Pediatric Hypertrophic Cardiomyopathy: Exploring the Genotype‐Phenotype Association

Nguyen, Minh; Mital, Seema; Mertens, Luc; Jeewa, Aamir; Friedberg, Mark K.; Aguet, Julien; Adler, Arnon; Lam, Christopher Z.; Dragulescu, Andréea; Rakowski, Harry; Villemain, Olivier

doi:10.1161/jaha.121.024220

Cited by 13 publications

(10 citation statements)

References 60 publications

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“…This adds to the existing literature correlating P/LP variants in thick filaments (particularly in MYH7 and MYBPC3 ) with worse outcomes in pediatric HCM. 10 , 23 , 24 However, this finding contrasts with our previous results in adult-diagnosed HCM, in which variants in thin filament genes were associated with a higher risk of incident LVSD. 11 In a retrospective study of 230 adults with HCM, thin filament–related HCM was associated with a lower prevalence of outflow tract obstruction and a lower maximal wall thickness but a higher predilection for advanced HF, systolic dysfunction, and restrictive physiology compared with thick filament–related HCM.…”

Section: Discussioncontrasting

confidence: 99%

Left Ventricular Systolic Dysfunction in Patients Diagnosed With Hypertrophic Cardiomyopathy During Childhood: Insights From the SHaRe Registry

et al. 2023

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BACKGROUND: The development of left ventricular systolic dysfunction (LVSD) in hypertrophic cardiomyopathy (HCM) is rare but serious and associated with poor outcomes in adults. Little is known about the prevalence, predictors, and prognosis of LVSD in patients diagnosed with HCM as children. METHODS: Data from patients with HCM in the international, multicenter SHaRe Registry (Sarcomeric Human Cardiomyopathy) were analyzed. LVSD was defined as left ventricular ejection fraction <50% on echocardiographic reports. Prognosis was assessed by a composite of death, cardiac transplantation, and left ventricular assist device implantation. Predictors of developing incident LVSD and subsequent prognosis with LVSD were assessed using Cox proportional hazards models. RESULTS: We studied 1010 patients diagnosed with HCM during childhood (<18 years of age) and compared them with 6741 patients with HCM diagnosed as adults. In the pediatric HCM cohort, median age at HCM diagnosis was 12.7 years (interquartile range, 8.0–15.3), and 393 (36%) patients were female. At initial SHaRe Registry site evaluation, 56 (5.5%) patients with childhood-diagnosed HCM had prevalent LVSD, and 92 (9.1%) developed incident LVSD during a median follow-up of 5.5 years. Overall LVSD prevalence was 14.7% compared with 8.7% in patients with adult-diagnosed HCM. Median age at incident LVSD was 32.6 years (interquartile range, 21.3–41.6) for the pediatric cohort and 57.2 years (interquartile range, 47.3–66.5) for the adult cohort. Predictors of developing incident LVSD in childhood-diagnosed HCM included age <12 years at HCM diagnosis (hazard ratio [HR], 1.72 [CI, 1.13–2.62), male sex (HR, 3.1 [CI, 1.88–5.2), carrying a pathogenic sarcomere variant (HR, 2.19 [CI, 1.08–4.4]), previous septal reduction therapy (HR, 2.34 [CI, 1.42–3.9]), and lower initial left ventricular ejection fraction (HR, 1.53 [CI, 1.38–1.69] per 5% decrease). Forty percent of patients with LVSD and HCM diagnosed during childhood met the composite outcome, with higher rates in female participants (HR, 2.60 [CI, 1.41–4.78]) and patients with a left ventricular ejection fraction <35% (HR, 3.76 [2.16–6.52]). CONCLUSIONS: Patients with childhood-diagnosed HCM have a significantly higher lifetime risk of developing LVSD, and LVSD emerges earlier than for patients with adult-diagnosed HCM. Regardless of age at diagnosis with HCM or LVSD, the prognosis with LVSD is poor, warranting careful surveillance for LVSD, especially as children with HCM transition to adult care.

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Section: Discussioncontrasting

confidence: 99%

Left Ventricular Systolic Dysfunction in Patients Diagnosed With Hypertrophic Cardiomyopathy During Childhood: Insights From the SHaRe Registry

et al. 2023

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“…Additionally, patient-8 was found to be homozygous for a nonsynonymous SNV in the MYH7 gene (p.Asp928Val). In fact, MYH7 mutations can lead to a direct effect of delayed relaxation due to abnormal myosin function at the molecular level, which in turn causes inefficient energy use at the myocardial tissue level(Alamo et al, 2017; Nguyen et al, 2022; Toepfer et al, 2020). In patients with MYH7, the most common symptom reported was palpitations in one study(Velicki et al, 2020) but other symptoms of HCM are fatigue, chest pain, and syncope(B. J.…”

Section: Discussionmentioning

confidence: 99%

“…The copyright holder for this this version posted December 20, 2023. ; https://doi.org/10.1101/2023.12.20.23300082 doi: medRxiv preprint level (Alamo et al, 2017;Nguyen et al, 2022;Toepfer et al, 2020). In patients with MYH7, the most common symptom reported was palpitations in one study (Velicki et al, 2020) but other symptoms of HCM are fatigue, chest pain, and syncope(B. J.…”

Section: (Which Was Not Certified By Peer Review) Preprintmentioning

confidence: 99%

Uncovering the Dual Role of Mitochondrial and Nuclear DNA Variants in Pediatric Cardiomyopathies

Temena,

Erzurumluoglu Gokalp,

Susam

et al. 2023

Preprint

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Myocardial defects, originating from disruptions in genes affecting mitochondrial proteins interacting with others, have received limited research attention. In our study involving 27 pediatric cardiomyopathy patients, we explored mitochondrial and nuclear genes for four main cardiomyopathy subtypes. Sequencing cardiomyopathy-associated genes in patients was followed by whole mtDNA sequencing in these individuals, with 31 healthy pediatric controls for the latter part. Our findings uncovered significant pathogenic variants: MYH7 variants in three hypertrophic cardiomyopathy cases, a notable TNNC1 variant inherited interestingly in an autosomal recessive manner in two related restrictive cardiomyopathy patients, and a pathogenic TRDN variant in a left-ventricular non-compaction patient. Both a variant in FOXRED1, functioning in mitochondrial complex I stability, and a MT-CO1 variant were detected in two siblings, influencing early onset together. Additionally, a novel MT-RNR1 variant (m.684T>C) in one case might explain the phenotype. Our study highlights how both mtDNA and nDNA variants could have interconnected roles in understanding cardiomyopathy genetics. This study emphasizes that the functional studies are needed to recognize this dual relationship within bioenergetic pathways in cardiac muscle.

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“…Variations of the genotype do not only cause classic HCM phenotype which is myocardial hypertrophy, but also other phenotypes including diastolic function, fibrosis, perfusion dysfunction, and ECG phenotype [12] . These parameters could impact the prognosis of pediatric HCM and thus signaling the importance of genetic testing and family member screening.…”

Section: Discussionmentioning

confidence: 99%

Rare Case of Pediatric Hypertrophic Obstructive Cardiomyopathy (HOCM) in A 6-year-old Boy: How to Recognize, Assess, and Manage the Risk?

Kartawan

Ashriyah

2023

CCJ

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Highlights: It discusses pediatric HCM which is usually caused by autosomal dominant traits caused by mutation in cardiac sarcomere protein genes. It explains how to recognize the cardiac risk Abstract: Hypertrophic Obstructive Cardiomyopathy (HOCM) is a disease characterized by increased left ventricular (LV) wall thickness and accompanied by obstructive physiology measured by increased LV outflow tract gradient. It is mainly inherited in autosomal dominant traits caused by a mutation in cardiac sarcomere protein genes. In pediatrics, HOCM is rare and comprises a different diagnosis and management approach compared to adults. The risk of sudden cardiac death (SCD) is also higher in the pediatric population. Case Summary. This report is about a case of HOCM found incidentally in a 6-year-old boy and a discussion based on the latest literature review. The patient first came for evaluation for cardiac murmur and abnormality in ECG and chest x-ray. Diagnosis of HOCM was made through echocardiography assessment. Discussion. ICD implantation for primary prevention of SCD was considered based on individualized 5-year SCD risk assessment which is around 7%. Optimal pharmacological therapy with beta-blocker, careful planning of ICD implantation with balanced benefit and risk, and septal reduction surgery when indicated should extend the life expectancy and quality of life of pediatric HOCM. It is both essential and interesting to recognize pediatric HOCM diagnostic findings and to pursue further research about therapies of this rare disease.

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Pediatric Hypertrophic Cardiomyopathy: Exploring the Genotype‐Phenotype Association

Cited by 13 publications

References 60 publications

Left Ventricular Systolic Dysfunction in Patients Diagnosed With Hypertrophic Cardiomyopathy During Childhood: Insights From the SHaRe Registry

Left Ventricular Systolic Dysfunction in Patients Diagnosed With Hypertrophic Cardiomyopathy During Childhood: Insights From the SHaRe Registry

Uncovering the Dual Role of Mitochondrial and Nuclear DNA Variants in Pediatric Cardiomyopathies

Rare Case of Pediatric Hypertrophic Obstructive Cardiomyopathy (HOCM) in A 6-year-old Boy: How to Recognize, Assess, and Manage the Risk?

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