Clinical Information

Long QT syndrome (LQTS) is a genetic cardiac arrhythmia condition characterized by QT prolongation and T-wave abnormalities on an electrocardiogram (ECG). LQTS may result in or present with recurrent syncope, ventricular arrhythmia (commonly torsade de pointes), sudden cardiac arrest, and sudden cardiac death. Some subtypes of LQTS are also referred to as Romano-Ward syndrome (RWS).(1)

LQTS has a prevalence of approximately 1:2000 and is caused by loss-of-function, disease-causing variants in genes that encode cardiac ion channels or associated proteins. It is estimated that up to 75% of individuals meeting clinical diagnostic criteria for LQTS are found to harbor a disease-causing variant in one of three genes: KCNQ1, KCNH2, and SCN5A.(2) Disease-causing variants in additional genes contribute to a minority of LQTS cases.(2) In most cases, LQTS follows an autosomal dominant pattern of inheritance.

Jervell and Lange-Nielsen syndrome (JLNS) is a rare condition characterized by prolonged QT interval and congenital profound bilateral sensorineural hearing loss. JLNS follows an autosomal recessive inheritance pattern and is caused by homozygous or compound heterozygous disease-causing variants in either KCNQ1 or KCNE1.(1)

Andersen-Tawil syndrome is a rare condition characterized by prolonged QT interval, ventricular arrhythmias, episodic muscle weakness, and congenital anomalies that may include facial dysmorphology, clinodactyly, hand/foot syndactyly, short stature, and scoliosis. Andersen-Tawil syndrome follows an autosomal dominant inheritance pattern and is caused by disease-causing variants in the KCNJ2 gene.(3)

Timothy syndrome is a rare, systemic condition involving prolonged QT interval in association with seizures, neurodevelopmental delays, recurrent infections, and congenital anomalies that may include hand/foot syndactyly, structural heart defects, and facial dysmorphology. Timothy syndrome follows an autosomal dominant patten of inheritance and is caused by disease-causing variants in the CACNA1C gene.(4)

Genetic testing in LQTS is recommended and supported by multiple consensus statements to confirm the clinical diagnosis, assist with risk stratification, guide management, and identify at-risk family members. Even individuals with a normal QT interval may still be at risk for a cardiac event and sudden cardiac death and, thus, ECG analysis alone is insufficient to rule out the diagnosis and genetic testing is necessary to confirm the presence or absence of disease in at-risk family members.(1-4)