Beyond the Beat, Next-Generation Sequencing Discovery of Novel

Background: Long QT syndrome (LQTS) is an inherited cardiac channelopathy marked by QT interval prolongation and increased risk of life-threatening arrhythmias. While variants in KCNQ1, KCNH2, and SCN5A explain most cases, many remain genetically unexplained. This study emphasizes the value of genetic testing in diagnosis and individualized therapy. Methods: A 9-year-old boy with recurrent syncope was evaluated for LQTS. Clinical workup included history, physical exam, ECG, echocardiography, exercise testing, electrophysiology studies (EPS), Holter monitoring, and cardiac MRI. Family history was assessed. Genetic testing involved whole-exome sequencing (WES) and Sanger confirmation, followed by bioinformatic pathogenicity analysis. Results: The boy's ECG showed a QTc of 470 ms, extending to 500 ms during EPS. No structural cardiac defects were detected. WES revealed a heterozygous missense variant, NM₀01035. 2: c. 12370A > C (p. Ser4124Arg), in the RYR2 gene. In silico tools predicted it to be pathogenic, and Sanger sequencing confirmed it. The variant was also identified in the patient's mother, who had a history of syncope, but not in the father. The patient responded well to propranolol and remained symptom-free for 18 months. Conclusion: Identification of a pathogenic RYR2 variant expands the known genetic spectrum of LQTS. The patient's clinical and familial findings highlight the need to consider RYR2 in genetic testing panels, especially for atypical LQTS cases. Continued research is essential to further clarify the genetics of LQTS and guide targeted management.