Genetic basis of hypertrophic cardiomyopathy in children

Rupp, Stefan; Felimban, Moataz; Schänzer, Anne; Schranz, Dietmar; Marschall, Christoph; Zenker, Martin; Logeswaran, Thushiha; Neuhäuser, Christoph; Thul, Josef; Jux, Christian; Hahn, Andreas

doi:10.1007/s00392-018-1354-8

Cited by 25 publications

(21 citation statements)

References 23 publications

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“…The observation that the development of left ventricular hypertrophy in individuals with familial disease often occurs during the period of somatic growth in adolescence has led to the suggestion that sarcomeric protein disease in very young children is rare 61,62 . However, studies of children with HCM have shown that, as in adults, sarcomeric protein gene mutations account for approximately 50% of cases of idiopathic HCM, even in infants and young children 63,64 .…”

Section: Childhood-onset Hcmmentioning

confidence: 99%

The genetics of hypertrophic cardiomyopathy

Akhtar

Elliott

2018

gcsp

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Hypertrophic cardiomyopathy (HCM) is most commonly transmitted as an autosomal dominant trait, caused by mutations in genes encoding cardiac sarcomere proteins1–3. Other inheritable causes of the disease include mutations in genes coding for proteins important in calcium handling or that form part of the cytoskeleton4–6. At present, the primary clinical role of genetic testing in HCM is to facilitate familial screening to allow the identification of individuals at risk of developing the disease7,8. It is also used to diagnose genocopies, such as lysosomal9–11 and glycogen storage disease which have different treatment strategies, rates of disease progression and prognosis12–14. The role of genetic testing in predicting prognosis is limited at present, but emerging data suggest that knowledge of the genetic basis of disease will assume an important role in disease stratification15–17 and offer potential targets for disease-modifying therapy in the near future18.

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Section: Childhood-onset Hcmmentioning

confidence: 99%

The genetics of hypertrophic cardiomyopathy

Akhtar

Elliott

2018

gcsp

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“…In this review we have chosen to discuss them due to the increased cardiac and therapeutic options related to these disorders. Cardiac manifestations include: cardiomyopathies (CMPs) mainly in their dilated and hypertrophic forms [ 1 , 5 , 6 , 7 , 8 ]; heart rhythm changes, including atrioventricular conduction defects (AVCD); supraventricular tachycardia (SVT); atrial fibrillation (AF) and life threatening ventricular arrhythmias (VA). (However, other less frequently observed manifestations in children include structural cardiac defects such as valvular abnormalities) [ 1 , 7 , 8 , 9 , 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

Myocardial and Arrhythmic Spectrum of Neuromuscular Disorders in Children

Baban¹,

Lodato²,

Parlapiano

et al. 2021

Biomolecules

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Neuromuscular disorders (NMDs) are highly heterogenous from both an etiological and clinical point of view. Their signs and symptoms are often multisystemic, with frequent cardiac involvement. In fact, childhood onset forms can predispose a person to various progressive cardiac abnormalities including cardiomyopathies (CMPs), valvulopathies, atrioventricular conduction defects (AVCD), supraventricular tachycardia (SVT) and ventricular arrhythmias (VA). In this review, we selected and described five specific NMDs: Friedreich’s Ataxia (FRDA), congenital and childhood forms of Myotonic Dystrophy type 1 (DM1), Kearns Sayre Syndrome (KSS), Ryanodine receptor type 1-related myopathies (RYR1-RM) and Laminopathies. These changes are widely investigated in adults but less researched in children. We focused on these specific topics due their relative frequency and their potential unexpected cardiac manifestations in children. Moreover these conditions present different inheritance patterns and mechanisms of action. We decided not to discuss Duchenne and Becker muscular dystrophies due to extensive work regarding the cardiac aspects in children. For each described NMD, we focused on the possible cardiac manifestations such as different types of CMPs (dilated-DCM, hypertrophic-HCM, restrictive-RCM or left ventricular non compaction-LVNC), structural heart abnormalities (including valvulopathies), and progressive heart rhythm changes (AVCD, SVT, VA). We describe the current management strategies for these conditions. We underline the importance, especially for children, of a serial multidisciplinary personalized approach and the need for periodic surveillance by a dedicated heart team. This is largely due to the fact that in children, the diagnosis of certain NMDs might be overlooked and the cardiac aspect can provide signs of their presence even prior to overt neurological diagnosis.

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“…Cirino et al compared the results from NGS panels in 41 HCM patients with whole genome sequencing (WGS) and concluded that WGS and panel testing provided similar diagnostics yield in adult patients [37]. In contrast, Rupp et al studying young patients with diagnosis of HCM before 18 years concluded that WES/WGS was an alternative after negative panel diagnostics [38]. Rupp et al pointed out that panels analyzing genes associated with CM should also focus on multisystemic conditions when applied in younger children.…”

Section: Discussionmentioning

confidence: 99%

Hereditary Hypertrophic Cardiomyopathy in Children and Young Adults—The Value of Reevaluating and Expanding Gene Panel Analyses

Fernlund

Kissopoulou

Gréen

et al. 2020

Genes

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Introduction: Sudden cardiac death (SCD) and early onset cardiomyopathy (CM) in the young will always lead to suspicion of an underlying genetic disorder. Incited by the rapid advances in genetic testing for disease we have revisited families, which previously tested “gene-negative” for familial predominantly pediatric CM, in hopes of finding a causative gene variant. Methods: 10 different families with non-syndromic pediatric CM or hypertrophic cardiomyopathy (HCM) with severe disease progression and/or heredity for HCM/CM related SCD with “gene-negative” results were included. The index patient underwent genetic testing with a recently updated gene panel for CM and SCD. In case of failure to detect a pathogenic variant in a relevant gene, the index patient and both parents underwent clinical (i.e., partial) exome sequencing (trio-exome) in order to catch pathogenic variants linked to the disease in genes that were not included in the CM panel. Results: The mean age at clinical presentation of the 10 index cases was 12.5 years (boys 13.4 years, n = 8; girls 9 years, n = 2) and the family history burden was 33 HCM/CM cases including 9 HCM-related SCD and one heart transplantation. In 5 (50%) families we identified a genetic variant classified as pathogenic or likely pathogenic, in accordance with the American College of Medical Genetics and Genomics (ACMG) criteria, in MYH7 (n = 2), RBM20, ALPK3, and PGM1, respectively, and genetic variants of unknown significance (VUS) segregating with the disease in an additional 3 (30%) families, in MYBPC3, ABCC9, and FLNC, respectively. Conclusion: Our results show the importance of renewed thorough clinical assessment and the necessity to challenge previous genetic test results with more comprehensive updated gene panels or exome sequencing if the initial test failed to identify a causative gene for early onset CM or SCD in children. In pediatric cardiomyopathy cases when the gene panel still fails to detect a causative variant, a trio exome sequencing strategy might resolve some unexplained cases, especially if a multisystemic condition is clinically missed.

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Genetic basis of hypertrophic cardiomyopathy in children

Cited by 25 publications

References 23 publications

The genetics of hypertrophic cardiomyopathy

The genetics of hypertrophic cardiomyopathy

Myocardial and Arrhythmic Spectrum of Neuromuscular Disorders in Children

Hereditary Hypertrophic Cardiomyopathy in Children and Young Adults—The Value of Reevaluating and Expanding Gene Panel Analyses

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