Abdulkarim Abdulrahman, MD: No financial relationships to disclose
Background: Congenital Long QT syndrome (LQTS) is the most common inherited primary arrhythmia syndrome, characterized by a prolonged QT interval and increased risk of ventricular arrhythmias.
Seven genes have definite or strong evidence for causality in LQTS (KCNQ1, KCNH2, SCN5A, CALM2, CALM1, TRDN, CALM3). 80% of cases have a pathogenic variant in KCNQ1, KCNH2 or SCN5A. Most gene-positive patients are heterozygous for a single nucleotide change (missense or nonsense variant) or small nucleotide insertion or deletion resulting in a frameshift variant. A subset of patients can have atypical genetic features. We explored the scope and phenotype of these non-classical genetic mechanisms for LQTS in the Canadian LQTS registry.
METHODS AND RESULTS: This is a retrospective observational study from the prospective National Hearts in Rhythm Organization Registry (HiRO), which includes patients and family members with LQTS. Genotype-positive LQTS cases enrolled across 23 pediatric and adult cardiogenetic clinics across Canada were included. Patients were screened for non-classical genotypes, defined as digenic, compound heterozygous or homozygous, or large deletions or duplications. Phenotypic and genotypic data were summarized and analyzed.
We screened 1284 cases with LQTS and included all 725 cases that had an identified pathogenic or likely pathogenic variant. 91% of cases had a variant in either KCNQ1 (60.6%), KCNH2 (25.8%) or SCN5A (4.6%). Twelve cases had non-classical genotypes. Median age at diagnosis and gender was similar in both groups. Table 1 compares both LQTS groups. Most cases with non-classical LQTS were probands (91.7%), while 55.3% of classical LQTS cases were identified through family screening (p=0.002). Patients with non-classical LQTS were less likely to have a family history of sudden death (9.1% vs 27.6%).
Symptoms were more common in the non-classical LQTS group compared to the classical LQTS group (58.3% vs 23%, p=0.01). The median QTc was longer in the non-classical LQTS cases, 484.9 msec compared to 460.1 msec. Over a median follow up of 13.3 months, non-classical LQTS patients were more likely to develop cardiac outcomes (syncope, appropriate ICD shock, cardiac arrest, or death during follow-up, 33.3% vs. 3.9%, p< 0.001). In a multivariate logistic regression model, the presence of non-classical genotypes increased the risk of cardiac outcomes by 7.1 times (p=0.004). Table 2 summarizes the details of nonclassical LQTS cases.
Conclusion: The presence of atypical LQTS variants is associated with a more severe phenotype and affects prognosis. Recognizing these “high risk” genotypes when undertaking genetic testing may inform risk stratification and guide management decisions.
