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Long QT Syndrome

April 07, 2017

Disease synonyms

Long QT syndrome (LQTS), Ward-Romano syndrome (WRS, Romano-Ward syndrome (RWS), Ventricular fibrillation with prolonged QT interval

Inheritance pattern

Autosomal dominant, autosomal recessive

Clinical features

Long QT syndrome (LQTS) is a rare cardiac disease associated with syncope and sudden death due to torsades de pointes and ventricular fibrillation. Syncope and sudden death are frequently associated with physical and emotional stress. LQTS is a cardiac electrophysiologic disorder, characterized by changes in the electrocardiogram (ECG), such as QT prolongation, T-wave abnormalities, accompanied by the ventricular tachycardia torsade de pointes (TdP). TdP have a tendency to self-terminate, leading to the loss of consciousness (syncope), the most common symptom in individuals with LQTS. Syncope typically occurs without warning during exercise and stress/high emotions.

Long QT syndrome (LQTS) should be suspected in individuals on the basis of ECG characteristics, clinical presentation, and family history.

Major clinical findings in LQTS-affected patients include the following:

  • Abnormal QT values on ECG
  • Prolonging of QT segments by specific drugs
  • Hypokalemia
  • Certain neurologic conditions including subarachnoid bleeding
  • Structural heart disease

Determination of QT intervals using measurement in resting and after exercise and intravenous pharmacological provocation testing are useful diagnostic procedures which can be used to clinically diagnose LQTS. However, approximately 50% of all LQTS patients who had one or few syncopal events have a positive family history and/or genetic background of the disease.1

The genetic forms of LQTS include the following:

  • Romano-Ward syndrome (RWS), which is characterized by isolated LQTS and an autosomal dominant pattern of inheritance
  • Jervell and Lange-Nielsen syndrome, where LQTS is associated with congenital deafness and the pattern of inheritance is autosomal recessive
  • Andersen syndrome, where LQTS is present in combination with periodic paralysis and dysmorphic features
  • Timothy syndrome, characterized by severe LQTS, cardiac and other malformations such as syndactyly and autism.

Presently, mutations in >15 genes have been associated with LQTS. Four genes have been associated with both LQTS and short QTS (characterized by shortening of the QT fragment): KCNQ1, KCNH2, KCNJ2, and CACNA1C. All of these encode subunits of calcium or potassium channels that regulate normal heart contractions and rhythm. Thus, LQTS has been shown to be an ion channelopathy associated with loss-of-function mutations in genes encoding repolarizing K1-ion channels, their subunits, and certain interacting proteins: ANK2, KCNE1, KCNQ1, KCNH2, KCNJ2, CACNA1C, and others (see Table 1).

Management of patients with LQTS consists of treatment with beta-blockers, implantable cardioverter-defibrillator (ICD) implantation and left cardiac sympathetic denervation (LCSD). Prohibition of competitive exercise and avoidance of QT-prolonging drugs are important issues in life-style modification.

CENTOGENE experts have designed the Long QT syndrome panel which includes the genes: AKAP9, ANK2, CACNA1C, CALM1, CALM2, CALM3, CAV3, KCNE1, KCNE2, KCNH2, KCNJ2, KCNJ5, KCNQ1, SCN4B, SCN5A, SNTA1, and TRDN (Table 1). CENTOGENE offers the Long QT syndrome panel, including sequencing and deletion/duplication analysis of selected genes (KCNE2, SCN5A, CAV3, KCNQ1, KCNH2, KCNE1, KCNJ2). In addition, any of the genes in the Long QT syndrome panel can also be ordered individually, for sequencing and deletion/duplication analysis.

Differential diagnosis

The differential diagnosis of Long QT syndrome-related disorders – depending on the major symptoms in the initial case – includes the following diseases1:

For QT segments interval prolongation:

  • QT-prolonging drugs
  • Hypokalemia
  • Certain neurologic conditions including subarachnoid bleed
  • Structural heart disease

For syncope or sudden death in the young:

  • Sudden infant death syndrome (SIDS)
  • Drug-induced QT prolongation
  • Vasovagal syncope (orthostatic hypotension)
  • Anomalous coronary artery
  • Familial ventricular fibrillation
  • Cardiomyopathies
  • Brugada syndrome
  • Seizures
  • Catecholaminergic polymorphic ventricular tachycardia

Testing strategy

CENTOGENE offers advanced, fast and cost-effective strategy to test large NGS panels and diagnose complex phenotypes based on the PCR-free whole genome sequencing and NGS technology. This approach offers an unparalleled advantage by reducing amplification/capture biases and provides sequencing of entire gene at a more uniform coverage.

To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for Long QT syndrome using NGS Panel Genomic targeted towards this specific phenotype:

Step 1: Whole genome sequencing from a single filter card. The sequencing covers the entire genic region (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the Long QT syndrome panel. Copy Number Variants analysis derived from NGS data is also included.

Step 2: If no mutation is identified after analysis of the Long QT syndrome panel, based on the approval and consent, we further recommend to continue the bioinformatics analysis of the data obtained by whole genome sequencing to cover genes that are either implicated in an overlapping phenotype or could be involved in a similar pathway but not strongly clinically implicated based on the current information in literature.

Referral reasons

The following individuals are candidates for this particular gene testing:

  • Individuals with a family history of disease and presentation of the most common symptoms
  • Individuals without a positive family history, but with symptoms resembling this disease
  • Individuals with a negative but suspected family history, in order to perform proper genetic counseling (prenatal analyses are recommended in families with affected individuals).

Test utility

Sequencing, deletion/duplication of this gene and related genes should be performed in all individuals suspected for this particular phenotype. In parallel, other genes reported to be related with this clinical phenotype should also be analyzed for the presence of mutations, due to the overlap in many clinical features caused by those particular genes.

Confirmation of a clinical diagnosis through genetic testing can allow for genetic counseling and may direct medical management.

Genetic counseling can provide a patient and/or family with the natural history of the condition, identify at-risk family members, provide reproductive risks as well as preconception/prenatal options, and allow for appropriate referral for patient support and/or resources.