of dilated cardiomyopathy. Annu. Rev. Med.; 2024; 75, pp. 417-426. [DOI: https://dx.doi.org/10.1146/annurev-med-052422-020535]
15. Kaviarasan, V.; Mohammed, V.; Veerabathiran, R. Genetic predisposition study of heart failure and its association with cardiomyopathy. Egypt Heart J.; 2022; 74, 5. [DOI: https://dx.doi.org/10.1186/s43044-022-00240-6]
16. Claes, G.R.F.; van Tienen, F.H.J.; Lindsey, P.; Krapels, I.P.C.; Helderman-van den Enden, A.T.J.M.; Hoos, M.; Barrois, Y.E.G.; Janssen, J.W.H.; Paulussen, A.D.C.; Sels, J.W.E.M. et al. Hypertrophic remodelling in cardiac regulatory myosin light chain (MYL2) founder mutation Carriers. Eur. Heart J.; 2016; 37, pp. 1815-1822. [DOI: https://dx.doi.org/10.1093/eurheartj/ehv522]
17. Andersen, P.S.; Havndrup, O.; Hougs, L.; Sorensen, K.M.; Jensen, M.; Larsen, L.A.; Hedley, L.A.; Thomsen, A.R.B.; Moolman-Smook, J.; Christiansen, M. et al. Diagnostic yield, interpretation, and clinical utility of mutation screening of sarcomere encoding genes in Danish hypertrophic cardiomyopathy patients and relatives. Hum. Mutat.; 2009; 30, pp. 363-370. [DOI: https://dx.doi.org/10.1002/humu.20862]
18. Marian, A.J.; Braunwald, E. Hypertrophic cardiomyopathy: Genetics, pathogenesis, clinical manifestations, diagnosis, and therapy. Circ. Res.; 2017; 121, pp. 749-770. [DOI: https://dx.doi.org/10.1161/CIRCRESAHA.117.311059]
19. Roma-Rodrigues, C.; Fernandes, A.R. Genetics of hypertrophic cardiomyopathy: Advances and pitfalls in molecular diagnosis and therapy. Appl. Clin. Genet.; 2014; 7, pp. 195-208.
20. Gruner, C.; Ivanov, J.; Care, M.; Williams, L.; Moravsky, G.; Yang, H.; Laczay, B.; Siminovitch, K.; Woo, A.; Rakwoski, H. Toronto hypertrophic cardiomyopathy genotype score for prediction of a positive genotype in hypertrophic cardiomyopathy. Circ. Cardiovasc. Genet.; 2013; 6, pp. 19-26. [DOI: https://dx.doi.org/10.1161/CIRCGENETICS.112.963363]
21. York, N.S.; Sanchez-Arias, J.C.; McAdam, A.C.H.; Rivera, J.E.; Arbour, L.T.; Swayne, L.A. Mechanisms underlying the role of ankyrin-B in cardiac and neurological health and disease. Front. Cardiovasc. Med.; 2022; 9, 964675. [DOI: https://dx.doi.org/10.3389/fcvm.2022.964675] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/35990955]
22. Ruggiero, A.; Chen, S.N.; Lombardi, R.; Rodriguez, G.; Marian, A.J. Pathogenesis of hypertrophic cardiomyopathy caused by myozenin 2 mutations is independent of calcineurin activity. Cardiovasc. Res.; 2013; 97, pp. 44-54. [DOI: https://dx.doi.org/10.1093/cvr/cvs294] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/22987565]
23. Yang, K.Q.; Lu, C.X.; Zhang, Y.; Yang, Y.; Li, K.C.; Lan, T.; Meng, X.; Fan, P.; Tian, T.; Wang, L.P. et al. A novel PRKAG2 mutation in a Chinese family with cardiac hypertrophy and ventricular preexcitation. Sci. Rep.; 2017; 7, 2407.
24. Yadav, S.; Sitbon, Y.H.; Kazmierczak, K.; Cordary, D.S. Hereditary heart disease: Pathophysiology, clinical presentation, and animal models of HCM, RCM and DCM associated with mutations in cardiac myosin light chains. Pflug. Arch.; 2019; 471, pp. 683-699. [DOI: https://dx.doi.org/10.1007/s00424-019-02257-4] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30706179]
25. Petrova, I.; Keltchevb, A.; Stankova, Z.; Vasilev, S. The journey of a patient with ACTA2 mutation—Literature review and case report. Cor. Vasa; 2022; 64, pp. 619-621. [DOI: https://dx.doi.org/10.33678/cor.2022.023]
26. Lee, J.H.; Lee, S.E.; Cho, M.C. Clinical implication of genetic testing in dilated cardiomyopathy. Int. J. Heart Fail; 2022; 4, pp. 1-11. [DOI: https://dx.doi.org/10.36628/ijhf.2021.0024]
27. Messer, A.E.; Marston, S.B. Investigating the role of uncoupling of troponin 1 phosphorylation from changes in myofibrillar Ca2+-sensitivity in the pathogenesis of cardiomyopathy. Front. Physiol.; 2014; 5, 315. [DOI: https://dx.doi.org/10.3389/fphys.2014.00315]
28. Towbin, J.A. Pediatric primary dilated cardiomyopathy gene testing and variant reclassification: Does it matter?. J. Am. Heart Assoc.; 2020; 9, e016910. [DOI: https://dx.doi.org/10.1161/JAHA.120.016910]
29. Hänselmann, A.; Veltmann, C.; Bauersachs, J.; Berliner, D. Dilated cardiomyopathies and non-compaction cardiomyopathy. Herz.; 2020; 45, pp. 212-220. [DOI: https://dx.doi.org/10.1007/s00059-020-04903-5]
30. Semsarian, C.; Semsarian, C.R. Variable penetrance in hypertrophic cardiomyopathy. J. Am. Coll. Cardiol.; 2020; 76, pp. 560-562. [DOI: https://dx.doi.org/10.1016/j.jacc.2020.06.023]
31. Kingdom, R.; Wright, C.F. Incomplete penetrance and variable expressivity: From clinical studies to population cohorts. Front. Genet.; 2022; 13, 920390. [DOI: https://dx.doi.org/10.3389/fgene.2022.920390] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/35983412]
32. Topriceanu, C.C.; Pereira, A.C.; Moon, J.C.; Captur, G.; Ho, C.Y. Meta-analysis of penetrance and systematic review on transition to disease in genetic hypertrophic cardiomyopathy. Circulation; 2024; 149, pp. 107-123. [DOI: https://dx.doi.org/10.1161/CIRCULATIONAHA.123.065987] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/37929589]
33. Furquim, S.R.; Linnenkamp, B.; Olivetti, N.Q.S.; Giugni, F.R.; Lipari, L.F.V.P.; Andrade, F.A.; Krieger, J.E. Challenges and applications of genetic testing in dilated cardiomyopathy: Genotype, phenotype and clinical implications. Arq. Bras. Cardiol.; 2023; 120, e20230174. [DOI: https://dx.doi.org/10.36660/abc.20230174] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/38055534]
34. McGurk, K.A.; Zhang, X.; Theotokis, P.; Thomson, K.; Harper, A.; Buchan, R.J.; Mazaika, E.; Ormondroyd, E.; Wright, W.T.; Macaya, D. et al. The penetrance of rare variants in cardiomyopathy-associated genes: A cross-sectional approach to estimating penetrance for secondary findings. Am. J. Hum. Genet.; 2023; 110, pp. 1482-1495. [DOI: https://dx.doi.org/10.1016/j.ajhg.2023.08.003] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/37652022]
35. Cabrera-Romero, E.; Ochoa, J.P.; Barriales-Villa, R.; Bermúdez-Jiménez, F.J.; Climent-Payá, V.; Zorio, E.; Espinosa, M.; Gallego-Delgado, A.M.; Navarro-Peñalver, M.; Arana-Achaga, X. et al. Penetrance of dilated cardiomyopathy in genotype-positive relatives. J. Am. Coll. Cardiol.; 2024; 83, pp. 1640-1651. [DOI: https://dx.doi.org/10.1016/j.jacc.2024.02.036]
36. Teekakirikul, P.; Zhu, W.; Huang, H.C.; Fung, E. Hypertrophic cardiomyopathy: An overview of genetics and management. Biomolecules; 2019; 9, 878. [DOI: https://dx.doi.org/10.3390/biom9120878]
37. Gersh, B.J.; Maron, B.J.; Bonow, R.O.; Dearani, J.A.; Fifer, M.A.; Link, M.S.; Naidu, S.S.; Nishimura, R.A.; Ommen, S.R.; Rakowski, H. et al. 2011 ACCF/AHA Guideline for the Diagnosis and Treatment of Hypertrophic Cardiomyopathy. J. Am. Coll. Cardiol.; 2011; 58, pp. e212-e260. [DOI: https://dx.doi.org/10.1016/j.jacc.2011.06.011]
38. Maron, B.J.; Doerer, J.J.; Haas, T.S.; Tierney, D.M.; Mueller, F.O. Sudden deaths in young competitive athletes analysis of 1866 deaths in the united states, 1980–2006. Circulation; 2009; 119, pp. 1085-1092. [DOI: https://dx.doi.org/10.1161/CIRCULATIONAHA.108.804617]
You have requested "on-the-fly" machine translation of selected content from our databases. This functionality is provided solely for your convenience and is in no way intended to replace human translation. Show full disclaimer
Neither ProQuest nor its licensors make any representations or warranties with respect to the translations. The translations are automatically generated "AS IS" and "AS AVAILABLE" and are not retained in our systems. PROQUEST AND ITS LICENSORS SPECIFICALLY DISCLAIM ANY AND ALL EXPRESS OR IMPLIED WARRANTIES, INCLUDING WITHOUT LIMITATION, ANY WARRANTIES FOR AVAILABILITY, ACCURACY, TIMELINESS, COMPLETENESS, NON-INFRINGMENT, MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE. Your use of the translations is subject to all use restrictions contained in your Electronic Products License Agreement and by using the translation functionality you agree to forgo any and all claims against ProQuest or its licensors for your use of the translation functionality and any output derived there from. Hide full disclaimer
© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.
Abstract
Background: Cardiomyopathy, including dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM), is a major cause of heart failure (HF) and a leading indication for heart transplantation. Of these patients, 20–50% have a genetic cause, so understanding the genetic basis of cardiomyopathy will provide knowledge about the pathogenesis of the disease for diagnosis, treatment, prevention, and genetic counseling for families. Methods: This study collected nine patients from different Vietnamese families for genetic analysis at The Cardiovascular Center, E Hospital, Hanoi, Vietnam. The patients were diagnosed with cardiomyopathy based on clinical symptoms. Whole-exome sequencing (WES) was performed in the Vietnamese patients to identify variants associated with cardiomyopathy, and the Sanger sequencing method was used to validate the variants in the patients’ families. The influence of the variants was predicted using in silico analysis tools. Results: Nine heterozygous variants were detected as a cause of disease in the patients, three of which were novel variants, including c.284C>G, p.Pro95Arg in the MYL2 gene, c.2356A>G, p.Thr786Ala in the MYH7 gene, and c.1223T>A, p.Leu408Gln in the DES gene. Two other variants were pathogenic variants (c.602T>C, p.Ile201Thr in the MYH7 gene and c.1391G>C, p.Gly464Ala in the PTPN11 gene), and four were variants of uncertain significance in the ACTA2, ANK2, MYOZ2, and PRKAG2 genes. The results of the in silico prediction software showed that the identified variants were pathogenic and responsible for the patients’ DCM. Conclusions: Our results contribute to the understanding of cardiomyopathy pathogenesis and provide a basis for diagnosis, treatment, prevention, and genetic counseling.
You have requested "on-the-fly" machine translation of selected content from our databases. This functionality is provided solely for your convenience and is in no way intended to replace human translation. Show full disclaimer
Neither ProQuest nor its licensors make any representations or warranties with respect to the translations. The translations are automatically generated "AS IS" and "AS AVAILABLE" and are not retained in our systems. PROQUEST AND ITS LICENSORS SPECIFICALLY DISCLAIM ANY AND ALL EXPRESS OR IMPLIED WARRANTIES, INCLUDING WITHOUT LIMITATION, ANY WARRANTIES FOR AVAILABILITY, ACCURACY, TIMELINESS, COMPLETENESS, NON-INFRINGMENT, MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE. Your use of the translations is subject to all use restrictions contained in your Electronic Products License Agreement and by using the translation functionality you agree to forgo any and all claims against ProQuest or its licensors for your use of the translation functionality and any output derived there from. Hide full disclaimer
Details


1 E Hospital, Ministry of Health, 89 Tran Cung Str., Cau Giay, Hanoi 100000, Vietnam;
2 Institute of Genome Research, Vietnam Academy of Science and Technology, 18-Hoang Quoc Viet Str., Cau Giay, Hanoi 100000, Vietnam;
3 Institute of Genome Research, Vietnam Academy of Science and Technology, 18-Hoang Quoc Viet Str., Cau Giay, Hanoi 100000, Vietnam;
4 Institute of Genome Research, Vietnam Academy of Science and Technology, 18-Hoang Quoc Viet Str., Cau Giay, Hanoi 100000, Vietnam;
5 Institute of Genome Research, Vietnam Academy of Science and Technology, 18-Hoang Quoc Viet Str., Cau Giay, Hanoi 100000, Vietnam;