Long QT Syndromes in Children: “More than Meets the Eyes”

Long QT syndrome (LQTS) presents a significant challenge, especially in the pediatric population, due to its heterogeneous milieu and risk of causing malignant arrhythmias that can lead to sudden cardiac death (SCD).[1,2] The recent study by Gu et al. provides a detailed examination of the genetic and clinical landscapes of LQTS in children, offering valuable insights into the crucial role of genetic framework and its potential application in a personalized diagnostic workflow.[3] This commentary aims to contextualize their findings, highlighting the implications for clinical practice and future research. LQTS is characterized by a delayed ventricular repolarization phase of the cardiomyocyte action potential, identifiable by a prolonged QT interval on an electrocardiogram (ECG).[1,2] The prevalence of congenital LQTS is approximately 1 in 2,000–2,500 live births, making early diagnosis and intervention crucial, particularly given its association with SCD risk among young individuals with structurally normal hearts.[1,2] LQTS comprises 17 subtypes, the most common of which are LQTS1, LQTS2, and LQTS3, accounting for about 75% of all LQTS patients. The genes commonly implicated are KCNQ1, KCNH2, and SCN5A.[1,2] These genetic mutations are associated with varying degrees of arrhythmic predisposition and sensitivity to triggers (e.g., exercise and emotional stress in LQTS1 and LQTS2 and sleep in LQTS3) [Table 1].Table 1: Clinical and genetic characteristics of the most common long QT syndrome subtypes in childrenIn this study, Gu et al. analyzed 18 children with prolonged QT intervals, utilizing whole exome sequencing and Sanger sequencing to identify pathogenic variants.[3] Of these patients, 44.4% (8 of 18) were eventually diagnosed with LQTS, with five patients displaying variants in the KCNQ1 gene and three in the SCN5A gene.[4] Notably, this study identified two novel variants in the SCN5A gene (c.1237G>T and c.4426C>A), broadening the known variant spectrum associated with LQTS.[5] Although these novel variants broaden the evolving understanding of the genetic basis of LQTS, it is necessary to confirm their clinical significance to justify a potential integrative role in the current genetic screening protocols. Interestingly, this study’s positive rate of genetic testing was higher than that of other reports, which typically show around a 30% positive rate.[6] This discrepancy could be explained by the adoption in this study of the new American College of Medical Genetics criteria refined by the ClinGen Sequence Variant Interpretation Working Group, which might be more accurate than previous classifications. Still, a potential selection bias due to the small and restricted study population (i.e., children) might have influenced this particular finding.[4] Moreover, in this study, patients with pathogenic variants exhibited a mean QTc (522 ± 36 ms) significantly higher than patients with negative genetic results (481 ± 15 ms), demonstrating also a strong concordance with the Schwartz score, a clinical tool commonly used for LQTS risk assessment.[7,8] Risk stratification is, indeed, intricate in LQTS, requiring an early identification of patients at high risk of life-threatening arrhythmias.[8,9] The current guidelines recommend a preliminary risk assessment starting from clinical features such as presenting symptoms, family history of SCD, and demographic characteristics for planning management strategies.[10] In this context, the authors emphasize the importance of genetic testing in screening for LQTS, particularly in patients with higher Schwartz scores (i.e., >3.5), which proved effective in 63.6% of their patients diagnosed with LQTS. These findings concur with those of Lankaputhra and Voskoboinik, who found that patients with a Schwartz score ≥3.5, QTc ≥500 ms, or close relatives with disease-causative variants had a higher rate of positive genetic testing.[11] The authors, therefore, suggest a diagnostic pathway that prioritizes genetic testing for high-risk patients, improving diagnostic accuracy and resource utilization by reserving timely genetic testing for those most likely to benefit. However, some particular reflections arise from these latter findings: Genetic testing in the context of LQTS holds significant importance across both pediatric and adult populations. While in children, early genetic testing facilitates timely diagnosis, risk stratification, and family screening, which are critical for preventing sudden cardiac events, in adults, particularly those with a family history of LQTS or SCD, genetic testing might help in identifying asymptomatic carriers and support personalized management strategies.[1,2] Second, the study by Gu et al. demonstrated a higher-than-average positive genetic testing rate (44.4%), particularly among patients with elevated Schwartz scores. This finding aligns with the current understanding that a higher Schwartz score, which indicates a more severe clinical phenotype, correlates with an increased likelihood of identifying pathogenic mutations through genetic testing.[3-5] Nonetheless, the diagnosis and management of LQTS in the pediatric population are further complicated by incomplete penetrance.[12] This phenomenon implies some individuals carrying pathogenic variants in LQTS-associated genes (e.g., KCNQ1, KCNH2, and SCN5A) may not exhibit prolonged QT intervals or experience arrhythmic events. Studies have shown that penetrance for LQTS can vary significantly, with estimates ranging from 25% to 50%.[12] Accordingly, the clinical manifestations of LQTS in this study cohort varied widely, from most of the patients primarily presenting with syncope to isolated asymptomatic carriers detected through incidental ECG abnormalities. Factors contributing to incomplete penetrance include genetic modifiers and environmental influences. In this complexity, the results of this study support a complementary approach combining clinical evaluation, ECG findings, and genetic testing to address the phenotypic heterogeneity of LQTS. Finally, the study also underlines the importance of considering LQTS in the differential diagnosis of seizure-like events.[13] LQTS can present with episodic loss of consciousness and convulsive activity, which may be misinterpreted as epileptic seizures, especially in the absence of cardiac symptoms or red flags like a family history of sudden death. Studies have shown that approximately 10% of individuals initially diagnosed with epilepsy actually have cardiac arrhythmias, with LQTS being one of the most common underlying conditions.[13] Gu et al. advocate for routine ECG screening in children with seizures to avoid misdiagnosis, a recommendation sustained by one of their cases initially diagnosed with epilepsy due to nocturnal seizures, which were ultimately attributed to severe arrhythmias caused by LQTS. This case exemplifies the critical need for awareness that LQTS may mimic or overlap with neurological disorders. Noteworthy, when investigating genetic family history for arrhythmias, also inquiring about sudden infant death syndrome (SIDS).[14] The case reports proved the validity of a link between the LQTS and SIDS and also demonstrated that spontaneous mutations in LQTS genes may manifest as and be indistinguishable from classic cases of near-SIDS or of SIDS itself.[15] On the other side, cautiousness is advisable as LQTS can be overdiagnosed when patients with apparently unexplained syncope and borderline QTc might be misclassified for LQTS without definitive proofs. While the genetic findings seem robust and supported by established methods, the study could benefit from a larger sample size to validate these results, further enhance our understanding of genotype–phenotype correlations, and inform personalized treatment strategies. Although the current cohort of 18 patients provides valuable insights, a larger population is needed to detect the genetic diversity and phenotypic variability of LQTS. In addition, the study’s retrospective nature may introduce selection bias and limit generalizability as it might not comprehensively represent the entire LQTS population. From a clinical perspective, identifying asymptomatic variant carriers with prolonged QTc intervals also raises essential considerations for family screening and genetic counseling. The ethical considerations of genetic testing in children, particularly regarding informed consent and permission from family members, warrant further investigation along with the moral implications of foreseeing the risk of adverse events from genetic mutations (e.g., in case of incomplete penetrance phenomenon), especially considering the potential psychological, social, and economic (i.e., health insurance and employment) impact on patients and their families. In conclusion, the study by Gu et al. fosters the knowledge of congenital LQTS in children and provides the basis for integrating genetic testing with clinical evaluation. Their findings reveal the genetic complexity of LQTS and the necessity for refining recommendations toward a tailored approach for screening, diagnosing, and treating this condition. Future research should focus on the progression of LQTS in the pediatric population and the interplay between genetic variants and clinical manifestations. In this scenario, a comprehensive multidisciplinary approach and genotype-guided management may become crucial in improving the outcomes of children with LQTS. Author contributions EB did the conception and design of the editorial, analysis, and interpretation of data, drafting of the manuscript, critical review, and final approval of the manuscript. JK and AA did the analysis and interpretation of data, critical review, and final approval of the manuscript. All authors have given final approval for the current version to be published. Conflicts of interest Dr. Antonio Abbate is an Editorial Board Member of Heart and Mind. The article was subject to the journal’s standard procedures, with peer review handled independently of Dr. Antonio Abbate and the research groups. There are no conflicts of interest.