A phenotype-enhanced variant classification framework to decrease the burden of missense variants of uncertain...

Area of Science:

• Genetics
• Cardiology
• Molecular Biology

Background:

• Pathogenic/likely pathogenic (P/LP) variants in KCNQ1 cause Long QT syndrome type 1 (LQT1).
• Despite current guidelines, variants of uncertain significance (VUS) represent approximately 30% of KCNQ1 variants in LQTS patients.

Purpose of the Study:

• To evaluate if a phenotype-enhanced (PE) variant classification approach can decrease the VUS burden in LQTS genetic testing.
• To assess the utility of integrating LQT1-specific clinical features into variant interpretation.

Main Methods:

• Retrospective analysis of 79 KCNQ1 missense variants in 356 patients (Mayo Clinic) and 42 variants in 225 patients (Amsterdam UMC).
• Initial variant classification using American College of Medical Genetics (ACMG) guidelines.
• Readjudication using a PE-ACMG framework incorporating the Schwartz score and LQT1-defining clinical features (T-wave morphology, exertion/swimming events, treadmill test).

Main Results:

• Initial ACMG classification yielded high VUS rates: 35% (Mayo Clinic) and 45% (Amsterdam UMC).
• PE-ACMG readjudication significantly reduced VUS burden to 16% (Mayo Clinic, P = .0007) and 29% (Amsterdam UMC, P = .02).
• The reduction in VUS was observed in two independent cohorts.

Conclusions:

• Phenotype-guided variant adjudication effectively reduces the VUS burden for KCNQ1 missense variants in LQT1.
• Incorporating LQT1-specific clinical and phenotype data enhances the interpretation of KCNQ1 variants found in LQTS genetic testing.