Cardiomyopathy, Dilated ; Cardiomyopathy, Hypertrophic ; genetics ; Humans ; Mutation

Cardiomyopathy, Hypertrophic ; genetics ; Humans ; Mutation

Hypertrophy cardiomyopathy (HCM) is an autosomal dominant disorder characterized by increased heart mass that occurs without a defined stimulus (such as hypertension or valvular disease). It is commonly recognized through the widespread use of non-invasive imaging. Epidemiological studies indicate that 1 of 500 individuals has unexplained cardiac hypertrophy, an observation that predicts a considerable role for genetics in this enigmatic disorder. Indeed, to date, more than 500 mutations had been identified in more than 12 genes encoding components of the thick and thin filament of the sarcomere and other myofilament-related proteins. Intensive studies of HCM continue to take our understandings about this fascinating disease in new directions. Mechanistic analyses have provided insights into how mutational alterations in these structural proteins may trigger the hypertrophic remodeling processes and other associated clinical features of HCM. Based on these studies, investigations have been initiated to assess whether early pharmacological interventions could prevent or attenuate the development of the disease and its clinical sequelae. By combining pathophysiology with knowledge of genetic cause and molecular responses, HCM has begun to exemplify opportunities for predictive and personalized medicine. With the emergence of newer technologies that enable high-throughput sequencing of DNA, it is timely to review clinical manifestations and genetic causes of this unique disease, and how intertwining these insights can improve contemporary diagnosis and management of HCM and other genetic forms of cardiac hypertrophy.
Cardiomyopathy, Hypertrophic ; diagnosis ; genetics ; pathology ; therapy ; Humans

Objective: To analyze the clinical and genetic characteristics of clinical subtypes of non-obstructive hypertrophic cardiomyopathy (HCM). Methods: It was a cohort study. Patients with non-obstructive HCM admitted to Fuwai Hospital, Chinese Academy of Medical Sciences, from January 1999 to April 2019 were enrolled. According to the characteristics of cardiac morphology and function shown by echocardiography, the patients were divided into common type, dilated type, restricted type and reduced ejection fraction type. The clinical data of the patients were recorded, and 8 sarcomere pathogenic genes were screened by full exon sequencing or panel sequencing. Patienst were followed up and cardiovascular endpoint events were recorded. Results: A total of 815 patients with non-obstructive HCM were enrolled, including 27 (3.3%) restricted type, 51 (6.3%) dilated type, 30 (3.7%) reduced ejection fraction type and 707 (86.7%) common type. A total of 704 out of 815 patients underwent genetic testing. Among them, 299 (42.5%) patients carried at least 1 sarcomere gene mutation. MYBPC3 and MYH7 mutation accounted for 42.1% (126/299) and 35.8% (107/299) respectively. 66.7% (16/24) of the patients with restricted type carried sarcomere gene mutation, which was higher than that in patients with dilated type (36.4% (16/44)) and in common type (41.5% (250/602), P=0.015). Among the patients with reduced ejection fraction, 56.7% (17/30) patients carried sarcomere gene mutations, 23.3% (7/30) carried multiple sarcomere mutations, which was higher than that in restricted type (8.3% (2/24)), in dilated type (9.1% (4/44)) and in common type 4.2% ((24/577), P<0.001). MYH7 and MYBPC3 were the main mutation gene types of all clinical subtypes, and the genotypes were similar among groups (all P>0.05). Seven hundred and three out 815 patients were followed up for 2.9 (1.4, 4.0) years. There were 53(7.5%) cardiovascular death. Cardiovascular death occurred in 5.0% (29/578) patients with common type, 13.0% (3/23) patients with restricted type, 16.3% (7/43) patients with dilated type and 46.7% (14/30) patients with decreased ejection fraction. Univariate Cox proportional hazards model analysis showed that the risk of cardiovascular death in patients with restricted, dilated and reduced ejection fraction type was higher than that in patients with common type (P<0.001). After adjusting for gender, age of onset, body mass index, history of hypertension, coronary heart disease and diabetes, multivariate Cox proportional hazards model analysis showed that the HR of cardiovascular death in patients with restricted, dilated and reduced ejection fraction type were 5.454 (95%CI 1.137-26.157, P=0.034) and 6.597 (95%CI 1.632-26.667, P=0.008) and 9.028 (95%CI 2.201-37.039, P=0.002) respectively, as compared to patients with common type. Conclusions: Most of the patients with non-obstructive HCM are common type, featured by mild clinical manifestations and good prognosis. Although the proportion of restricted type and dilated type is relatively low, and cardiac systolic function is mostly preserved, the clinical phenotype and prognosis of these patients are similarly severe and poor as patients with reduced ejection fraction. The genotypes are similar in different clinical subtypes, but the proportion of patients with sarcomere gene mutation is higher in restricted type, and the proportion of patients with multiple sarcomere gene mutation is higher in decreased ejection fraction type.
Cardiomyopathy, Hypertrophic/genetics* ; Cohort Studies ; Humans ; Mutation ; Phenotype ; Sarcomeres/genetics*

Adolescent ; Adult ; Cardiomyopathy, Hypertrophic ; genetics ; Child ; Humans ; Male

Cardiomyopathy, Hypertrophic/genetics* ; Humans ; Molecular Biology ; Mutation ; Pedigree

Cardiomyopathy, Hypertrophic/genetics* ; Female ; Genetic Testing ; Humans ; Pregnancy ; Text Messaging

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.
Female ; Humans ; Cardiomyopathy, Dilated/genetics* ; Cardiomyopathy, Hypertrophic ; Genetic Counseling ; Genomics ; Heterozygote ; Muscle Proteins/genetics* ; Transcription Factors ; LIM-Homeodomain Proteins/genetics*

No abstract available.
Cardiomyopathy, Hypertrophic/genetics ; Chromosome Aberrations ; Heart Defects, Congenital/genetics ; Heart Diseases/*genetics ; Human

No abstract available.
Cardiomyopathy, Hypertrophic/genetics ; Chromosome Aberrations ; Heart Defects, Congenital/genetics ; Heart Diseases/*genetics ; Human