Objectives: We identified the long QT syndrome (LQTS) patients, and detected the potential risk of LQTS in family members by using genetic testing and electrophysiological analysis, which helped provide clinical evaluation and appropriate treatment.
Methods: Detailed clinical characteristics and familiar history were obtained from the whole family members of an idiopathic pediatric LQTS patient. Two hundred healthy subjects with the same ethnic background were recruited as controls. The entire coding sequences of three candidate genes including KCNQ1, KCNH2 and SCN5A were screened for mutations in the proband. The function of the mutation was then explored by whole-cell patch clamp techniques, and the genetic testing and risk assessment of the family members were performed.
Results: The proband was clinically preliminary diagnosed as LQTS by 12-lead electrocardiogram. On the third day of metoprolol intake (25 mg, bid), she died suddenly at lunch. One heterozygous missense mutation (SCN5A-V411M) was identified in this proband, but the mutation was absent in 200 healthy subjects. The electrophysiological analysis indicated that SCN5A-V411M significantly increased the peak current density ((230.8 ± 27.6)pA/pF vs. (101.2 ± 10.9)pA/pF, n=10, P<0.01) and the late sodium current ((156.6 ± 13.6)pA/pF vs. (95.9 ± 7.9)pA/pF, n=12, P<0.01) of sodium channel compared to wide type. The enhanced sodium channel activation with a negative shift in the peak I-V relationship was significantly higher by -50 mV than wide type (85.0%± 7.4% vs. 41.5% ± 2.6%, P<0.01), while the steady-state inactivation curves remained unchanged. Additionally, mother and grandmother of the proband were the silent mutation carriers with no symptoms, who needed the appropriate clinical assessment and follow-up. The proband's twin sister and aunt died of sudden infant death syndrome.
Conclusions: We firstly reported a heterozygote missense mutation (SCN5A-V411M) in this Chinese family. V411M induced "gain of function" of sodium channel and formed the basis of type-3 LQTS. Genetic testing could help to increase the diagnostic accuracy, and facilitate clinical assessment and appropriate therapy to prevent sudden cardiac death of individuals with SCN5A-V411M mutation.