講演情報
[I-AEPCYIA-5]Genetic Background of Patients with Childhood-Onset Cardiomyopathy: Results from a Retrospective Cohort Study
○Wannes Renders1, Evelien Cansse1, Max Basciali2, Joseph Panzer1, Hans De Wilde1, Kristof Van De Kerckhove1, Bert Callewaert3, Arnaud Van Lander1, Katya De Groote1, Daniel De Wolf1, Laura Muiño Mosquera1 (1.Department of pediatrics, Ghent University Hospital Ghent Belgium, 2.Faculty of medicine and health sciences, Ghent University Ghent Belgium, 3.Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium)
キーワード：
Genetics、Childhood-onset cardiomyopathy、sarcomere genes
INTRODUCTION:Childhood-onset cardiomyopathy (CMP) has a rare incidence of approximately 1/100 000 children. 40-50% of children have a positive familial history of cardiomyopathy or sudden cardiac death and the general yielding across the different types of CMP is 50-60%, with dilated CMP (DCM) having the lowest genetic yield (20-30%). A high proportion of rare disease phenocopies such as metabolic disorders and RASopathies is generally found in early childhood (<10yrs).
AIM: To investigate genotype-phenotype correlations and cardiac outcomes.
METHODS:Children under 18yrs who presented at our institution between 1990-2024 with any type of CMP, were included in the study. Demographic, genetic, and cardiac outcome data were collected and analyzed.
RESULTS:A total of 157 children (63.1% male, mean age: 5.3±5.8yrs) were diagnosed with CMP. The most frequent subtypes were DCM (49%) and hypertrophic CMP (HCM, 47.1%) with fewer cases of restrictive CMP (RCM, 5 patients) and arrhythmogenic CMP (ACM, 1 patient). Nearly half of the patients (46.5%) were diagnosed during infancy. Genetic screening was performed in 68.8% of patients, most frequently in HCM (74.3%). Overall, a causative variant was identified in 56.5%. Genetic yield was higher in children with HCM in comparison to those with DCM (65.4% vs 46.9%, p=0.067). Additionally, in 15.7% variants of unknown significance (VUS) were found. A trend of higher genetic yield was seen in older age groups. In infants (0-1yrs), a variant in a metabolic or RASopathy gene was found in 57.1%. Notably, sarcomere gene variants, traditionally associated with adult-onset CMP, contributed to 28.6% of infant cases. Major cardiac events occurred in 43.3%. Of all patients 25.5% died, 12.1% underwent a heart transplant and 7% received an implantable cardioverter-defibrillator. No significant differences in outcomes were observed across CMP subtypes.
CONCLUSIONS:Genetic testing identified the underlying etiology in over 50% of patients with childhood-onset CMP. While rare disease phenocopies are highly prevalent in infants, sarcomere gene variants –once thought to be limited to adult-onset CMP– can also manifest in a very young age. These findings underscore the importance of early genetic testing to guide diagnosis and management.
Figure 1. a) Distribution of cardiomyopathy subtypes. DCM= Dilated CMP, HCM = Hypertrophic CMP, RCM = Restrictive CMP, ACM = Arrhythmogenic CMP b) Causative variants (likely pathogenic and pathogenic) per gene category, displayed according to age group. In the “structural” group genes encoding the Z-disc (ACTN2, NEXN2), nuclear envelope (LMNA), cytoskeletal (FLNC, DES) and junctional membrane (JPH2) are included.
AIM: To investigate genotype-phenotype correlations and cardiac outcomes.
METHODS:Children under 18yrs who presented at our institution between 1990-2024 with any type of CMP, were included in the study. Demographic, genetic, and cardiac outcome data were collected and analyzed.
RESULTS:A total of 157 children (63.1% male, mean age: 5.3±5.8yrs) were diagnosed with CMP. The most frequent subtypes were DCM (49%) and hypertrophic CMP (HCM, 47.1%) with fewer cases of restrictive CMP (RCM, 5 patients) and arrhythmogenic CMP (ACM, 1 patient). Nearly half of the patients (46.5%) were diagnosed during infancy. Genetic screening was performed in 68.8% of patients, most frequently in HCM (74.3%). Overall, a causative variant was identified in 56.5%. Genetic yield was higher in children with HCM in comparison to those with DCM (65.4% vs 46.9%, p=0.067). Additionally, in 15.7% variants of unknown significance (VUS) were found. A trend of higher genetic yield was seen in older age groups. In infants (0-1yrs), a variant in a metabolic or RASopathy gene was found in 57.1%. Notably, sarcomere gene variants, traditionally associated with adult-onset CMP, contributed to 28.6% of infant cases. Major cardiac events occurred in 43.3%. Of all patients 25.5% died, 12.1% underwent a heart transplant and 7% received an implantable cardioverter-defibrillator. No significant differences in outcomes were observed across CMP subtypes.
CONCLUSIONS:Genetic testing identified the underlying etiology in over 50% of patients with childhood-onset CMP. While rare disease phenocopies are highly prevalent in infants, sarcomere gene variants –once thought to be limited to adult-onset CMP– can also manifest in a very young age. These findings underscore the importance of early genetic testing to guide diagnosis and management.
Figure 1. a) Distribution of cardiomyopathy subtypes. DCM= Dilated CMP, HCM = Hypertrophic CMP, RCM = Restrictive CMP, ACM = Arrhythmogenic CMP b) Causative variants (likely pathogenic and pathogenic) per gene category, displayed according to age group. In the “structural” group genes encoding the Z-disc (ACTN2, NEXN2), nuclear envelope (LMNA), cytoskeletal (FLNC, DES) and junctional membrane (JPH2) are included.
