Observed genes

Polygenic score

Influential genes: NOS1AP

Variations in the NOS1AP gene have been associated with the QT interval duration and an increased risk of LQTS.

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Overview

Long QT syndrome represents a heterogeneous family of cardiac disorders affecting the heart’s electrical activity. It is classified as channelopathy, a disease characterized by a change in the flow of ions through the cell membrane. In the heart, this movement of particles (electrically charged particles of sodium, calcium, potassium, and chloride) through ion channels generates the cardiac action potential - an electrical signal, which propagates through the cells to induce a contraction of the heart - and is, therefore, the cornerstone of the heart’s electrical activity.^[4]

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In LQTS, the cardiac conduction system takes longer to recharge after each electrical signal, and therefore the heart is more likely to develop ventricular arrhythmias.^[4] To be precise, LQTS is known to be associated with a characteristic, life-threatening type of cardiac arrhythmia called torsades de pointes.^[1] It is, in fact, a polymorphic ventricular tachycardia, also known as twisting of the points for its characteristic shape seen on an ECG. In this arrhythmia, the ventricles beat rapidly, chaotically, and out of sync. This results in insufficient ventricular contractions and therefore less blood leaving the heart. The lack of oxygenated blood flowing to the brain causes a sudden loss of consciousness, often without any warning. The episode usually terminates spontaneously, if not, fainting may be followed by a full-body seizure. If the dangerous rhythm is not corrected, life-threatening ventricular fibrillation (during which the ventricles merely quiver instead of contracting and the heart is unable to pump blood at all) can occur. This then results in cardiac arrest.^[3]

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As already mentioned, most of the arrhythmias associated with LQTS are ventricular tachyarrhythmias, but others such as bradycardia, atrioventricular (AV) block, and atrial arrhythmias may occur rarely.^[7]

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Long QT syndrome is often divided into two big categories: congenital and acquired. 

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CONGENITAL long QT syndrome applies to those who have been born with the condition. To date, more than 17 genes and hundreds of mutations connected to the syndrome have been described.^[1] 

Congenital LQTS can arise from a variety of genetic variants and combinations and therefore sometimes has different typical features. All these variants are united by their effect on ion channels and QT interval length. Based on the differences between the variants and their genetic background, numerous clinical subtypes have been described.^[6]

• Romano-Ward syndrome is by far the most common form (accounting for up to 99% of cases). It is inherited in an autosomal dominant manner and is characterized by a disturbance of the electrical activity of the heart without the involvement of other organs.^[6]
• Jervell and Lange-Nielsen syndrome is less common. Inheritance is autosomal recessive and is characterized by a combination of the extremely prolonged QT interval and congenital deafness.^[6]
• Anderson-Tawil syndrome is another rare form, characterized by a prolonged QT interval, periodic paralysis, and facial and skeletal abnormalities. It is also an autosomal dominant form.^[6]
• Timothy syndrome, another very rare variant, is in addition to a long QT interval associated with abnormalities of the heart structure, syndactyly, and autism spectrum disorder. It is also an autosomal dominant form.^[6]

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ACQUIRED long QT syndrome usually results from pharmacological therapy. More than 100 drugs are known to prolong the QT interval in otherwise healthy people. Although this group is separate from the hereditary form, it is thought that they may overlap in some cases because patients' sensitivity to these drugs may also be related to genetic predispositions. Furthermore, cases of drug-related LQTS representing a form of congenital LQTS in which a mutation in one of the genes is clinically hidden until the patient is exposed to a specific drug or other predisposing factor have been described as well.^{[2, 3]} See the table below with the most frequent medications in question.

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Certain mineral imbalances in the body and other underlying conditions may affect the QT interval as well:

• Low potassium level (hypokalemia) ^[3]
• Low calcium level (hypocalcemia) ^[3]
• Low magnesium level (hypomagnesemia) ^[3]
• COVID-19 infection ^[3]
  
  

Prevalence & Risk factors

Unlike other less common channelopathies, the estimated prevalence of congenital LQTS is at least 1 in 2000. This prevalence is based on a study of 44,000 newborns that combined ECG findings and genetic testing, and refers to newborns who are positive for both a genetic variant and a truly prolonged QT interval. ^[7]  

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Based on available data and statistics, the risk of developing congenital or acquired long QT syndrome or its symptoms increases in the presence of the following: ^{[2, 3, 4, 8]}

• Gender - men are at higher risk during childhood and women from teenage life onward ^[8]
• Advanced age ^[2]
• Underlying heart disease ^[2]
• A clinical history of cardiac arrest and/or unexplained syncope ^{[3, 8]}
• First-degree relative with LQTS ^[3]
• Using medications known to affect the QT interval ^[3]
• Excessive vomiting, diarrhea, and eating disorders which can cause electrolyte imbalances ^[3]
• Family history of unexplained sudden death or syncopes ^[4]
• Congenital deafness ^[4]
• Impaired hepatic and/or renal function ^[2]
• Postpartum period ^[10]

Genetics

Long QT interval syndrome is an autosomal dominant disorder (only one dominant allele is sufficient to cause the disease) caused by mutations in 1 of at least 17 different genes encoding ion channels in the membranes of heart muscle cells. The presence of more than one mutation usually leads to more severe symptoms, and there are also assumptions and hypotheses that the risk increases when first-degree relatives are affected. In addition, compound heterozygous (two mutations within a single gene), digenic (mutations in two different genes), and homozygous (same mutation in both copies of a gene) alleles are also considered to cause LQTS.^[5] 

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More than 1400 gene variants associated with LQTS have been described; however, the most likely causative genes include KCNQ1, KCNH2, and SCN5A, which contribute to 75% of all cases and have been discovered more than two decades ago. Mutations in minor susceptibility genes are thought to account for an additional 5%. The rest of the patients with a clinical diagnosis of congenital LQTS are referred to as either genetically elusive LQTS or genotype-negative LQTS, as their gene mutations are unknown and yet to be described.^{[5], [12, 13]}

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Currently, at least 15 genes for autosomal dominant congenital Romano-Ward type LQTS and two genes for autosomal recessive forms of Jervell and Lange-Nielsen syndrome have been localized. The most common single nucleotide polymorphisms (SNPs) were identified in the NOS1AP, KCNQ1, KCNH2, SCN5A, or KCNJ2 genes.^[12]

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Genetic testing allows us to detect whether you have the predisposition to develop this disease and therefore directs us to take steps toward prevention, monitoring, and possible treatment options. We can help you with all of this here, in Macromo. For evaluation, we use polygenic risk scores and causative evidence-based genetic variants. The polygenic risk score (PRS) represents the total number of genetic variants that increase an individual's risk of developing a particular disease. All variants across their genome are summed and ranked according to their effect on disease development.

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Signs & Symptoms

LQTS can occur at any time during a person's life. In many individuals, it can also persist throughout life in an asymptomatic form. Clinical episodes are often triggered by specific events such as exercise (especially swimming and diving), intense emotions, and acute excitement (in the case of sudden awakening from sleep by an alarm clock, telephone, thunder, etc.). ^{[7, 8]}

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The commonly described symptoms are mostly associated with ventricular tachycardia and torsades de pointes. These are:

• Warning signs like lightheadedness, heart palpitations, weakness, or blurred vision
• Fainting (syncopes)
• Seizures
• Sudden cardiac death

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Because seizures in ventricular arrhythmias are still relatively common, LQTS is still often misdiagnosed as epilepsy. ^[8]

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‍Diagnosis

To date, the most common tests used for the diagnosis of LQTS are: 

• ECG
• Exercise stress test
• Holter and event monitor (devices recording ECG for a longer or a specific period of time)
• Genetic testing 

Clinical history and family history contribute to the final diagnosis as well. ^[3]

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Therapy

Treatment options for the LQTS differ depending on whether it is a congenital or acquired form. The acquired form can often be reversed when the underlying cause is addressed and eliminated. This can be done in various ways - medications can be stopped, electrolytes can be supplied intravenously, a pacemaker can be implanted, etc.

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The treatment tactics of congenital LQTS are different (because of the different pathophysiology).

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Prevention

Regardless of the genetic variant, age, and previous clinical history, all patients with congenital LQTS should follow the general recommended precautions. These include avoiding medications with the potential to prolong QT, replacing electrolytes after vomiting and diarrhea, and reducing fever whenever appropriate.^[9] Arrhythmias in congenital LQTS are also often triggered by certain things (as mentioned above). These often include intense exercise, loud / sudden noises, or diving into cold water. Avoiding these triggers as much as possible can help reduce the risk of potential complications.^[10]

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With regular health checkups and good communication with your doctor, you can also prevent some of the health problems that lead to some types of acquired LQTS.^[3] Specific precautions are, however, hard to determine as the etiology spectrum is very wide and variable. 

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Prognosis

The prognosis of treated patients (especially patients on beta-blockers) is generally good. If an episode of torsade de pointes occurs, it usually terminates spontaneously without severe complications. It is estimated that only 4-5% of cardiac events are fatal. High-risk patients who have survived cardiac arrest or keep experiencing recurrent arrhythmias despite treatment with beta-blockers have a significantly increased risk of sudden cardiac death. These patients are indicated for treatment with an ICD, which significantly improves their prognosis.^[11]   

Recommendations

• Find out which sports are safe. Avoid performing physical activity (especially swimming) alone.^[3]
• Eliminate possible triggers by lowering the volume of electronic devices that may startle you (especially in your sleep).^[3]
• Avoid drugs that are known to prolong the QT interval. If you are unsure, consult your doctor. If you are diagnosed with LQTS, always consult your cardiologist for new medications and dietary supplements.^[3]
• Get regular health checkups.^[3]

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