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Genetics and Clinical Features of Noncompaction Cardiomyopathy in the Fetal Population.

ABSTRACT: Objectives: Noncompaction Cardiomyopathy (NCCM) has been classified as primary genetic cardiomyopathy and has gained increasing clinical awareness; however, little is known about NCCM in the fetal population. We aimed to investigate the clinical characteristics and genetic spectrum of a fetal population with NCCM. Methods: We retrospectively reviewed all fetuses with a prenatal diagnosis of NCCM at a single center between October 2010 and December 2019. These cases were investigated for gestational age at diagnosis, gender, left or biventricular involvement, associated cardiac phenotypes, outcomes, and genetic testing data. Results: We identified 37 fetuses with NCCM out of 49,898 fetuses, indicating that the incidence of NCCM in the fetal population was 0.07%. Of the 37 fetuses, 26 were male, ten were female and one was of unknown gender. NCCM involvement biventricle is the most common (n = 16, 43%), followed by confined to the left ventricle (n = 14, 38%). Nineteen (51%) had additional congenital heart defects, with right-sided lesions being the most common (n = 14, 74%), followed by ventricular septal defects (n = 10, 53%). Hydrops fetalis was present in 12 cases (32%), of which four were atypical (pericardial effusion only). Sequencing analysis was performed at autopsy (n = 19) or postnatally (n = 1) on 20 fetuses. Of the 20 fetuses undergoing copy number variation sequencing and whole-exome sequencing, nine (47%) had positive genetic results, including one with a pathogenic copy number variant and eight with pathogenic/likely pathogenic variants. Non-sarcomere gene mutations accounted for the vast majority (n = 7). In contrast, sarcomere gene mutations occurred in only one case (TPM1), and no mutations were identified in the three most common sarcomere genes (MYH7, TTN, and MYBPC3) of pediatric and adult patients. Pathogenic/likely pathogenic variants were significantly more frequent in fetuses with congenital heart defects than those without congenital heart defects. Conclusions: Our data demonstrate that fetal NCCM is a unique entity. Compared with pediatric and adult NCCM, fetal NCCM is more prone to biventricle involvement, more likely to be complicated with congenital heart defects, and has a distinct genetic spectrum.

SUBMITTER: Sun H

PROVIDER: S-EPMC7854697 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Genetics and Clinical Features of Noncompaction Cardiomyopathy in the Fetal Population.

Sun Hairui H Hao Xiaoyan X Wang Xin X Zhou Xiaoxue X Zhang Ye Y Liu Xiaowei X Han Jiancheng J Gu Xiaoyan X Sun Lin L Zhao Ying Y Yi Tong T Zhang Hongjia H He Yihua Y

Frontiers in cardiovascular medicine 20210120

<b>Objectives:</b> Noncompaction Cardiomyopathy (NCCM) has been classified as primary genetic cardiomyopathy and has gained increasing clinical awareness; however, little is known about NCCM in the fetal population. We aimed to investigate the clinical characteristics and genetic spectrum of a fetal population with NCCM. <b>Methods:</b> We retrospectively reviewed all fetuses with a prenatal diagnosis of NCCM at a single center between October 2010 and December 2019. These cases were investigate ...[more]

PMID: 33553264

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Project description:Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease and defined by unexplained isolated progressive myocardial hypertrophy, systolic and diastolic ventricular dysfunction, arrhythmias, sudden cardiac death and histopathologic changes, such as myocyte disarray and myocardial fibrosis. Mutations in genes encoding for proteins of the contractile apparatus of the cardiomyocyte, such as ?-myosin heavy chain and myosin binding protein C, have been identified as cause of the disease. Disease is caused by altered biophysical properties of the cardiomyocyte, disturbed calcium handling, and abnormal cellular metabolism. Mutations in sarcomere genes can also activate other signaling pathways via transcriptional activation and can influence non-cardiac cells, such as fibroblasts. Additional environmental, genetic and epigenetic factors result in heterogeneous disease expression. The clinical course of the disease varies greatly with some patients presenting during childhood while others remain asymptomatic until late in life. Patients can present with either heart failure symptoms or the first symptom can be sudden death due to malignant ventricular arrhythmias. The morphological and pathological heterogeneity results in prognosis uncertainty and makes patient management challenging. Current standard therapeutic measures include the prevention of sudden death by prohibition of competitive sport participation and the implantation of cardioverter-defibrillators if indicated, as well as symptomatic heart failure therapies or cardiac transplantation. There exists no causal therapy for this monogenic autosomal-dominant inherited disorder, so that the focus of current management is on early identification of asymptomatic patients at risk through molecular diagnostic and clinical cascade screening of family members, optimal sudden death risk stratification, and timely initiation of preventative therapies to avoid disease progression to the irreversible adverse myocardial remodeling stage. Genetic diagnosis allowing identification of asymptomatic affected patients prior to clinical disease onset, new imaging technologies, and the establishment of international guidelines have optimized treatment and sudden death risk stratification lowering mortality dramatically within the last decade. However, a thorough understanding of underlying disease pathogenesis, regular clinical follow-up, family counseling, and preventative treatment is required to minimize morbidity and mortality of affected patients. This review summarizes current knowledge about molecular genetics and pathogenesis of HCM secondary to mutations in the sarcomere and provides an overview about current evidence and guidelines in clinical patient management. The overview will focus on clinical staging based on disease mechanism allowing timely initiation of preventative measures. An outlook about so far experimental treatments and potential for future therapies will be provided.

Project description:Noncompaction cardiomyopathy (NCCM) is a rare condition characterized by prominent trabeculae, deep intertrabecular recesses, and a left ventricular myocardium with a two-layered structure, characterized by a spongy endocardial layer and a thinner and compacted epicardial one. NCCM can be isolated or associated with other congenital heart diseases and complex syndromes involving neuromuscular disorders and facial dysmorphisms. To date, more than 40 genes coding for sarcomeric, cytoskeletal, ion channels, and desmosomal proteins have been identified. Clinical presentation is also highly variable, ranging from no symptoms to end-stage heart failure (HF), lethal arrhythmias, sudden cardiac death, or thromboembolic events. In particular, the prevalence of thromboembolism in NCCM patients appears to be higher than that of a similar, age-matched population without NCCM. Thromboembolism has a multifactorial aetiology, which is linked to genetic, as well as traditional cardiovascular risk factors. In previous studies, atrial fibrillation (AF) was observed in approximately 25-30% of adult NCCM patients and embolism had a cardiac source in ~63-69% of cases; therefore, AF represents a strong predictor of adverse events, especially if associated to HF and neuromuscular disorders. Left ventricular dysfunction is another risk factor for thromboembolism, as a result of blood stagnation and local myocardial injury. Moreover, it is not completely clarified if the presence of deep intertrabecular recesses causing stagnant blood flow can constitute per se a thrombogenic substrate even in absence of ventricular dysfunction. For the clinical management of NCCM patients, an appropriate stratification of the thromboembolic risk is of utmost importance for a timely initiation of anticoagulant therapy. The aim of the present study is to review the available literature on NCCM with particular attention on thromboembolic risk stratification and prevention and the current evidence for oral anticoagulation therapy. The use of direct oral anticoagulants vs. vitamin K antagonists is also discussed with important implications for patient treatment and prognosis.

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Genetics and Clinical Features of Noncompaction Cardiomyopathy in the Fetal Population.

Publications

Genetics and Clinical Features of Noncompaction Cardiomyopathy in the Fetal Population.

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