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Pediatric Cardiomyopathies: From Genotype to Phenotype

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A special issue of Journal of Cardiovascular Development and Disease (ISSN 2308-3425). This special issue belongs to the section "Pediatric Cardiology and Congenital Heart Disease".

Deadline for manuscript submissions: closed (28 February 2022) | Viewed by 36512

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Special Issue Editors

Dr. Anwar Baban

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Guest Editor

Cardiogenetic Service, Rare Diseases and Medical Genetics Units, Bambino Gesù Children Hospital & Research Institute, IRCCS, 00165 Rome, Italy
Interests: clinical genetics and genomics; multidisciplinary and cardiogenetic management in congenital heart defects; cardiomyopathies; channelopathies/arrhythmias; aortopathies; pulmonary hypertension

Prof. Dr. Sabine Klaassen

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Co-Guest Editor

Experimental and Clinical Research Center, a cooperation between the Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, and the Charité - Universitätsmedizin Berlin, Lindenberger Weg 80, 13125 Berlin, Germany
Interests: human genetics; cardiomyopathy; pediatrics; heart failure; genomics

Special Issue Information

Dear Colleagues,

Cardiomyopathies in children are rare diseases (estimated incidence of ≈1 per 100 000 children). They are a major cause of morbidity, and major indications for heart transplantation and mortality. If we compare Children cardiomyopathy to other rare diseases (including cancers), a clear divergence is observed in terms of advances in research and dedicated scientific meetings in the latter group. The main focus of this Issue is to offer an updated landscape and increase knowledge in specific characteristics related to childhood onset cardiomyopathies and to attempt to establish personalized management workflows that can help clinicians when facing specific and sometimes “ultra-rare” cardiomyopathies in children.

Dr. Anwar Baban
Prof. Dr. Sabine Klaassen
Guest Editor

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Keywords

children cardiomyopathy
personalized medicine
genotyping and phenotyping in trios
heterogeneity

Published Papers (13 papers)

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Research

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14 pages, 1078 KiB

Open AccessArticle

Cardiovascular Involvement in Pediatric FLNC Variants: A Case Series of Fourteen Patients

by Anwar Baban, Viola Alesi, Monia Magliozzi, Giovanni Parlapiano, Silvia Genovese, Marianna Cicenia, Sara Loddo, Valentina Lodato, Luca Di Chiara, Fabiana Fattori, Adele D’Amico, Paola Francalanci, Antonio Amodeo, Antonio Novelli and Fabrizio Drago

J. Cardiovasc. Dev. Dis. 2022, 9(10), 332; https://doi.org/10.3390/jcdd9100332 - 30 Sep 2022

Cited by 2 | Viewed by 1863

Abstract

Filamin C is a protein specifically expressed in myocytes and cardiomyocytes and is involved in several biological functions, including sarcomere contractile activity, signaling, cellular adhesion, and repair. FLNC variants are associated with different disorders ranging from striated muscle (myofibrillar distal or proximal) myopathy to cardiomyopathies (CMPs) (restrictive, hypertrophic, and dilated), or both. The outcome depends on functional consequences of the detected variants, which result either in FLNC haploinsufficiency or in an aberrant protein, the latter affecting sarcomere structure leading to protein aggregates. Cardiac manifestations of filaminopathies are most often described as adult onset CMPs and limited reports are available in children or on other cardiac spectrums (congenital heart defects—CHDs, or arrhythmias). Here we report on 13 variants in 14 children (2.8%) out of 500 pediatric patients with early-onset different cardiac features ranging from CMP to arrhythmias and CHDs. In one patient, we identified a deletion encompassing FLNC detected by microarray, which was overlooked by next generation sequencing. We established a potential genotype–phenotype correlation of the p.Ala1186Val variant in severe and early-onset restrictive cardiomyopathy (RCM) associated with a limb-girdle defect (two new patients in addition to the five reported in the literature). Moreover, in three patients (21%), we identified a relatively frequent finding of long QT syndrome (LQTS) associated with RCM (n = 2) and a hypertrabeculated left ventricle (n = 1). RCM and LQTS in children might represent a specific red flag for FLNC variants. Further studies are warranted in pediatric cohorts to delineate potential expanding phenotypes related to FLNC. Full article

(This article belongs to the Special Issue Pediatric Cardiomyopathies: From Genotype to Phenotype)

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17 pages, 1551 KiB

Open AccessArticle

Pathogenic Variants in Cardiomyopathy Disorder Genes Underlie Pediatric Myocarditis—Further Impact of Heterozygous Immune Disorder Gene Variants?

by Franziska Seidel, Kai Thorsten Laser, Karin Klingel, Josephine Dartsch, Simon Theisen, Thomas Pickardt, Manuel Holtgrewe, Anna Gärtner, Felix Berger, Dieter Beule, Hendrik Milting, Stephan Schubert, Sabine Klaassen and Jirko Kühnisch

J. Cardiovasc. Dev. Dis. 2022, 9(7), 216; https://doi.org/10.3390/jcdd9070216 - 05 Jul 2022

Cited by 4 | Viewed by 2294

Abstract

Myocarditis is an inflammatory disease of the heart. Pediatric myocarditis with the dilated cardiomyopathy (DCM) phenotype may be caused by likely pathogenic or pathogenic genetic variants [(L)P] in cardiomyopathy (CMP) genes. Systematic analysis of immune disorder gene defects has not been performed so far. We analyzed 12 patients with biopsy-proven myocarditis and the DCM phenotype together with their parents using whole-exome sequencing (WES). The WES data were filtered for rare pathogenic variants in CMP (n = 89) and immune disorder genes (n = 631). Twelve children with a median age of 2.9 (1.0–6.8) years had a mean left ventricular ejection fraction of 28% (22–32%) and myocarditis was confirmed by endomyocardial biopsy. Patients with primary immunodeficiency were excluded from the study. Four patients underwent implantation of a ventricular assist device and subsequent heart transplantation. Genetic analysis of the 12 families revealed an (L)P variant in the CMP gene in 8/12 index patients explaining DCM. Screening of recessive immune disorder genes identified a heterozygous (L)P variant in 3/12 index patients. This study supports the genetic impact of CMP genes for pediatric myocarditis with the DCM phenotype. Piloting the idea that additional immune-related genetic defects promote myocarditis suggests that the presence of heterozygous variants in these genes needs further investigation. Altered cilium function might play an additional role in inducing inflammation in the context of CMP. Full article

(This article belongs to the Special Issue Pediatric Cardiomyopathies: From Genotype to Phenotype)

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14 pages, 933 KiB

Open AccessArticle

Imaging Features of Pediatric Left Ventricular Noncompaction Cardiomyopathy in Echocardiography and Cardiovascular Magnetic Resonance

by Agata Paszkowska, Jędrzej Sarnecki, Alicja Mirecka-Rola, Monika Kowalczyk-Domagała, Łukasz Mazurkiewicz and Lidia Ziółkowska

J. Cardiovasc. Dev. Dis. 2022, 9(3), 77; https://doi.org/10.3390/jcdd9030077 - 05 Mar 2022

Cited by 3 | Viewed by 2132

Abstract

Background: Left ventricular noncompaction (LVNC) is a distinct cardiomyopathy characterized by the presence of a two-layer myocardium with prominent trabeculation and deep intertrabecular recesses. The diagnosis of LVNC can be challenging because the diagnostic criteria are not uniform. The aim of our study was to evaluate echocardiographic and CMR findings in a group of children with isolated LVNC. Methods: From February 2008 to July 2021, pediatric patients under 18 years of age at the time of diagnosis with echocardiographic evidence of isolated LVNC were prospectively enrolled. The patients underwent echocardiography and contrast-enhanced cardiovascular magnetic resonance (CMR) with late gadolinium enhancement to assess myocardial noncompaction, ventricular size, and function. Results: A total of 34 patients, with a median age of 11.9 years, were recruited. The patients were followed prospectively for a median of 5.1 years. Of the 31 patients who met Jenni’s criteria in echocardiography, CMR was performed on 27 (79%). Further comprehensive analysis was performed in the group of 25 patients who met the echocardiographic and CMR criteria for LVNC. In echocardiography, the median NC/C ratio in systole was 2.60 and in diastole 3.40. In 25 out of 27 children (93%), LVNC was confirmed by CMR, according to Petersen’s criteria, with a median NC/C ratio of 3.27. Conclusions: (1) Echocardiography precisely identifies patients with LVNC. (2) Echocardiography is a good method for monitoring LV systolic function, but CMR is indicated for the precise assessment of LV remodeling and RV size and function, as well as for the detection of myocardial fibrosis. Full article

(This article belongs to the Special Issue Pediatric Cardiomyopathies: From Genotype to Phenotype)

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11 pages, 471 KiB

Open AccessEditor’s ChoiceArticle

It Is Not Carved in Stone—The Need for a Genetic Reevaluation of Variants in Pediatric Cardiomyopathies

by Dominik Sebastian Westphal, Kathrin Pollmann, Christoph Marschall, Annette Wacker-Gussmann, Renate Oberhoffer-Fritz, Karl-Ludwig Laugwitz, Peter Ewert and Cordula Maria Wolf

J. Cardiovasc. Dev. Dis. 2022, 9(2), 41; https://doi.org/10.3390/jcdd9020041 - 25 Jan 2022

Cited by 2 | Viewed by 2387

Abstract

(1) Background: In cardiomyopathies, identification of genetic variants is important for the correct diagnosis and impacts family cascade screening. A classification system was published by the American College of Medical Genetics and Genomics (ACMG) in 2015 to standardize variants’ classification. The aim of the study was to determine the rate of reclassification of previously identified variants in patients with childhood-onset cardiomyopathies. (2) Methods: Medical records of patients and their relatives were screened for clinical and genetic information at the Department of Congenital Heart Defects and Pediatric Cardiology, German Heart Center Munich. Patients without an identified genetic variant were excluded from further analyses. Previously reported variants were reevaluated by the ACMG criteria in November 2021. (3) Results: Data from 167 patients or relatives of patients with childhood-onset cardiomyopathy from 137 families were analyzed. In total, 45 different genetic variants were identified in 71 individuals. Classification changed in 29% (13/45) with the greatest shift in “variants of unknown significance” to “(likely) benign” (9/13). (4) Conclusions: In patients with childhood-onset cardiomyopathies, nearly a third of reported genetic variants change mostly to more benign classes upon reclassification. Given the impact on patient management and cascade screening, this finding underlines the importance of continuous genetic counseling and variant. Full article

(This article belongs to the Special Issue Pediatric Cardiomyopathies: From Genotype to Phenotype)

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14 pages, 1430 KiB

Open AccessArticle

ICD Outcome in Pediatric Cardiomyopathies

by Massimo Stefano Silvetti, Ilaria Tamburri, Marta Campisi, Fabio Anselmo Saputo, Ilaria Cazzoli, Nicoletta Cantarutti, Marianna Cicenia, Rachele Adorisio, Anwar Baban, Lucilla Ravà and Fabrizio Drago

J. Cardiovasc. Dev. Dis. 2022, 9(2), 33; https://doi.org/10.3390/jcdd9020033 - 20 Jan 2022

Cited by 4 | Viewed by 2574

Abstract

Background: Pediatric patients with cardiomyopathies are at risk of malignant arrhythmias and sudden cardiac death (SCD). An ICD may prevent SCD. The aim of this study was to evaluate ICD implantation outcomes, and to compare transvenous and subcutaneous ICDs (S-ICDs) implanted in pediatric patients with cardiomyopathies. Methods: The study is single center and retrospective, and includes pediatric patients with cardiomyopathies who required ICD implantation (2010–2021). Outcomes were recorded for appropriate/inappropriate ICD therapy and surgical complications. Transvenous ICD and S-ICD were compared. Data are presented as median values (25th–75th centiles). Results: Forty-four patients with cardiomyopathies (hypertrophic 39%, arrhythmogenic 32%, dilated 27%, and restrictive 2%) underwent transvenous (52%) and S-ICD (48%) implantation at 14 (12–17) years of age, mostly for primary prevention (73%). The follow-up period was 29 (14–60) months. Appropriate ICD therapies were delivered in 25% of patients, without defibrillation failures. Lower age at implantation and secondary prevention were significant risk factors for malignant ventricular arrhythmias that required appropriate ICD therapies. ICD-related complications were surgical complications (18%) and inappropriate shocks (7%). No significant differences in outcomes were recorded, either when comparing transvenous and S-ICD or comparing the different cardiomyopathies. Conclusions: In pediatric patients with cardiomyopathy, ICD therapy is effective, with a low rate of inappropriate shocks. Neither ICD type (transvenous and S-ICDs) nor the cardiomyopathies subgroup revealed divergent outcomes. Full article

(This article belongs to the Special Issue Pediatric Cardiomyopathies: From Genotype to Phenotype)

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15 pages, 2950 KiB

Open AccessEditor’s ChoiceArticle

Not Only Diagnostic Yield: Whole-Exome Sequencing in Infantile Cardiomyopathies Impacts on Clinical and Family Management

by Laura Pezzoli, Lidia Pezzani, Ezio Bonanomi, Chiara Marrone, Agnese Scatigno, Anna Cereda, Maria Francesca Bedeschi, Angelo Selicorni, Serena Gasperini, Paolo Bini, Silvia Maitz, Carla Maccioni, Cristina Pedron, Lorenzo Colombo, Daniela Marchetti, Matteo Bellini, Anna Rita Lincesso, Loredana Perego, Monica Pingue, Nunzia Della Malva, Giovanna Mangili, Paolo Ferrazzi and Maria Iascone Show full author list Hide full author list

J. Cardiovasc. Dev. Dis. 2022, 9(1), 2; https://doi.org/10.3390/jcdd9010002 - 21 Dec 2021

Cited by 12 | Viewed by 3375

Abstract

Whole-exome sequencing (WES) is a powerful and comprehensive tool for the genetic diagnosis of rare diseases, but few reports describe its timely application and clinical impact on infantile cardiomyopathies (CM). We conducted a retrospective analysis of patients with infantile CMs who had trio (proband and parents)-WES to determine whether results contributed to clinical management in urgent and non-urgent settings. Twenty-nine out of 42 enrolled patients (69.0%) received a definitive molecular diagnosis. The mean time-to-diagnosis was 9.7 days in urgent settings, and 17 out of 24 patients (70.8%) obtained an etiological classification. In non-urgent settings, the mean time-to-diagnosis was 225 days, and 12 out of 18 patients (66.7%) had a molecular diagnosis. In 37 out of 42 patients (88.1%), the genetic findings contributed to clinical management, including heart transplantation, palliative care, or medical treatment, independent of the patient’s critical condition. All 29 patients and families with a definitive diagnosis received specific counseling about recurrence risk, and in seven (24.1%) cases, the result facilitated diagnosis in parents or siblings. In conclusion, genetic diagnosis significantly contributes to patients’ clinical and family management, and trio-WES should be performed promptly to be an essential part of care in infantile cardiomyopathy, maximizing its clinical utility. Full article

(This article belongs to the Special Issue Pediatric Cardiomyopathies: From Genotype to Phenotype)

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Review

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14 pages, 896 KiB

Open AccessEditor’s ChoiceReview

Left Ventricular Noncompaction in Children: The Role of Genetics, Morphology, and Function for Outcome

by Sabine Klaassen, Jirko Kühnisch, Alina Schultze-Berndt and Franziska Seidel

J. Cardiovasc. Dev. Dis. 2022, 9(7), 206; https://doi.org/10.3390/jcdd9070206 - 30 Jun 2022

Cited by 1 | Viewed by 2372

Abstract

Left ventricular noncompaction (LVNC) is a ventricular wall anomaly morphologically characterized by numerous, excessively prominent trabeculations and deep intertrabecular recesses. Accumulating data now suggest that LVNC is a distinct phenotype but must not constitute a pathological phenotype. Some individuals fulfill the morphologic criteria of LVNC and are without clinical manifestations. Most importantly, morphologic criteria for LVNC are insufficient to diagnose patients with an associated cardiomyopathy (CMP). Genetic testing has become relevant to establish a diagnosis associated with CMP, congenital heart disease, neuromuscular disease, inborn error of metabolism, or syndromic disorder. Genetic factors play a more decisive role in children than in adults and severe courses of LVNC tend to occur in childhood. We reviewed the current literature and highlight the difficulties in establishing the correct diagnosis for children with LVNC. Novel insights show that the interplay of genetics, morphology, and function determine the outcome in pediatric LVNC. Full article

(This article belongs to the Special Issue Pediatric Cardiomyopathies: From Genotype to Phenotype)

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15 pages, 1423 KiB

Open AccessEditor’s ChoiceReview

Pediatric Myocarditis: What Have We Learnt So Far?

by Elettra Pomiato, Marco Alfonso Perrone, Rosalinda Palmieri and Maria Giulia Gagliardi

J. Cardiovasc. Dev. Dis. 2022, 9(5), 143; https://doi.org/10.3390/jcdd9050143 - 03 May 2022

Cited by 7 | Viewed by 4292

Abstract

Myocarditis is an inflammatory disease of the myocardium that is troublesome to diagnose and manage, especially in children. Since the introduction of endomyocardial biopsy (EMB), new diagnostic tools have provided useful data. Especially when enhanced with immunohistochemistry and polymerase chain reaction (PCR) studies, EMB remains the gold standard for the diagnosis. Notably, cardiac magnetic resonance (MRI) is a non-invasive tool that can confirm the diagnosis and has a particular usefulness during the follow-up. The causes of myocarditis are heterogeneous (mostly viral in children). The course and outcome of the illness in the pediatric population represent a complex interaction between etiologic agents and the immune system, which is still not fully understood. The clinical presentation and course of myocarditis vary widely from paucisymptomatic illness to acute heart failure refractory to therapy, arrhythmias, angina-like presentation and sudden cardiac death. In this setting, cardiac biomarkers (i.e., troponins and BNP), although unspecific, can be used to support the diagnosis. Finally, the efficacy of therapeutic strategies is controversial and not confirmed by clinical trials. In this review, we summarized the milestones in diagnosis and provided an overview of the therapeutic options for myocarditis in children. Full article

(This article belongs to the Special Issue Pediatric Cardiomyopathies: From Genotype to Phenotype)

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24 pages, 2046 KiB

Open AccessReview

What Aspects of Phenotype Determine Risk for Sudden Cardiac Death in Pediatric Hypertrophic Cardiomyopathy?

by Ingegerd Östman-Smith

J. Cardiovasc. Dev. Dis. 2022, 9(5), 124; https://doi.org/10.3390/jcdd9050124 - 21 Apr 2022

Cited by 1 | Viewed by 2540

Abstract

Sudden cardiac death due to hypertrophic cardiomyopathy (HCM), is the most common autopsy-proven cause of unexpected medical death in children after infancy. This mode of death is preventable by implantation of an internal cardiac defibrillator (ICD), a procedure that has considerable morbidity in childhood patients, and even mortality. Since HCM is an inheritable disease (usually autosomal dominant, occasionally recessive), family screening may identify subjects at risk. This review summarizes published studies carried out to identify which phenotypic markers are important risk factors in childhood patients with HCM and reviews the performance of existing risk-stratification algorithms (HCM Risk-Kids, PRIMaCY) against those of single phenotypic markers. A significant proportion of HCM-patients diagnosed in childhood are associated with RASopathies such as Noonan syndrome, but a knowledge gap exists over risk stratification in this patient group. In conclusion, pediatric risk-stratification algorithms for sudden cardiac death perform better in children than adult HCM risk-stratification strategies. However, current multivariable algorithms overestimate risk substantially without having high sensitivity, and remain ‘a work in progress’. To include additional phenotypic parameters that can be reproducibly measured such as ECG-markers, e.g., ECG risk score (which has high sensitivity and negative predictive value), tissue Doppler diastolic function measurements, and quantification of myocardial scarring on cardiac magnetic resonance imaging, has the potential to improve risk-stratification algorithms. Until that work has been achieved, these are three factors that the clinician can combine with the current algorithm-calculated per cent risk, in order better to assess risk. Full article

(This article belongs to the Special Issue Pediatric Cardiomyopathies: From Genotype to Phenotype)

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11 pages, 1254 KiB

Open AccessEditor’s ChoiceReview

Arrhythmogenic Cardiomyopathy: Diagnosis, Evolution, Risk Stratification and Pediatric Population—Where Are We?

by Marianna Cicenia and Fabrizio Drago

J. Cardiovasc. Dev. Dis. 2022, 9(4), 98; https://doi.org/10.3390/jcdd9040098 - 27 Mar 2022

Cited by 10 | Viewed by 2423

Abstract

Arrhythmogenic cardiomyopathy (ACM) is a cardiomyopathy characterized by the occurrence of a high risk of life-threatening ventricular arrhythmias and sudden cardiac death even at presentation. Diagnosis, evolution and outcomes in adults have been extensively reported, but little data in pediatric population are available. Risk stratification in this particular setting is still a matter of debate and new risk factors are needed in a model of an ever more “individualized medicine”. Full article

(This article belongs to the Special Issue Pediatric Cardiomyopathies: From Genotype to Phenotype)

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11 pages, 270 KiB

Open AccessEditor’s ChoiceReview

Endomyocardial Biopsy in Pediatric Myocarditis and Dilated Cardiomyopathy: A Tool in Search for a Role

by Mara Pilati, Micol Rebonato, Roberto Formigari and Gianfranco Butera

J. Cardiovasc. Dev. Dis. 2022, 9(1), 24; https://doi.org/10.3390/jcdd9010024 - 12 Jan 2022

Cited by 10 | Viewed by 2898

Abstract

Endomyocardial biopsy (EMB) is a well-known diagnostic tool for the investigation and treatment of myocardial diseases and remains the gold standard for the diagnosis of myocarditis. Due to its invasiveness, with a complication rate ranging from 1 to 15%, its role in the diagnostic work-up of pediatric heart failure is not well established. The aim of this review is to define the role of EMB as diagnostic technique in the work up of children presenting with severe left ventricular dysfunction with the support of our center experience. Full article

(This article belongs to the Special Issue Pediatric Cardiomyopathies: From Genotype to Phenotype)

7 pages, 1092 KiB

Open AccessEditor’s ChoiceReview

When Should Premature Ventricular Contractions Be Considered as a Red Flag in Children with Cardiomyopathy?

by Marianna Cicenia, Massimo S. Silvetti and Fabrizio Drago

J. Cardiovasc. Dev. Dis. 2021, 8(12), 176; https://doi.org/10.3390/jcdd8120176 - 10 Dec 2021

Cited by 3 | Viewed by 3718

Abstract

Premature ventricular contractions (PVCs) are common and generally benign in childhood and tend to resolve spontaneously in most cases. When PVCs occur frequently, an arrhythmia-induced cardiomyopathy may be present requiring medical or catheter ablation. PVCs are only rarely the manifestation of a cardiomyopathy. The purpose of this review is to provide some tips and tricks to raise the suspicion of a cardiac disease based on the presence and characteristics of PVCs in children. Full article

(This article belongs to the Special Issue Pediatric Cardiomyopathies: From Genotype to Phenotype)

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Other

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7 pages, 1394 KiB

Open AccessCase Report

Further Evidence of Autosomal Recessive Inheritance of RPL3L Pathogenic Variants with Rapidly Progressive Neonatal Dilated Cardiomyopathy

by Hemanth Nannapaneni, Stephanie Ghaleb, Sandeep Arya, Viswanath Gajula, Mary B. Taylor and Bibhuti B. Das

J. Cardiovasc. Dev. Dis. 2022, 9(3), 65; https://doi.org/10.3390/jcdd9030065 - 22 Feb 2022

Cited by 6 | Viewed by 2131

Abstract

Neonatal dilated cardiomyopathy (DCM) is rare with high etiologic heterogeneity. Recently, biallelic, autosomal recessive, pathogenic variants in RPL3L (ribosomal protein L3-like) have been reported in the literature with severe early-onset DCM. In the present brief report, we identified two pathogenic RPL3L variants, each harbored in unaffected heterozygous parents: mother (RPL3L c.1076_1080delCCGTG (p.Ala359Glyfs*4)) and father (RPL3L c.80G > A (p.Gly27Asp)). Pathogenic variants were segregated as autosomal recessive to two offspring born with compound heterozygous RPL3L variants and affected by neonatal DCM. This is the second report in the literature to the best of our knowledge and our findings support the pathogenicity of biallelic RPL3L pathologic variants associated with rapidly progressive neonatal DCM and heart failure with a poor prognosis. Full article

(This article belongs to the Special Issue Pediatric Cardiomyopathies: From Genotype to Phenotype)

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