講演情報
[II-TKIS-P-8]Systematic Re-evaluation of Genetic Variants in Pediatric Inherited Arrhythmia Syndrome
○Yoji Nomura, Takanori Suzuki, Hiromu Ukai, Saori Sugawara, Yuya Yamada, Yu Tanaka, Machiko Kito, Satoru Kawai, Shuichiro Yoshida (The Department of Pediatric Cardiology, Aichi Children's Medical and Health Center, Aichi, Japan)
キーワード：
Pediatric inherited arrhythmia、Genetic variant reclassification、Genetic testing reinterpretation
Background
Interpretation of genetic variants associated with pediatric inherited arrhythmia syndromes may change over time as evidence accumulates. Genetic testing performed in childhood is often interpreted using limited contemporary evidence. However, variant reclassification in pediatric arrhythmia cohorts remains insufficiently characterized.
Methods
Patients with pediatric-onset inherited arrhythmia syndromes followed at Aichi Children's Health and Medical Center between 2005 and 2025 were included. Genetic variants identified through clinical genetic testing in 76 pediatric probands and their family members (197 tests) were systematically re-evaluated. Initial classifications were reassessed using updated American College of Medical Genetics and Genomics criteria. Family testing was included as variant-level evidence incorporating segregation information. Reclassification was analyzed at the variant level and summarized across genes.
Results
Sixty-one variants across 10 arrhythmia-related genes were re-evaluated. The most frequent genes were KCNQ1 (n=19), KCNH2 (n=13), and RYR2 (n=10). After re-evaluation, 49 variants (80%) remained pathogenic or likely pathogenic, whereas 12 (20%) were reclassified as VUS or likely benign. No variants initially classified as benign or likely benign were upgraded.
Conclusions
Systematic re-evaluation reduced potential overclassification while preserving stability of benign variants. Continued reinterpretation of childhood genetic test results may improve long-term genetic diagnosis and clinical management in pediatric patients.
Interpretation of genetic variants associated with pediatric inherited arrhythmia syndromes may change over time as evidence accumulates. Genetic testing performed in childhood is often interpreted using limited contemporary evidence. However, variant reclassification in pediatric arrhythmia cohorts remains insufficiently characterized.
Methods
Patients with pediatric-onset inherited arrhythmia syndromes followed at Aichi Children's Health and Medical Center between 2005 and 2025 were included. Genetic variants identified through clinical genetic testing in 76 pediatric probands and their family members (197 tests) were systematically re-evaluated. Initial classifications were reassessed using updated American College of Medical Genetics and Genomics criteria. Family testing was included as variant-level evidence incorporating segregation information. Reclassification was analyzed at the variant level and summarized across genes.
Results
Sixty-one variants across 10 arrhythmia-related genes were re-evaluated. The most frequent genes were KCNQ1 (n=19), KCNH2 (n=13), and RYR2 (n=10). After re-evaluation, 49 variants (80%) remained pathogenic or likely pathogenic, whereas 12 (20%) were reclassified as VUS or likely benign. No variants initially classified as benign or likely benign were upgraded.
Conclusions
Systematic re-evaluation reduced potential overclassification while preserving stability of benign variants. Continued reinterpretation of childhood genetic test results may improve long-term genetic diagnosis and clinical management in pediatric patients.