Background
- Mutation/variant-site specific risk stratification in long-QT syndrome type 1 (LQT1) has been well investigated, but it is still challenging to adapt current enormous genomic information to clinical aspects caused by each mutation/variant. We assessed a novel variant-specific risk stratification in LQT1 patients.
Methods
- We classified a pathogenicity of 141
KCNQ1
variants among 927 LQT1 patients (536 probands) based on the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP) guidelines and evaluated whether the ACMG/AMP-based classification was associated with arrhythmic risk in LQT1 patients.
Results
- Among 141
KCNQ1
variants, 61 (43.3%), 55 (39.0%), and 25 (17.7%) variants were classified into pathogenic (P), likely pathogenic (LP), and variant of unknown significance (VUS), respectively. Multivariable analysis showed that proband (HR = 2.53; 95%CI = 1.94-3.32; p <0.0001), longer QTc (≥500ms) (HR = 1.44; 95%CI = 1.13-1.83; p = 0.004), variants at membrane spanning (MS) (vs. those at N/C terminus) (HR = 1.42; 95%CI = 1.08-1.88; p = 0.01), C-loop (vs. N/C terminus) (HR = 1.52; 95%CI = 1.06-2.16; p = 0.02), and P variants [(vs. LP) (HR = 1.72; 95%CI = 1.32-2.26; p <0.0001), (vs. VUS) (HR = 1.81; 95%CI = 1.15-2.99; p = 0.009)] were significantly associated with syncopal events. The ACMG/AMP-based
KCNQ1
evaluation was useful for risk stratification not only in family members but also in probands. A clinical score (0~4) based on proband, QTc (≥500ms), variant location (MS or C-loop) and P variant by ACMG/AMP guidelines allowed identification of patients more likely to have arrhythmic events.
Conclusions
- Comprehensive evaluation of clinical findings and pathogenicity of
KCNQ1
variants based on the ACMG/AMP-based evaluation may stratify arrhythmic risk of congenital long-QT syndrome type 1.
The Common Long-QT Syndrome Mutation KCNQ1/A341V Causes Unusually Severe Clinical Manifestations in Patients With Different Ethnic Backgrounds
