Clinical Diagnosis

The diagnosis of Romano-Ward syndrome (RWS) is made on the basis of one of the following:

• A prolonged QT interval on the ECG

• Typical T-wave abnormalities and typical LQTS-type syncope with a parent having diagnostic QT prolongation or positive molecular genetic testing

• Two or more offspring with diagnostic QT prolongation or positive molecular genetic testing

• Identification of a mutation in KCNQ1, KCNH2, SCN5A, KCNE1, or KCNE2 in the absence of profound congenital sensorineural deafness (the presence of which strongly suggests Jervell and Lange-Nielsen syndrome; see Genetically Related Disorders).

QTc values on resting ECG. The QTc on resting ECG is neither completely sensitive nor specific for the diagnosis of RWS. Table 1 shows the diagnostic criteria for the resting ECG QTc value in the absence of the following, all of which can lengthen the QTc interval and cause a form of acquired LQTS [Vincent et al 1992, Vincent 2000]:

• QT-prolonging drugs

• Hypokalemia

• Certain neurologic conditions including subarachnoid bleed

• Structural heart disease

QTc on exercise and ambulatory ECG and during pharmacologic provocation testing. These tests are particularly helpful for further evaluation of individuals with "uncertain" QTc values on resting ECG:

• Exercise ECG commonly shows failure of the QTc to shorten normally [Jervell & Lange-Nielsen 1957, Vincent et al 1991, Swan et al 1998] and prolongation of the QTc to values in Table 1. Many individuals develop characteristic T-wave abnormalities [Zhang et al 2000].

• Ambulatory ECG may demonstrate similar findings [Viitasalo et al 2002] but less frequently than the exercise ECG. QTc as high as 500 msec may be seen on ambulatory ECG in normal individuals, and thus a higher value is required for suspicion of RWS.

• Intravenous pharmacologic provocation testing, such as with epinephrine, may be helpful by demonstrating inappropriate prolongation of the QTc interval [Ackerman et al 2002]. The sensitivity and specificity have not been evaluated in a large sample of individuals with LQTS and normals. With the small risk of induction of arrhythmia, such provocative testing is best performed in laboratories experienced in arrhythmia induction and control.

Other ECG changes. T-wave patterns characteristic of each phenotype may assist in diagnosis [Zhang et al 2000]. The heart rate may be lower than normal. The presence of the ventricular arrhythmia torsade de pointes is characteristic of QT prolongation syndromes but not specific for RWS.

History. A family history or personal history of syncope, aborted cardiac arrest, or sudden death in a child or young adult may lead to suspicion of RWS. The syncope is typically precipitous and without warning, thus differing from the common vasovagal and orthostatic forms of syncope in which presyncope and other warning symptoms occur. Absence of aura, incontinence, and postictal findings help differentiate RWS from seizures.

Family history. A family history consistent with autosomal dominant inheritance supports the diagnosis.

Testing

No other routine clinical tests are helpful in the diagnosis of RWS.

Molecular Genetic Testing

Genes. Five genes (KCNQ1, KCNE1, KCNH2, KCNE2, and SCN5A) [Splawski et al 2000, Mohler et al 2003] are known to be associated with RWS.

Other genes

• SCN4B. A mutation in SCN4B was identified in a 21-month-old female with intermittent 2:1 AV block and QTc of 712 ms [Medeiros-Domingo et al 2007]. The mutation caused a significant increase in late sodium current, similar to that seen in the LQT3 phenotype. It has been suggested that SCN4B be designated LQT10; with additional verification, it may be added as the sixth gene to be associated with RWS.

• ANK2 and KCNJ2 have been proposed as LQT4 and LQT7, respectively. Whether the LQTS designation is appropriate is uncertain [Zhang et al 2005]; further study is underway.

• CAV3. Mutations in CAV3, the gene encoding caveolin 3, which has been proposed as LQT9, have been associated with sudden infant death syndrome (SIDS). These mutations cause an increase in late sodium current similar to that seen in the LQT3 phenotype. CAV3 mutations are also associated with a range of muscular disease (see Caveolinopathies). The caveolin 3 disorder may become one of the “atypical” or “complex” long QT syndromes [Vatta et al 2006, Amestad et al 2007, Cronk et al 2007].

• Approximately 30% of families with clinically diagnosed RWS do not have a detectable mutation in one of the five genes (KCNQ1, KCNE1, KCNH2, KCNE2, and SCN5A) known to be associated with RWS, suggesting that mutations in other genes can also cause RWS and/or that current test methods do not detect mutations (e.g., exonic or whole-gene deletions or other rearrangements) in these genes.
  
  Note: Among those individuals with clinically suspected LQTS who do not have a mutation identified in one the five known RWS-related genes, the majority have T-wave patterns consistent with the phenotype associated with one of the known genes, suggesting that undetected mutations of the known genes may be the primary cause of the negative genetic test results (see Research testing).

Clinical testing

• Mutation scanning and sequence analysis. Mutation scanning and sequence analysis of KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 are available on a clinical basis.

• Deletion/duplication analysis. Deletion/duplication analysis is available clinically to detect deletions and or duplications in KCNH2 and KCNE1.

Research testing. Zhang et al [2004] reported that mutations in intronic sequences other than invariant splice sites can cause RWS. As these mutations are not identifiable using sequence analysis of coding regions, they may account for some or all of the approximately 30% of individuals with RWS in whom a mutation has not yet been identified.

Table 2. Summary of Molecular Genetic Testing Used in Romano-Ward Syndrome (RWS)

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Gene Symbol	Proportion of RWS Attributed to Mutations in This Gene	Test Method	Mutation Detection Frequency by Gene and Test Method 1	Test Availability
KCNQ1	58%	Sequence analysis/ mutation scanning	70% 2	Clinical
KCNH2	35%	Sequence analysis/ mutation scanning	70% 2	Clinical
		Partial- or whole-gene deletions or duplications 3	Unknown
SCN5A	5%	Sequence analysis/ mutation scanning	70% 2	Clinical
KCNE1	1%	Sequence analysis/ mutation scanning	Unknown	Clinical
		Partial- or whole-gene deletions or duplications 3,4
KCNE2	1%	Sequence analysis/ mutation scanning	Unknown	Clinical

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Not all laboratories do (or have done in the past) locus mapping before sequence analysis; thus, the mutation detection frequency for each gene is not known [Author, personal observation].

3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment. See array GH.

4. Because deletion/duplication testing of KCNH2 and KCNE1 has become available clinically only recently, data regarding the frequency of exonic, multiexonic, or whole-gene deletions are limited/unknown. The mutation detection rates may be very low and may vary by laboratory. (Note: By definition, deletion/duplication analysis identifies rearrangements that are not identifiable by sequence analysis of genomic DNA.)

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm the diagnosis in a proband

• Identification of prolonged QTc on exercise or ambulatory ECG, or during pharmacologic provocation testing

• Identification of a disease-causing mutation in one of the five genes known to be associated with RWS: KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2
  
  Note: The clinical phenotype has been shown to predict the genotype with a high degree of accuracy [Zhang et al 2004]. Consequently, molecular genetic testing is more efficient if the gene(s) associated with the individual’s clinical phenotype (e.g., LQT1, LQT2 or LQT3) are tested first.

Predictive testing for at-risk asymptomatic family members can be performed by one of the following:

• QTc analysis on resting and exercise ECGs
  
  Note: The diagnostic accuracy by QTc analysis is considerably improved by evaluation of the exercise ECG QTc intervals, in addition to the resting ECG, using the QTc values listed in Table 1.

• Specific mutation testing when the disease-causing mutation in the family is known

Genetically Related (Allelic) Disorders

Jervell and Lange-Nielsen syndrome (JLNS) is characterized by congenital profound bilateral sensorineural hearing loss and long QTc interval usually greater than 500 msec. Prolongation of the QTc interval is associated with tachyarrhythmias, including: ventricular tachycardia; episodes of torsade de pointes ventricular tachycardia; and ventricular fibrillation, which may culminate in syncope or sudden death. More than half of untreated individuals with JLNS die before age 15 years. JLNS, inherited in an autosomal recessive manner, is caused by homozygous disease-causing mutations in either KCNQ1 (locus name LQT1) or KCNE1 (locus name LQT5).

Brugada syndrome. Mutations in SCN5A (locus name LQT3) are associated with rapid polymorphic ventricular tachycardia/ventricular fibrillation and sudden death.

Acquired, drug-induced long QT syndrome. Some individuals with drug-induced LQTS have a genetic predisposition to LQTS caused by a mutation of one of the five genes associated with RWS [Napolitano et al 2000].

Natural History

Romano-Ward syndrome (RWS) is characterized by QT prolongation and T-wave abnormalities on ECG, which are associated with tachyarrhythmias, typically the ventricular tachycardia torsade de pointes (TdP). TdP is usually self-terminating, thus causing syncope, the most common symptom in individuals with RWS. Syncope is typically precipitous and without warning. In some instances, TdP degenerates to ventricular fibrillation and aborted cardiac arrest (if the individual is defibrillated) or sudden death.

Three clinical phenotypes are recognized in individuals with RWS (see Table 3):

• LQT1, caused by mutations in KCNQ1 or KCNE1 and leading to abnormal IKs potassium channel function

• LQT2, caused by mutations in KCNH2 or KCNE2 and leading to IKr potassium channel dysfunction

• LQT3, caused by mutations in SCN5A, the cardiac sodium channel gene, and leading to abnormal INa channel function

The LQT1 phenotype accounts for approximately 60% of cases, LQT2 approximately 35%, and LQT3 fewer than 5%.

Approximately 50% or fewer individuals with a disease-causing mutation in one of the genes associated with RWS have symptoms and 50% or more never show symptoms [Vincent et al 1992, Zareba et al 1998]. The number of syncopal events in symptomatic individuals ranges from one to hundreds, averaging just a few.

The primary triggers for cardiac events in RWS [Schwartz et al 2001a]:

• LQT1. Exercise and sudden emotion

• LQT2. Exercise/emotion/sleep

• LQT3. Sleep

Cardiac events may occur from infancy through middle age but are most common from the pre-teen years through the 20s, with the risk generally diminishing throughout that time period. The usual age range of events differs somewhat for each genotype. Cardiac events are uncommon after age 30-40 years; when present, they are often triggered by administration of a QT-prolonging drug or hypokalemia or are associated with the LQT3 phenotype.

Of individuals who die of complications of RWS, death is the first sign of the disorder in an estimated 10%-15%. The risk for sudden death from birth to age 40 years has been reported at approximately 4% in each of the phenotypes [Zareba et al 1998]. Although syncopal events are most common in LQT1 (63%), followed by LQT2 (46%) and LQT3 (18%), the incidence of death is similar in all three.

QTc range is similar across phenotypes (~400-600+ msec). The average QTc values are similar for the LQT1 and LQT2 phenotypes and somewhat longer for the LQT3 phenotype. T-wave patterns characteristic for the LQT1, 2, and 3 phenotypes have been reported and can assist in directing molecular genetic testing strategies to identify the gene involved [Zhang et al 2000]. The predominant triggering stimuli for cardiac events vary by phenotype. In general, the phenotype does not vary much by mutation type; however, a recent study indicated that individuals with the LQT2 phenotype and mutations in the pore region of KCNH2 had a higher risk of sudden death than those individuals with mutations in other regions of KCNH2. In those individuals with KCNQ1 mutations, the risk is the same in pore versus other region mutations.

Genotype-Phenotype Correlations

The known genotype-phenotype correlations are described in Table 3.

Penetrance

RWS exhibits reduced penetrance of the ECG changes and symptoms. Overall, approximately 31% of individuals with a disease-causing mutation have a QTc between 400 and 460 msec (Table 1), values that overlap with those of normals; 12% with the LQT1 phenotype, 17% with the LQT2 phenotype, and 5% with the LQT3 phenotype (Table 3) actually have a normal QTc (defined as <440 msec) on baseline ECG.

Approximately 80% of individuals with a disease-causing mutation have a T-wave pattern characteristic for their genotype.

As noted in Table 3, penetrance for symptoms is also reduced. At least 37% of individuals with the LQT1 phenotype, 54% with the LQT2 phenotype, and 82% with the LQT3 phenotype remain asymptomatic.

Anticipation

Genetic anticipation has not been identified in individuals with RWS.

Nomenclature

Articles in the medical literature may use the terminology LQT1, LQT2 (etc) to refer to any of the following:

• The locus name of genes involved in long QT syndrome (see Molecular Genetics)

• Individuals with mutations in the specific genes at those loci

• Phenotypes associated with mutations in specific genes (see Table 3)

For clarity and to enable appropriate diagnosis and management, it is suggested that forms of inherited long QT syndrome other than RWS be called “atypical” or “complex” LQTS because they include:

• High-frequency, bidirectional ventricular tachycardia (Andersen-Tawil syndrome [LQT7] rather than TdP)

• Non-cardiac features (Andersen-Tawil syndrome [LQT7], Timothy syndrome [LQT8], and caveolinopathy [proposed as LQT9])

• QT prolongation in only a minority of individuals with a mutation (ANK2 disorder [LQT4] and Andersen-Tawil syndrome [LQT7])

Prevalence

RWS is the most common form of inherited long QT syndrome.

The prevalence of RWS has been estimated at 1:3000-1:7000, with the 1:3000 figure progressively appearing the more likely.

The disorder has been identified in all races. Prevalence studies by race have not been performed.

A founder effect has been reported in the state of Utah (US) and in Finland with a prevalence of around 1:5000 [Piippo et al 2001]. Preliminary evidence suggests a lower prevalence in Africans.

Evaluations to Establish the Diagnosis

To establish the diagnosis in an individual suspected of having Romano-Ward syndrome (RWS), determine whether symptoms are attributable to LQTS or to some other disorder. For example, dizziness, pre-syncope, palpitations, vasovagal syncope, and orthostatic syncope are common in the general population and rarely caused by LQTS. Treatment decisions should be based on LQTS-related events, not on unrelated disorders.

Treatment of Manifestations

All symptomatic persons should be treated. Complete cessation of symptoms is the goal. Management is focused on the prevention of syncope, cardiac arrest, and sudden death through use of the following:

• Beta blockers. Beta blockers are the mainstay of therapy for the LQT1 phenotype (see Table 3) and the LQT2 phenotype; however, their use in the management of the LQT3 phenotype is controversial. Some individuals have symptoms despite the use of beta blockers [Moss et al 2000]: It has recently been demonstrated that the very large majority of cardiac events that occur in individuals with LQT1 “on beta-blockers” are not caused by failure of the medication, but in fact by failure to take the medication (non-compliance) and/or the administration of QT prolonging drugs [Vincent et al 2009]. It is suspected that the same holds true for individuals with LQT2 but that has not been systematically studied.

  • In some individuals, recurrence of events while on medication is the result of inadequate dosing; thus, the dose must be adjusted regularly in growing children, and the efficacy must be evaluated by assessment of the exercise ECG or ambulatory ECG.

  • Many events “on beta blockers” appear to be caused by non-compliance (failure to take the medication). It is important to emphasize that beta blockers must be taken daily and to have strategies in place in case of missed doses.

  • Many events “on beta blockers” appear to be caused by the administration of QT-prolonging drugs (see Agents/Circumstances to Avoid). QT-prolonging drugs should not be administered to persons with LQTS without careful consideration of risk versus benefit by patient(s) and physician(s).

• Pacemakers. Pacemakers may be necessary for those individuals with symptomatic bradycardia associated with beta-blocker therapy [Viskin 2000].

• External defibrillators. Having automatic external defibrillators readily available at home, at school, and in play areas may be appropriate in some cases.

• Implantable cardioverter-defibrillators (ICDs). ICDs may be necessary for those individuals with beta-blocker-resistant symptoms, inability to take beta blockers (significant asthma, severe fatigue), history of cardiac arrest, and LQTS associated with syndactyly (Timothy syndrome). ICD therapy may be best for symptomatic individuals with the LQT3 phenotype [Wilde 2002].
  
  Note: Implantable cardioverter-defibrillators have largely replaced left thoracic sympathectomy as the preferred treatment in individuals for whom beta blockers are ineffective.

Prevention of Primary Manifestations

Although the percent of affected individuals who experience cardiac arrest or sudden death is small, all affected but asymptomatic persons younger than age 40 years should be treated prophylactically (usually with beta blockers) because it is not possible to identify those individuals who are at greatest risk for these events.

Because symptoms occur primarily in the pre-teen years to early 20s, prophylactic treatment may not be necessary for those affected individuals who (1) are older than age 40 years at diagnosis and (2) either are life-long asymptomatic or have a very remote history of LQTS-type syncope.

As emphasized in Treatment of Manifestations, QT-prolonging drugs should not be used unless the benefit of taking the QT-prolonging drug clearly outweighs the risk of torsade de pointes.

Prevention of Secondary Complications

Examine the past medical history for asthma, orthostatic hypotension, depression, and diabetes mellitus because these disorders may be exacerbated by treatment with beta blockers.

Although the incidence of arrhythmias during elective interventions such as surgery, endoscopies, childbirth, or dental work is low, it is prudent to monitor the ECG during such interventions and to alert the appropriate medical personnel in case intervention is needed.

Surveillance

Beta-blocker dose should be regularly assessed for efficacy and adverse effects; doses should be altered as needed. Because dose adjustment is especially important in growing children, evaluation is appropriate every three to six months during rapid growth phases.

Affected individuals should have regular, periodic evaluations of ICDs for inappropriate shocks and pocket or lead complications.

Agents/Circumstances to Avoid

Drugs that cause further prolongation of the QT interval or provoke torsade de pointes should be avoided. See www.qtdrugs.org [Woosley 2001] for a complete and updated list.

Epinephrine given as part of local anesthetics can trigger arrhythmias and is best avoided.

Individuals with the LQT1 or LQT2 phenotype should be advised to avoid competitive sports and activities likely to be associated with intense physical activity and/or emotional stress (e.g., amusement park rides, scary movies, jumping into cold water).

Testing of Relatives at Risk

Presymptomatic diagnosis of at-risk relatives by ECG and/or molecular genetic testing (if the disease-causing mutation in the family is known) followed by treatment is necessary to prevent syncope and sudden death in those individuals who are affected. At-risk family members should be alerted to their risk and the need to be evaluated.

Note: Relatives at high potential risk who require further testing include members of a family:

• That has documented LQTS

• In which evaluation for LQTS has not been performed

Relatives at low potential risk who do not require further testing include members of a family in which the symptomatic ancestor:

• Had a low probability of LQTS based on QTc interval (see Table 1) and no relative who experienced LQTS-type events

• Had a negative molecular genetic test result and normal QTc interval

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Most affected individuals live normal lifestyles. Education of adult individuals and the parents of affected children is an important aspect of management.

No other medications have been proven to be effective in preventing the arrhythmias and symptoms.

Individuals with LQTS do not need antibiotics for SBE prophylaxis.

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

Romano-Ward syndrome (RWS) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Most individuals diagnosed with RWS have an affected parent.

• A proband with RWS may have the disorder as the result of a de novo gene mutation. The proportion of cases caused by de novo mutations is small.

• Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include exercise ECG evaluation and (when possible) molecular genetic testing.

Note: Although most individuals diagnosed with RWS have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or reduced penetrance.

Sibs of a proband

• The risk to the sibs of the proband depends on the genetic status of the proband's parents.

• If a parent of the proband is affected, the risk to the sibs is 50%.

• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low:

  • If the disease-causing mutation identified in the proband cannot be detected in the DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband.

  • Although no instances of germline mosaicism have been reported, it remains a possibility.

Offspring of a proband. Each child of the proband has a 50% chance of inheriting the disease-causing mutation.

Other family members of a proband. The risk to other family members depends on the genetic status of the proband's parents. If a parent is affected, his or her family members are at risk.

Specific risk issues. With the reduced penetrance of symptoms in individuals with RWS, careful ECG evaluation, including exercise ECG, is often necessary to identify affected family members accurately. The absence of a family history of sudden death is common and does not negate the diagnosis or preclude the possibility of sudden death in relatives.

Related Genetic Counseling Issues

Testing of at-risk asymptomatic adults and children. Testing of at-risk asymptomatic adults for RWS is available using the same techniques described in Molecular Genetic Testing. Such testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals. To facilitate the use of morbidity-/mortality-reducing interventions, presymptomatic testing of all at-risk family members, including individuals younger than age 18 years, should be considered (see Management, Testing of Relatives at Risk). When testing at-risk individuals for RWS, an affected family member should be tested first to identify the disease-causing mutation in the family.

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (i.e., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning. The optimal time for determination of genetic risk is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of having inherited a disease-causing mutation.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions such as RWS that do not affect intellect and have some treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Molecular Genetic Pathogenesis

The genes in which mutation causes RWS encode for potassium or sodium cardiac ion channels [Splawski et al 2000]. Mutations cause abnormal ion channel function: a loss of function in the potassium channels and a gain of function in the sodium channel. This abnormal ion function results in prolongation of the cardiac action potential and susceptibility of the cardiac myocytes to early after depolarizations (EADs), which initiate the ventricular arrhythmia, torsade de pointes (TdP).

Published Guidelines/Consensus Statements

1. Vincent GM. Role of DNA testing for diagnosis, management, and genetic screening in long QT syndrome, hypertrophic cardiomyopathy, and Marfan syndrome. HEART. 2001;86:12–4. [PMC free article: PMC1729812] [PubMed: 11410552]

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Revision History

• 4 August 2009 (cd) Revision: prenatal diagnosis available for LQT1, LQT2, LQT3, LQT5, LQT6

• 7 May 2009 (gmv) Revision: deletion/duplication analysis available clinically for LQT2 and LQT3; additions to Management

• 21 May 2008 (me) Comprehensive update posted live

• 7 July 2005 (me) Comprehensive update posted to live Web site

• 28 February 2005 (gmv) Revision: sequence analysis clinically available; LQt4 moved to Differential Diagnosis

• 13 April 2004 (cd) Revision: ANK2 testing clinically available

• 11 February 2004 (bp/gmv) Revisions

• 18 November 2003 (gmv) Revisions

• 16 June 2003 (gmv) Revision: Table 4

• 20 February 2003 (me) Review posted to live Web site

• 25 October 2002 (gmv) Original submission