A 15-year-old male carrying pathogenic variants in both SCN5A and KCNH2 presented with an atypical arrhythmic phenotype characterized predominantly by atrial arrhythmias, AV conduction abnormalities, and sinus node disease without the characteristic electrocardiographic features of either Brugada syndrome or LQT2, highlighting the complexity of genotype-phenotype correlations in inherited arrhythmia syndromes.
Key Findings
Background
A 15-year-old male was found to carry two pathogenic variants simultaneously: one in SCN5A (associated with Brugada syndrome) and one in KCNH2 (associated with LQT2).
SCN5A variants are classically associated with Brugada syndrome
KCNH2 variants are classically associated with Long QT Syndrome type 2 (LQT2)
Both conditions predispose affected individuals to ventricular arrhythmias and sudden cardiac death
The co-occurrence of pathogenic variants in both genes in the same patient represents a complex genetic substrate
Results
The patient presented with an atypical phenotype lacking the characteristic electrocardiographic features of either Brugada syndrome or LQT2.
Clinical presentation was characterized predominantly by atrial arrhythmias
The classic ECG findings expected for either Brugada syndrome or LQT2 were absent
Discussion
The arrhythmic phenotype was attributed predominantly to the SCN5A variant rather than the KCNH2 variant.
The SCN5A variant was identified as the most likely primary driver of the clinical phenotype
SCN5A loss-of-function can impair atrial conduction, sinus node function, and AV conduction in addition to causing Brugada syndrome
The atrial and conduction system abnormalities observed are consistent with SCN5A dysfunction
Results
A transvenous implantable cardioverter-defibrillator (ICD) was implanted due to unpredictable high-grade conduction block and potential ventricular arrhythmia risk.
The patient experienced episodes of high-grade conduction block that were unpredictable
Risk of ventricular arrhythmias was considered given the dual genetic substrate
A transvenous ICD was chosen as the management strategy
The decision reflects individualized genetics-informed management
Results
Family screening revealed that the SCN5A and KCNH2 variants segregated in different relatives, each exhibiting mild or absent phenotype.
Relatives carrying only the SCN5A variant had mild or absent phenotype
Relatives carrying only the KCNH2 variant had mild or absent phenotype
The segregation pattern suggests that co-inheritance of both variants contributed to the severity and atypicality of the proband's phenotype
Family screening was essential in characterizing the genetic architecture of the arrhythmia syndrome in this family
Conclusions
This case highlights the complexity of genotype-phenotype correlations when multiple pathogenic variants in cardiac ion channel genes co-occur in a single patient.
The simultaneous presence of SCN5A and KCNH2 variants produced a phenotype not typical of either syndrome alone
Standard diagnostic criteria for Brugada syndrome or LQT2 may be insufficient to capture complex multi-gene presentations
The authors emphasize the importance of individualized genetics-informed management in such cases
Inherited arrhythmia syndromes can have overlapping and atypical presentations when multiple channelopathy-associated variants are present
What This Means
This research describes a case of a 15-year-old boy who was found to carry two different genetic mutations affecting the electrical system of his heart — one in a gene called SCN5A and another in a gene called KCNH2. Each of these mutations on its own is known to cause a specific inherited heart rhythm disorder: SCN5A mutations typically cause Brugada syndrome, and KCNH2 mutations typically cause Long QT syndrome type 2. Both conditions can lead to dangerous heart rhythm problems and sudden cardiac death. However, this patient did not show the classic warning signs on his electrocardiogram (ECG) for either condition. Instead, he had unusual symptoms including problems with his heart's upper chambers (atrial arrhythmias), abnormal electrical conduction between the upper and lower chambers of his heart, and dysfunction of the heart's natural pacemaker. The researchers concluded that the SCN5A mutation was primarily responsible for his unusual presentation.
When the patient's family members were tested, the two mutations were found to be inherited from different sides of the family, with each relative carrying only one of the two mutations having mild or no symptoms. This suggests that having both mutations together created a more complex and unpredictable condition than either mutation alone would produce. Because the patient had episodes of dangerous conduction block and an ongoing risk of life-threatening heart rhythms, doctors implanted a device called an implantable cardioverter-defibrillator (ICD) to protect him.
This research suggests that when patients carry mutations in more than one cardiac ion channel gene, the resulting heart condition can look very different from what doctors typically expect based on each gene alone. This makes diagnosis and treatment more challenging and underscores the importance of comprehensive genetic testing and personalized care in young patients with unexplained heart rhythm problems. Standard diagnostic criteria for these inherited conditions may not be sufficient when multiple genetic variants are present simultaneously.
Bienjonetti-Boudreau D, Tremblay-Laganiere C, Gkogkou E, Martinez A, Gonzalez Corcia C. (2026). A Complex Arrhythmic Phenotype in a Pediatric Patient with Variants in SCN5A and KCNH2.. Genes. https://doi.org/10.3390/genes17080885