A case of dilated cardiomyopathy caused by FHL2 gene variant and a literature review / 中华医学遗传学杂志

OBJECTIVE@#To explore the clinical phenotype and genetic features of a child with dilated cardiomyopathy (DCM).@*METHODS@#Clinical data of the child who had presented at the Zhengzhou Children's Hospital on April 28, 2020 was collected. Trio-whole exome sequencing (trio-WES) was carried out for the child and her parents, and candidate variants were validated by Sanger sequencing. "FHL2" was taken as the key word to retrieve related literature from January 1, 1997 to October 31, 2021 in the PubMed database and was also searched in the ClinVar database as a supplement to analyze the correlation between genetic variants and clinical features.@*RESULTS@#The patient was a 5-month-old female infant presented with left ventricular enlargement and reduced systolic function. A heterozygous missense variant c.391C>T (p.Arg131Cys) in FHL2 gene was identified through trio-WES. The same variant was not detected in either of her parents. A total of 10 patients with FHL2 gene variants have been reported in the literature, 6 of them had presented with DCM, 2 with hypertrophic cardiomyopathy (HCM), and 2 with sudden unexplained death (SUD). Phenotypic analysis revealed that patients with variants in the LIM 3 domain presented hypertrophic cardiomyopathy and those with variants of the LIM 0~2 and LIM 4 domains had mainly presented DCM. The c.391C>T (p.Arg131Cys) has been identified in a child with DCM, though it has not been validated among the patient's family members. Based on the guidelines of the American College of Medical Genetics and Genomics, the c.391C>T(p.Arg131Cys) variant was re-classified as likely pathogenic (PS2+PM2_Supporting+PP3+PP5).@*CONCLUSION@#The heterozygous missense variant of c.391C>T (p.Arg131Cys) in the FHL2 gene probably predisposed to the DCM in this child, which has highlighted the importance of WES in the clinical diagnosis and genetic counseling.

Phenotype and genotype characteristics of children with cardiomyopathy associated with MYH7 gene mutation: a retrospective analysis / 中国当代儿科杂志

OBJECTIVES@#To investigate the clinical phenotype and genotype characteristics of children withcardiomyopathy (CM) associated with MYH7 gene mutation.@*METHODS@#A retrospective analysis was conducted on the medical data of five children with CM caused by MYH7 gene mutation who were diagnosed and treated in the Department of Cardiology, Hebei Children's Hospital.@*RESULTS@#Among the five children with CM, there were three girls and two boys, all of whom carried MYH7 gene mutation. Seven mutation sites were identified, among which five were not reported before. Among the five children, there were three children with hypertrophic cardiomyopathy, one child with dilated cardiomyopathy, and one child with noncompaction cardiomyopathy. The age ranged from 6 to 156 months at the initial diagnosis. At the initial diagnosis, two children had the manifestations of heart failure such as cough, shortness of breath, poor feeding, and cyanosis of lips, as well as delayed development; one child had palpitation, blackness, and syncope; one child had fever, runny nose, and abnormal liver function; all five children had a reduction in activity endurance. All five children received pharmacotherapy for improving cardiac function and survived after follow-up for 7-24 months.@*CONCLUSIONS@#The age of onset varies in children with CM caused by MYH7 gene mutation, and most children lack specific clinical manifestations at the initial diagnosis and may have the phenotype of hypertrophic cardiomyopathy, dilated cardiomyopathy or noncompaction cardiomyopathy. The children receiving early genetic diagnosis and pharmacological intervention result in a favorable short-term prognosis.

Genetic testing and clinical analysis of a patient with Dilated cardiomyopathy due to variant of FLNC gene / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a patient with Dilated cardiomyopathy.@*METHODS@#A patient admitted to Beijing Anzhen Hospital Affiliated to Capital Medical University in April 2022 was selected as the study subject. Clinical data and family history of the patient was collected. Targeted exome sequencing was carried out. Candidate variant was verified by Sanger sequencing and bioinformatic analysis based on guidelines of the American College of Medical Genetics and Genomics (ACMG).@*RESULTS@#DNA sequencing revealed that the patient has harbored a heterozygous c.5044dupG frameshift variant of the FLNC gene. Based on the ACMG guidelines, the variant was predicted to be likely pathogenic (PVS1+PM2_Supporting+PP4).@*CONCLUSION@#The heterozygous c.5044dupG variant of the FLNC gene probably underlay the pathogenesis in this patient, which has provided a basis for the genetic counseling for his family.

Expert consensus on the genetic diagnosis for Dystrophinopathies / 中华医学遗传学杂志

Dystrophinopathies, including Duchenne muscular dystrophy, Becker muscular dystrophy and dilated cardiomyopathy, are X-linked recessive genetic disorders due to variants of the dystrophin gene, which can seriously affect quality of life and health. Genetic diagnosis plays a crucial role in their diagnosis, treatment, and prevention. How to rationally select and standardize the use of various genetic techniques is a skill that clinicians must acquire. By compiling expertise of experts from the relevant areas and guidelines published home and abroad, this consensus has provided a guidance from the perspective of genetic diagnosis for the selection of genetic techniques, testing strategies, and detection process for dystrophinopathies.

Identification of dysregulated microRNAs involved in arachidonic acid metabolism regulation in dilated cardiomyopathy-mediated heart failure patients / 生理学报

Heart failure (HF), a clinical syndrome with high morbidity and mortality, is becoming a growing public health problem. Dilated cardiomyopathy (DCM) is one of the major causes of HF, yet the molecular mechanisms underlying DCM-mediated HF are not completely understood. Previous studies have shown that dysregulation of arachidonic acid (AA) metabolism could contribute to the development of HF. To explore the roles of microRNAs (miRNAs) in regulating AA metabolism in HF, we used two public datasets to analyze the expression changes of miRNAs in the patients of DCM-mediated HF. A total of 101 and 88 miRNAs with significant abundance alterations in the two dataset were obtained, respectively. Around 1/3 of these miRNAs were predicted to target AA metabolic pathway genes. We also investigated the distribution of known single nucleotide polymorphisms (SNPs) within the sequences of miRNAs dysregulated in DCM-mediated HF patients, and identified miRNAs harboring high number of SNPs in either the seed regions or the entire sequences. These information could provide clues for further functional studies of miRNAs in the pathogeny of DCM-mediated HF.

CD14 genotype and functional dichotomy of CD14+ and CD14- cells are associated with activated immune response and development of Chagas dilated cardiomyopathy

We aimed to investigate the association of CD14 -260C/T (rs2569190) polymorphism and Chagas cardiomyopathy and the functional characteristics of CD14+ and CD14- monocytes upon infection with Trypanosoma cruzi. We observed an association between the T- genotype (absence of allele -260T) related to low CD14 expression and the dilated cardiomyopathy type of Chagas disease. Furthermore, we observed that CD14- monocytes showed a more activated profile upon in vitro infection with T. cruzi than CD14+ monocytes. Our findings suggest that T- genotype is associated with susceptibility to develop Chagas dilated cardiomyopathy, likely linked to the T. cruzi-induced inflammatory profile of CD14- monocytes.

Importance of Genetic Testing in Dilated Cardiomyopathy: Applications and Challenges in Clinical Practice / Importância do Teste Genético na Miocardiopatia Dilatada: Aplicações e Desafios na Prática Clínica

Abstract Dilated cardiomyopathy (DCM) is a clinical syndrome characterized by left ventricular dilatation and contractile dysfunction. It is the most common cause of heart failure in young adults. The advent of next-generation sequencing has contributed to the discovery of a large amount of genomic data related to DCM. Mutations involving genes that encode cytoskeletal proteins, the sarcomere, and ion channels account for approximately 40% of cases previously classified as idiopathic DCM. In this scenario, geneticists and cardiovascular genetics specialists have begun to work together, building knowledge and establishing more accurate diagnoses. However, proper interpretation of genetic results is essential and multidisciplinary teams dedicated to the management and analysis of the obtained information should be considered. In this review, we approach genetic factors associated with DCM and their prognostic relevance and discuss how the use of genetic testing, when well recommended, can help cardiologists in the decision-making process.

Resumo A miocardiopatia dilatada (MCD) é uma síndrome caracterizada por dilatação ventricular esquerda e disfunção contrátil, sendo considerada a causa mais comum de insuficiência cardíaca em adultos jovens. O uso do sequenciamento de nova geração tem contribuído com a descoberta de uma grande quantidade de dados genômicos relacionados à MCD, identificando mutações que envolvem genes que codificam proteínas do citoesqueleto, sarcômero e canais iônicos, os quais são responsáveis por aproximadamente 40% dos casos classificados como MCD idiopática. Nesse cenário, geneticistas e especialistas em genética cardiovascular passaram a atuar em conjunto, agregando conhecimento e estabelecendo diagnósticos mais precisos. No entanto, é fundamental interpretar corretamente os resultados genéticos, sendo necessário criar e fomentar equipes multidisciplinares dedicadas à gestão e análise das informações coletadas. Nesta revisão, abordamos os fatores genéticos associados à MCD, aspectos prognósticos, além de discutirmos como o emprego dos testes genéticos, quando bem indicados, pode ser útil na tomada de decisão na prática clínica dos cardiologistas.

HLA-DR3 antigen in the resistance to idiopathic dilated cardiomyopathy

Idiopathic dilated cardiomyopathy (IDC) has been hypothesized as a multifactorial disorder initiated by an environment trigger in individuals with predisposing human leukocyte antigen (HLA) alleles. Published data on the association between HLA-DR3 antigen and IDC risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. Studies were identified by searching the PUBMED and Embase database (starting from June 2015). A total of 19 case-control studies including 1378 cases and 10383 controls provided data on the association between HLA-DR3 antigen and genetic susceptibility to IDC. Overall, significantly decreased frequency of HLA-DR3 allele (OR=0.72; 95%CI=0.58-0.90; P=0.004) was found in patients with IDC compared with controls. When stratified by myocardial biopsy or non-biopsy cases, statistically decreased risk was found for IDC in myocardial biopsy cases (OR=0.69; 95%CI=0.57-0.84; P=0.0003). In the subgroup analysis by ethnicity, borderline statistically significantly decreased risk was found among Europeans from 12 case-control studies (OR=0.76; 95%CI=0.58-1.00; P=0.05). In conclusion, our results suggest that individuals with HLA-DR3 antigen may have a protective effect against IDC.

Analyzing gene expression profiles in dilated cardiomyopathy via bioinformatics methods

Dilated cardiomyopathy (DCM) is characterized by ventricular dilatation, and it is a common cause of heart failure and cardiac transplantation. This study aimed to explore potential DCM-related genes and their underlying regulatory mechanism using methods of bioinformatics. The gene expression profiles of GSE3586 were downloaded from Gene Expression Omnibus database, including 15 normal samples and 13 DCM samples. The differentially expressed genes (DEGs) were identified between normal and DCM samples using Limma package in R language. Pathway enrichment analysis of DEGs was then performed. Meanwhile, the potential transcription factors (TFs) and microRNAs (miRNAs) of these DEGs were predicted based on their binding sequences. In addition, DEGs were mapped to the cMap database to find the potential small molecule drugs. A total of 4777 genes were identified as DEGs by comparing gene expression profiles between DCM and control samples. DEGs were significantly enriched in 26 pathways, such as lymphocyte TarBase pathway and androgen receptor signaling pathway. Furthermore, potential TFs (SP1, LEF1, and NFAT) were identified, as well as potential miRNAs (miR-9, miR-200 family, and miR-30 family). Additionally, small molecules like isoflupredone and trihexyphenidyl were found to be potential therapeutic drugs for DCM. The identified DEGs (PRSS12 and FOXG1), potential TFs, as well as potential miRNAs, might be involved in DCM.

Miocardiopatía dilatada: aspectos genéticos, infecciosos, inflamatorios y del sistema inmune / Dilated cardiomyopathy: genetics, infectious, inflammatory and immune aspects

En la última década se ha producido un incremento sustancial en el conocimiento de las bases genéticas de las cardiomiopatías, en consideración a lo cual las Sociedades Americanas y Europea de Cardiología, han propuesto una nueva clasificación con el fin de incluir tales aspectos, Aunque se carece de datos precisos, aproximadamente el 30% de los pacientes con miocardiopatías referidos para pruebas genéticas presentan una variante genética patogénica. En la herencia de la miocardiopatía dilatada familiar, la modalidad predominante es la autosómica dominante, siendo mucho menos frecuentes las ligadas al cromosoma X, la herencia autosómica recesiva y la mitocondrial. A su vez, pruebas provenientes de ensayos clínicos y experimentales indican que la infección, la inflamación y el sistema inmunológico están de alguna manera interrelacionados en los mecanismos patogénicos implicados en la miocardiopatía dilatada, No hay duda que en un futuro próximo las mejoras en la secuenciación de genes y el mayor conocimiento de la patogenia influirán decididamente en el diagnóstico, evaluación y tratamiento de esta entidad.

In the last time, a substantial increase in the knowledge of the genetic basis of cardiomyopathy has occurred. Therefore in the last decade the American Heart Association, the American College of Cardiology and the European Society of Cardiology have proposed a new revision of the classification of cardiomyopathies in order to include the genetic basis on the etiology, Although precise data are lacking, approximately 30% of patients currently referred for clinical genetic testing will be found to have a pathogenic genetic variant. The predominant mode of inheritance for familial dilated cardiomyopathy is autosomal dominant, with X linked autosomal recessive and mitochondrial inheritance being less frequent. Evidence from experimental and clinical trials indicates that infection, inflammation and the immune system are in some way interrelated on the pathogenic mechanisms involved in the dilated cardiomyopathy, There is no doubt that in the future, improvements in sequencing genes and insight into pathogenesis will influence the diagnosis, evaluation and management of familial dilated cardiomyopathy.

Genetic variations of β-MYH7 in hypertrophic cardiomyopathy and dilated cardiomyopathy.

CONTEXT: Hypertrophic cardiomyopathy (HCM) is known to be manifested by mutations in 12 sarcomeric genes and dilated cardiomyopathy (DCM) is known to manifest due to cytoskeletal mutations. Studies have revealed that sarcomeric mutations can also lead to DCM. Therefore, in the present study, we have made an attempt to compare and analyze the genetic variations of beta-myosin heavy chain gene (β-MYH7), which are interestingly found to be common in both HCM and DCM. The underlying pathophysiological mechanism leading to two different phenotypes has been discussed in this study. Till date, about 186 and 73 different mutations have been reported in HCM and DCM, respectively, with respect to this gene. AIM: The screening of β-MYH7 gene in both HCM and DCM has revealed some common genetic variations. The aim of the present study is to understand the pathophysiological mechanism underlying the manifestation of two different phenotypes. MATERIALS AND METHODS: 100 controls, 95 HCM and 97 DCM samples were collected. Genomic DNA was extracted following rapid nonenzymatic method as described by Lahiri and Nurnberger (1991), and the extracted DNA was later subjected to polymerase chain reaction (PCR) based single stranded conformation polymorphism (SSCP) analysis to identify single nucleotide polymorphism (SNP)s/mutations associated with the diseased phenotypes. RESULTS AND CONCLUSION: Similar variations were observed in β-MYH7 exons 7, 12, 19 and 20 in both HCM and DCM. This could be attributed to impaired energy compromise, or to dose effect of the mutant protein, or to even environmental factors/modifier gene effects wherein an HCM could progress to a DCM phenotype affecting both right and left ventricles, leading to heart failure.

Epidemiology and genetics of dilated cardiomyopathy in the Indian context.

Background: Dilated cardiomyopathy (DCM) still remains to be a poorly understood and less analyzed group of cardiac-muscle disorders when compared to hypertrophic cardiomyopathy (HCM). Also, the vast clinical heterogeneity among the patients has rendered the small and isolated kindred studies less informative on the genetics and epidemiology of DCM. Aim of the study: The study aimed at understanding the epidemiology and genetics of DCMs in the Indian context. Materials and methods/ Statistical analysis: One hundred seven DCM patients and 105 healthy individuals were included in the study for epidemiological and genetic risk factor identification and to fit the possible mode of inheritance. Single's ascertainment methodology for segregation analysis and Penrose frequency estimates were followed to evaluate for the role of specific epidemiological factors in the disease etiology. Chi-square analysis was carried out to interpret the results statistically. Results and Conclusion: Our study suggests that epidemiological factors like gender, age at onset and vegetarian diet in conjunction with sarcomere gene mutations may play a role in the disease expression. Similarly, segregation analysis for the possible mode of inheritance showed a deviation from the autosomal dominant mode of inheritance, strengthening the underlying genetic heterogeneity of DCM.

Lamin A/C mutations associated with familial and sporadic cases of dilated cardiomyopathy in Koreans

Dilated cardiomyopathy (DCM) is characterized by cardiac dilation and systolic dysfunction. So far sixteen genes have been shown to cause autosomal dominant familial dilated cardiomyopathy (FDC). We identified a large Korean family from the Jeju island showing a clear Mendelian inheritance of FDC. A genomewide linkage scan at 9 cM marker density identified a peak multipoint LOD score of 2.82 at D1S195. Haplotyping of the region with 15 additional markers defined a candidate interval that included a known candidate gene encoding the lamin A/C (LMNA). Sequencing of the LMNA exons revealed one missense mutation at C568T (Arg190Trp) in the alpha-helical rod domain of the LMNA gene cosegregating with FDC with conduction-system disease. The same mutation was found in patients of another Korean family with FDC without conduction-system disease. Upon screening 14 sporadic DCM cases, we found three LMNA mutations including a case having a previously described (Glu161Lys) mutation and two having novel mutations (Glu53Val and Glu186Lys). Our results suggest that variable genotypes of laminopathy are implicated in not only familial but also considerable proportion of sporadic DCM.

Correlación del polimorfismo (I/D) del gen de la ECA y la función ventricular en pacientes con miocardiopatía dilatada de origen isquémico e idiopático / ACE gene polymorphysm correlation (I/D) with the ventricular function in patients with ischemic and dilate idiopathic cardiomyopathy

Dilated cardiomyopathy is a myocardial disease, characterized by biventricular expansion. Renin-angiotensin-aldosterone system (RAAS) is closely related with the progress of this pathology. Has been shown that angiotensin converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism influences as much in the plasmatic concentration as in activity of ACE. In addition, ACE I/D polymorphism has been associated with remodeling phenomena and an increased risk to develop several cardiovascular diseases. On virtue of the influence of ACE gene polymorphism on RAAS, we studied the correlation between ACE I/D polymorphism with morphologic and functional clinical alterations in ischemic or idiopathic dilated cardiomyopathy in one attempt to establish its utility as prognosis factor. Methods and results. We studied 30 patients of The National Institute of Cardiology. Ventricular function was evaluated by transthoracic echocardiography. ACE genotype was determined by polymerase chain reaction (PCR). Results for left ventricle shown: Tei Index was increased in patients with II genotype (0.84 vs. 0.48) when were compared to patients with DD genotype p < 0.01. Eccentricity Index was lesser in the group with II genotype (0.64), than in the group DD (0.86) p < 0.01. Ventricular mass was increased in DD patients when was compared with II group (174 g vs. 133 g) Isovolumetric contraction time was shorter in group DD than in II (45 mseg vs. 139 mseg) p < O.OB. These findings denote better preservation of left ventricular function in patients with DD genotype. In opposition, right ventricle shown an increased Tei Index in the group with DD genotype (1.01) when was compared with II genotype (0.55), p < 0.05. Pulmonary artery systolic pressure tended to be higher in DD genotype group without reach statistic significance. Conclusions. In our group of study, patients with DD genotype shown better left ventricular function in ischemia or idiopathic dilated cardiomyopathy. On the opposite right ventricular function were more deteriorated in patients with ACE DD genotype.

La miocardiopatía dilatada es una enfermedad primaria del miocardio, caracterizada por dilatación biventricular. El sistema renina-angiotensina-aldosterona (SRAA) está estrechamente relacionado con el progreso de esta patología. Se ha demostrado que el polimorfismo inserción/deleción (I/D) del gen de la enzima convertidora de angiotensina (ECA) influye en la concentración plasmática y la actividad de esta enzima, además este polimorfismo se ha asociado con fenómenos de remodelación e incremento en el riesgo de padecer diferentes enfermedades cardiovasculares. En virtud de la influencia de las variantes polimórficas del gen de la ECA sobre la respuesta del SRAA, en el presente trabajo se estudió la posible correlación del polimorfismo I/D del gen de la ECA con las alteraciones clínicas morfológicas y funcionales de la cardiomiopatía dilatada tanto de origen isquémico como de origen idiopático con el fin de establecer su posible utilidad como factor pronóstico. Métodos y resultados. El estudio incluyó a 30 pacientes seleccionados de la consulta externa del Instituto Nacional de Cardiología <>, la función ventricular se valoró mediante ecocardiografía transtorácica. El genotipo de la ECA se determinó por reacción en cadena de la polimerasa (PCR). Resultados para el ventrículo izquierdo: El índice de Tei se observó visiblemente incrementado en los pacientes con genotipo II 0.84 vs. 0.48 de los pacientes con genotipo DD p < 0.01. El índice de excentricidad fue menor en los casos con genotipo II: 0.64, comparado con aquellos con genotipo DD: 0.86 p < 0.01. La masa ventricular tendió a ser mayor en el grupo DD en relación con el II (174 g vs. 133 g). El tiempo de contracción isovolumétrica fue menor en el grupo DD en comparación al II (45 mseg vs. 139 mseg) p < 0.05, estos hallazgos denotan una mejor preservación de la función ventricular izquierda en los pacientes con genotipo DD. Por otra parte, el ventrículo derecho mostró un comportamiento distinto al observado para el ventrículo izquierdo, pues el índice de Tei fue mayor para los pacientes con el genotipo DD (1.01) comparado con el grupo del genotipo II (0.55), p < 0.05. La presión sistólica de la arteria pulmonar tendió a ser mayor en los pacientes con genotipo DD sin alcanzar una significancia estadística. Conclusión. El genotipo DD se asocia con una mejor función ventricular izquierda en los pacientes con miocardiopatía dilatada de origen tanto isquémico como idiopático; por el contrario, la función ventricular derecha de los pacientes con genotipo DD muestra una mayor alteración en el índice de Tei en esta patología.

Philadelphia chromosome positive essential thrombocythemia with dilated cardiomyopathy.

We report here an unusual case of a 30-year old male patient with essential thrombocythemia (ET) and dilated cardiomyopathy, who on further investigation was found to have Philadelphia chromosome positive (Ph+) cells in the bone marrow. The reverse transcriptase-polymerase chain reaction (RT-PCR) test on his peripheral blood leucocytes revealed b2a2 transcript of the bcr-abl fusion gene. Literature shows that the boundary line between Ph+ essential thrombocythemia and chronic myeloid leukemia (CML) is getting blurred day by day. Each one may be a part of the spectrum of a single clonal proliferative disease. Association of dilated cardiomyopathy with ET has not been reported.