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Romano-Ward Syndrome

Synonyms: Long QT Syndrome, Autosomal Dominant; Romano-Ward Long QT Syndrome. Includes: Long QT Syndrome 1, Long QT Syndrome 2, Long QT Syndrome 3, Long QT Syndrome 5, Long QT Syndrome 6, Long QT Syndrome 9, Long QT Syndrome 10, Long QT Syndrome 11, Long QT Syndrome 12, Long QT Syndrome 13

, PhD and , PhD.

Author Information
, PhD
Department of Clinical Genetics
Academic Medical Center
University of Amsterdam
Amsterdam, The Netherlands
, PhD
Head, DNA-Diagnostics Laboratory
Associate Professor, Department of Clinical Genetics
Academic Medical Center
University of Amsterdam
Amsterdam, The Netherlands

Initial Posting: ; Last Update: May 31, 2012.

Summary

Disease characteristics. Romano-Ward syndrome (RWS) is purely a cardiac electrophysiologic disorder, characterized by QT prolongation and T-wave abnormalities on the ECG and the ventricular tachycardia torsade de pointes (TdP). TdP is usually self-terminating, thus causing a syncopal event, the most common symptom in individuals with RWS. Syncope typically occurs during exercise and high emotions, less frequently at rest or during sleep, and usually without warning. In some instances, TdP degenerates to ventricular fibrillation and causes aborted cardiac arrest (if the individual is defibrillated) or sudden death. Approximately 50% of individuals with a disease-causing mutation in one of the genes associated with RWS have symptoms, usually one to a few syncopal spells. While cardiac events may occur from infancy through middle age, they are most common from the pre-teen years through the 20s.

Diagnosis/testing. Diagnosis of RWS is established by prolongation of the QTc interval in the absence of specific conditions known to lengthen it (for example, QT-prolonging drugs) and/or molecular genetic testing of the genes known to be associated with RWS, of which KCNQ1 (locus name LQT1), KCNH2 (locus name LQT2) and SCN5A (locus name LQT3) are the most common. Other, less frequently involved genes are KCNE1 (locus name LQT5), KCNE2 (locus name LQT6), CAV3 (locus name LQT9), SCN4B (locus name LQT10), AKAP9 (locus name LQT11), SNTA1 (locus name LQT12) and KCNJ5 (locus name LQT13). Approximately 25% of families meeting clinical diagnostic criteria for RWS do not have detectable mutations in one of the above genes.

Management. Treatment of manifestations: Beta-blocker medication is the primary treatment for RWS; possible use of a pacemaker in those individuals with LQT1 and LQT2 phenotypes with symptomatic bradycardia associated with beta-blocker therapy; possible implantable cardioverter-defibrillator (ICD) for symptomatic individuals with the LQT3 phenotype.

Prevention of primary manifestations: Prophylactic use of beta blockers in asymptomatic children and adults dependent on genotype and age to prevent syncope, cardiac arrest, and sudden death; possible ICD for those with beta-blocker-resistant symptoms, inability to take beta blockers, and/or history of cardiac arrest.

Surveillance: Regular assessment of beta-blocker dose for efficacy and adverse effects in all individuals and, in particular, every three to six months in children during rapid growth; 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; competitive sports/activities associated with intense physical activity and/or emotional stress.

Evaluation of relatives at risk: Presymptomatic diagnosis and treatment to prevent syncope and sudden death.

Other: For some individuals, availability of automatic external defibrillators at home, at school, and in play areas.

Genetic counseling. RWS is inherited in an autosomal dominant manner. Most individuals diagnosed with RWS have an affected parent. The proportion of cases caused by de novo mutation is small. Each child of an individual with RWS has a 50% risk of inheriting the disease-causing mutation. Penetrance of the disease may vary. Prenatal testing for pregnancies at increased risk is possible once the disease-causing mutation has been identified in the family.

Diagnosis

Clinical Diagnosis

The diagnosis of Romano-Ward syndrome (RWS) is made on the basis of ECG characteristics, clinical presentation, and family history. Schwartz et al [1993] proposed a score system to diagnose RWS, which has recently been updated [Schwartz & Crotti 2011]. Points are assigned to various criteria (see Table 1).

Table 1. Scoring System for Diagnosis of Romano-Ward Syndrome

FindingsPoints
ECG 1QTc 2 ≥480 ms3
=460-479 ms2
=450-459 ms1
≥480 ms during 4th minute of recovery from exercise stress test1
Torsade de pointes 32
T wave alternans1
Notched T wave in 3 leads1
Low heart rate for age 40.5
Clinical historySyncope 3 With stress2
Without stress1
Family members with definite LQTS 51
Family historyUnexplained sudden cardiac death before age 30 years among immediate family members 50.5
Total score

Adapted from Schwartz & Crotti [2011]

Scoring:

≤1.0 point = low probability of LQTS

1.5-3.0 points = intermediate probability of LQTS

≥3.5 points = high probability of LQTS

1. In the absence of medications or disorders known to affect these electrocardiographic features

2. QTc (corrected QT) calculated by Bazett’s formula where QTc = QT/√RR

3. Mutually exclusive

4. Resting heart rate <2nd percentile for age

5. The same family member cannot be counted for both criteria.

QTc values on resting ECG. The QTc on resting ECG is neither completely sensitive nor specific for the diagnosis of RWS. Table 2 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 long QT syndrome (LQTS) [Vincent et al 1992, Vincent 2000]:

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

Table 2. Utility of the Resting QTc or Exercise ECG Maximum QTc Interval in Diagnosis of RWS

Certainty of RWS Diagnosis% of Affected IndividualsQTc
MalesFemales
Positive68%>470 msec>480 msec
Uncertain20%450-460 msec 1 460-470 msec 1
11%400-450 msec400-450 msec
Negative<<1%<390 msec 2 <400 msec 2

1. In a member of a family with documented RWS, the diagnosis of RWS is suspected in males with a QTc >450 msec and in females with a QTc >460 msec. These criteria are not applicable to the general population, which includes many more normal than abnormal individuals with these values.

2. QT measurement varies by observer; therefore, some differences in reporting are found. However, only a few instances of an individual with a disease-causing mutation and QTc <400 msec have been reported.

QTc on exercise and ambulatory ECG and during pharmacologic provocation testing. The following 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 2. 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. Ten genes (KCNQ1, KCNE1, KCNH2, KCNE2, SCN5A, CAV3, SCN4B, AKAP9, SNTA1, and KCNJ5) are known to be associated with RWS [Splawski et al 2000, Vatta et al 2006, Chen et al 2007, Medeiros-Domingo et al 2007, Ueda et al 2008, Yang et al 2010].

Other genes. RWS is defined as a purely cardiac electrophysiologic disorder. Prolonged QT interval can also be associated with other cardiac and non-cardiac abnormalities.

  • ANK2 has been proposed as LQT4. ANK2 mutations can cause a broad spectrum of clinical cardiac phenotypes, such as catecholaminergic polymorphic ventricular arrhythmias, sinus node dysfunction, atrial fibrillation, and prolonged QT syndrome. Based on this wide variety of symptoms the term “ankyrin B syndrome” has been proposed [Mohler et al 2003, Mohler et al 2007].
  • KCNJ2 has been proposed as LQT7. Mutations in KCNJ2 also cause Andersen Tawil syndrome (ATS) (see Differential Diagnosis).
  • CACNA1C has been proposed as LQT8. Mutations in CACNA1C cause Timothy syndrome (see Differential Diagnosis).

Approximately 25% of families with a clinically firm diagnosis of RWS do not have a detectable mutation in one of the ten genes (KCNQ1, KCNE1, KCNH2, KCNE2, SCN5A, CAV3, SCN4B, AKAP9, SNTA1, and KCNJ5) 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 all mutations in the known genes.

Clinical testing

Table 3. Summary of Molecular Genetic Testing Used in Romano-Ward Syndrome

Gene 1Proportion of RWS Attributed to Mutations in This Gene 2Test MethodMutations Detected 3
KCNQ146%Sequence analysis 4 / mutation scanning 5Sequence variants
Deletion/duplication analysis 6Exonic or whole-gene deletions
KCNH238%Sequence analysis 4 / mutation scanning 5Sequence variants
Deletion/duplication analysis 6Exonic or whole-gene deletions / duplications
SCN5A13%Sequence analysis 4 / mutation scanning 5Sequence variants
Deletion/duplication analysis 6None reported 7, 8
KCNE12%Sequence analysis 4 / mutation scanning 5Sequence variants
Deletion/duplication analysis 6None reported 7
KCNE21%Sequence analysis 4 / mutation scanning 5Sequence variants
Deletion/duplication analysis 6None reported 7
CAV3RareSequence analysis 4 / mutation scanning 5Sequence variants
Deletion/duplication analysis 6None reported 7
SCN4BRare (1 case)Sequence analysis 4 / mutation scanning 5Sequence variants 
Deletion/duplication analysis 6None reported 7
AKAP9Rare (1 case)Sequence analysis 4 / mutation scanning 5Sequence variants 
Deletion/duplication analysis 6None reported 7
SNTA1Rare (2 cases)Sequence analysis 4 / mutation scanning 5Sequence variants
Deletion/duplication analysis 6None reported 7
KCNJ5Rare (1 case)Sequence analysis 4 / mutation scanning 5Sequence variants

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. Proportion of RWS caused by a mutation in each gene is based on Splawski et al [2000], Napolitano et al [2005], Tester et al [2005], Kapa et al [2009], Kapplinger et al [2009].

3. See Molecular Genetics for information on allelic variants.

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. Sequence analysis and mutation scanning of the entire gene can have similar mutation detection frequencies; however, mutation detection rates for mutation scanning may vary considerably between laboratories depending on the specific protocol used.

6. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

7. Deletions or duplications involving KCNQ1 or KCNH2 have been shown to be causal for Romano-Ward syndrome in ~3% of cases [Barc et al 2011]. Deletions or duplications in the other genes have not been reported. (Note: By definition, deletion/duplication analysis identifies rearrangements that are not identifiable by sequence analysis of genomic DNA.)

8. The mutations in SCN5A that cause RWS are gain-of-function mutations (loss-of-function mutations in SCN5A cause Brugada syndrome). Therefore, it is highly unlikely that deletions or duplications in SCN5A will be identified as a cause of RWS.

Multi-gene panels. Multi-gene panels can be used for the simultaneous analysis of some or all of the genes known to cause RWS. The panels vary by methods used and genes included; thus, the ability of a panel to detect a causative mutation(s) in any given individual with prolonged QT phenotype also varies.

Testing Strategy

To confirm/establish 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 ten genes known to be associated with RWS: KCNQ1, KCNE1, KCNH2, KCNE2, SCN5A, CAV3, SCN4B, AKAP9, SNTA1 and KCNJ5.

    Analysis of the genes may be done either simultaneously or sequentially.
    • Because the clinical phenotype has been shown to predict the genotype [Zhang et al 2000, van Langen et al 2003], the gene(s) associated with the individual’s clinical phenotype could be analyzed first (see Table 4).
    • Alternatively, the strategy could be based on the proportion of RWS cases caused by mutations in each gene. Analysis of KCNQ1 and KCNH2 can be considered first followed by analysis of SCN5A. If neither a KCNQ1, KCNH2, or SCN5A mutation is identified, analysis of the remaining genes can be considered.
    • Alternatively, a panel in which some or all of the genes known to cause RWS are evaluated simultaneously could be pursued. This panel may consist of either the more commonly mutated genes (KCNQ, KCNH2, SCN5A, KCNE1, and KCNE2) or may also include the remaining, rarely mutated genes.
    • Deletion/duplication analysis of KCNQ1 and KCNH2 is included in the standard test in some laboratories and needs to be requested as a separate test in other laboratories.

Note: If a sequential screening strategy has been chosen and a variant of unknown clinical significance has been identified, continued screening of the remaining genes is recommended. Another mutation may be present.

Predictive testing for at-risk asymptomatic family members can be performed by one or both 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

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

Romano-Ward syndrome (RWS) is characterized by QT prolongation and T-wave abnormalities on ECG that 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.

Mutations in KCNQ1, KCNH2 and SCN5A account for the vast majority of cases (46%, 38%, and 13% respectively) and distinct genotype-phenotype correlations have been reported (see Table 4). Three clinical phenotypes are recognized in individuals with RWS:

  • LQT1, caused by mutations in KCNQ1 and leading to abnormal IKs potassium channel function
  • LQT2, caused by mutations in KCNH2 leading to IKr potassium channel dysfunction
  • LQT3, caused by mutations in SCN5A, the cardiac sodium channel gene, and leading to abnormal INa channel function

Approximately 50% or fewer of 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 2001]:

  • LQT1. Exercise and sudden emotion
  • LQT2. Exercise, emotion, and 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 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.

Table 4. Romano-Ward Phenotypes

% of Persons with RWSPhenotypeGeneAverage QTcST-T-Wave MorphologyIncidence of Cardiac EventsCardiac Event TriggerSudden Death Risk
>60%LQT1KCNQ1480 msecBroad-base T-wave63%Exercise, emotion4%
~35%LQT2KCNH2Bifid T-waves46%Exercise, emotion, sleep4% 1
<5%LQT3SCN5A~490 msecLong ST, small T18%Sleep4%

1. Sudden death risk may be higher in individuals with specific KCNH2 mutations.

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 for 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 as in other region mutations.

Genotype-Phenotype Correlations

The known genotype-phenotype correlations are described in Table 4.

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 2), values that overlap with those of normals; 12% with the LQT1 phenotype, 17% with the LQT2 phenotype, and 5% with the LQT3 phenotype (Table 4) 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 4, 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, and so on 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 4)

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.

Differential Diagnosis

LQTS with syndactyly (Timothy syndrome or syndactyly-related LQTS) is characterized by cardiac (LQTS and/or congenital heart defects), hand (variable unilateral or bilateral cutaneous syndactyly of fingers or toes), facial, and neurodevelopmental features. LQTS typically manifests with a rate-corrected QT interval between 480 ms and 700 ms. Facial anomalies include: flat nasal bridge, low-set ears, thin upper lip, and round face. Neurologic symptoms include: autism, seizures, intellectual disability, and hypotonia. Ventricular tachyarrhythmia is the leading cause of death; average age of death is 2.5 years. Timothy syndrome is diagnosed by clinical features and by the presence of the de novo p.Gly406Arg mutation in the CaV1.2 calcium channel gene, CACNA1C, the only gene known to be associated with Timothy syndrome [Splawski et al 2004].

This disorder is designated LQT8 and best fits as one of the “atypical” or “complex” forms of LQTS (see Nomenclature).

Jervell and Lange-Nielsen syndrome. See Genetically Related Disorders.

Brugada syndrome. See Genetically Related Disorders.

Andersen-Tawil syndrome (ATS) is characterized by a triad of episodic flaccid muscle weakness (i.e., periodic paralysis), ventricular arrhythmias and prolonged QT interval, and anomalies including low-set ears, ocular hypertelorism, small mandible, fifth-digit clinodactyly, syndactyly, short stature, and scoliosis. KCNJ2 is the only gene known to be associated with ATS [Plaster et al 2001, Ai et al 2002, Tristani-Firouzi et al 2002, Zhang et al 2005]. Approximately 70% of individuals with ATS have a detectable mutation in KCNJ2.

Other causes of syncope or sudden death to be considered in children and young adults:

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to Romano-Ward syndrome, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

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 4) 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).

Evaluation 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 have inherited the disease-causing mutation and/or have ECG findings consistent with RWS. 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 no evidence of a mutation in one of the genes known to cause RWS (or the family-specific mutation, if known) and normal QTc interval.

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

Pregnancy Management

The postpartum period is associated with increased risk for a cardiac event, especially in individuals with the LQT2 phenotype. Beta blocker treatment was associated with a reduction of events in this nine-month time period after delivery [Seth et al 2007].

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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

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

Risk to Family Members

Parents of a proband

  • The majority of individuals diagnosed with RWS have inherited the mutation from a parent. However, 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.
  • If the parent from whom the proband inherited the gene mutation cannot be determined on the basis of clinical and family history, molecular genetic testing should be offered to both parents to identify which one has the mutation identified in the proband.
  • 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.

Sibs of a proband

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 clinically affected or has a disease-causing mutation, 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 possible using the 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- and mortality-reducing interventions, presymptomatic testing of all at-risk family members, including individuals younger than age 18 years, should be considered (see Management, Evaluation 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. If no mutation is identified in an affected family member (the case in ~30% of families with RWS), at-risk relatives should undergo careful clinical examination.

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 (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is 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.

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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutation has been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

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 which (like RWS) 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 an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Library of Medicine Genetics Home Reference
  • Canadian SADS Foundation
    9-6975 Meadowvale Town Centre Circle
    Suite 314
    Mississauga Ontario L5N 2V7
    Canada
    Phone: 877-525-5995 (toll-free); 905-826-6303
    Fax: 905-826-9068
    Email: info@sads.ca
  • European Long QT Syndrome Information Center
    Switzerland
    Email: info@qtsyndrome.ch
  • SADS Australia
    PO Box 19
    Noble Park Victoria 3174
    Australia
    Email: info@sads.org.au
  • SADS UK
    Churchill House
    Horndon Industrial Park
    Suite 6
    West Horndon Essex CM13 3XD
    United Kingdom
    Phone: 01277 811215
    Email: sadsuk@btconnect.com
  • Sudden Arrhythmia Death Syndromes (SADS) Foundation
    508 East South Temple
    Suite #20
    Salt Lake City UT 84102
    Phone: 800-786-7723 (toll-free); 801-531-0937
    Email: sads@sads.org
  • Long QT Syndrome (LQTS) Registry
    An ongoing research study with the goal of contributing to a better understanding of the genetics, natural history, and treatment of LQTS. Currently enrolling families in which a mutation has already been identified.
    University of Rochester Medical Center
    265 Crittenden Boulevard
    CU 420653
    Rochester NY 14642-0653
    Phone: 585-276-0016
    Fax: 585-273-5283

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Romano-Ward Syndrome: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Romano-Ward Syndrome (View All in OMIM)

152427POTASSIUM CHANNEL, VOLTAGE-GATED, SUBFAMILY H, MEMBER 2; KCNH2
176261POTASSIUM CHANNEL, VOLTAGE-GATED, ISK-RELATED SUBFAMILY, MEMBER 1; KCNE1
192500LONG QT SYNDROME 1; LQT1
600163SODIUM CHANNEL, VOLTAGE-GATED, TYPE V, ALPHA SUBUNIT; SCN5A
600734POTASSIUM CHANNEL, INWARDLY RECTIFYING, SUBFAMILY J, MEMBER 5; KCNJ5
601017SYNTROPHIN, ALPHA-1; SNTA1
601253CAVEOLIN 3; CAV3
603796POTASSIUM CHANNEL, VOLTAGE-GATED, ISK-RELATED SUBFAMILY, MEMBER 2; KCNE2
603830LONG QT SYNDROME 3; LQT3
604001A-KINASE ANCHOR PROTEIN 9; AKAP9
607542POTASSIUM CHANNEL, VOLTAGE-GATED, KQT-LIKE SUBFAMILY, MEMBER 1; KCNQ1
608256SODIUM CHANNEL, VOLTAGE-GATED, TYPE IV, BETA SUBUNIT; SCN4B
611818LONG QT SYNDROME 9; LQT9
611819LONG QT SYNDROME 10; LQT10
611820LONG QT SYNDROME 11; LQT11
612955LONG QT SYNDROME 12; LQT12
613485LONG QT SYNDROME 13; LQT13
613688LONG QT SYNDROME 2; LQT2
613693LONG QT SYNDROME 6; LQT6
613695LONG QT SYNDROME 5; LQT5

Molecular Genetic Pathogenesis

The genes associated with RWS encode for potassium or sodium cardiac ion channels or interacting proteins. Mutations in these genes 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).

For a detailed summary of gene and protein information, see Table A, Gene Symbol.

KCNQ1

Gene structure. KCNQ1 is located at chromosome 11p15.5-p15.4 and spans approximately 400 kb. The predominant isoform (isoform 1, refseq NM_000218.2) consists of 16 exons and produces a protein of 676 amino acids. Other isoforms, encoding a protein with an alternative N terminal domain (isoform 2) or non-coding transcripts exist.

Pathogenic allelic variants. More than 400 mutations of KCNQ1 have been reported, including missense, nonsense, splice site, and frameshift mutations as well as large multiexonic deletions (see Note).

Normal gene product. The potassium voltage-gated channel subfamily KQT member 1 is the alpha subunit forming the slowly activating potassium delayed rectifier IKs [Keating & Sanguinetti 2001].

Abnormal gene product. IKs channel with reduced function

KCNE1

Gene structure. KCNE1 is located at chromosome 21q22.11-q22.12, consists of three exons spanning approximately 40 kb, and encodes a protein of 129 amino acids (NM_000219.3).

Pathogenic allelic variants. At least 36 mutations have been described, including missense, nonsense, and frameshift mutations (see Note).

Normal gene product. The potassium voltage-gated channel subfamily E member 1 is the beta subunit forming the slowly activating potassium delayed rectifier IKs. The two subunits encoded by KCNE1 and KCNQ1 coassemble to form the IKs channel.

Abnormal gene product. IKs channel with reduced function

KCNH2

Gene structure. KCNH2 is located at chromosome 7q36.1, spanning approximately 19 kb. The longest isoform consists of 16 exons and produces a protein of 1159 amino acids (NM_000238.3). Two shorter isoforms of KCNH2 exist.

Pathogenic allelic variants. More than 500 mutations have been reported, including missense, nonsense, splice site and frameshift mutations as well as large multiexonic deletions (see Note).

Normal gene product. The potassium voltage-gated channel subfamily H member 2 is the alpha subunit forming the rapidly activating potassium delayed rectifier Ikr.

Abnormal gene product. IKr channel with reduced function

KCNE2

Gene structure. KCNE2 is located at chromosome 21q22.11, consists of three exons spanning approximately 40 kb, and encodes a protein of 123 amino acids (NM_172201.1).

Pathogenic allelic variants. At least 12 mutations have been reported; they include missense and frameshift mutations (see Molecular Genetic Pathogenesis).

Normal gene product. The potassium voltage-gated channel subfamily E member 2 is the beta subunit forming the rapidly activating potassium delayed rectifier IKr. The two subunits encoded by KCNH2 and KCNE2 coassemble to form the IKr channel.

Abnormal gene product. IKr channel with reduced function

SCN5A

Gene structure. SCN5A is located at chromosome 3p22.2, consists of 28 exons, spans approximately 80 kb, and encodes a protein of 2016 amino acids (NM_198056.2). An isoform lacking amino acid Gln1077 exists.

Pathogenic allelic variants. More than 100 mutations are known; they include missense mutations and in-frame deletions or insertions.

Normal gene product. The sodium channel protein type V alpha subunit is the alpha subunit forming the cardiac sodium channel.

Abnormal gene product. Gain-of-function mutation resulting in a cardiac sodium channel with increased persistent inward current

CAV3

Gene structure. CAV3 is located at chromosome 3p25, consists of two exons spanning approximately 12 kb, and encodes a protein of 151 amino acids (NM_033337.2).

Pathogenic allelic variants. Two probable LQT causing missense mutations in CAV3 have been described.

Normal gene product. The caveolin-3 protein is the major scaffolding protein present in caveolae in the heart.

Abnormal gene product. Persistent late sodium current

SCN4B

Gene structure. SCN4B is located at chromosome 11q23.3; it consists of five exons spanning approximately 20 kb and encodes a protein of 228 amino acids (NM_174934). A shorter isoform exists.

Pathogenic allelic variants. One missense mutation in SCN4B has been described.

Normal gene product. The sodium channel protein type IV beta subunit is a beta subunit forming the cardiac sodium channel.

Abnormal gene product. Loss-of-function mutation resulting in a cardiac sodium channel with increased persistent inward current

AKAP9

Gene structure. AKAP9 is located at chromosome 7q21.2, consists of 50 exons and encodes a protein of 3907 amino acids (NM_005751.4). A shorter isoform exists.

Pathogenic allelic variants. One missense mutation in AKAP9 has been described.

Normal gene product. The A kinase (prka) anchor protein (yotiao) 9 is involved in macromolecular complexes controlling phosphorylation of a number of proteins, including the Iks channel.

Abnormal gene product. Loss-of-function mutation resulting in an IKs channel with reduced function

SNTA1

Gene structure. SNTA1 is located at chromosome 20q11.21, consists of eight exons spanning approximately 35 kb, and encodes a protein of 505 amino acids (NM_003098.2).

Pathogenic allelic variants. Two missense mutations in SNTA1 have been described.

Normal gene product. The alpha-1 syntrophin is a scaffolding protein involved in macromolecular complexes controlling the function of, among others, the cardiac sodium channel.

Abnormal gene product. Loss-of-function mutation resulting in a cardiac sodium channel with increased persistent inward current

KCNJ5

Gene structure. KCNJ5 is located at chromosome 11q24.3, consists of three exons spanning approximately 30 kb and encodes a protein of 419 amino acids (NM_000890.3).

Pathogenic allelic variants. One missense mutation in KCNJ5 has been described.

Normal gene product. The potassium inwardly-rectifying channel, subfamily J, member 5 is a subunit of the cardiac inwardly rectifying potassium channel IKACh.

Abnormal gene product. Loss of function mutation resulting in an IKACh channel with reduced function

Note

More than 900 mutations in the ten LQTS-related genes have been reported and are listed in the various databases found in Table A. In general, approximately 70% are missense mutations, 15% are frameshift mutations, and in-frame deletions, nonsense mutations, and splice site mutations make up 3%-6% each. However, this distribution varies by gene. Radical mutations such as frameshift, nonsense, and splice site mutations are relatively more frequent in KCNQ1 and KCNH2 and are not present in SCN5A in individuals with LQT (such mutations in SCN5A cause Brugada syndrome rather than LQTS).

References

Published Guidelines/Consensus Statements

American College of Cardiology/American Heart Association Task Force, and the European Society of Cardiology/Committee for Practice Guidelines. Guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Available online. 2006. Accessed 5-13-14.

Vincent GM. Role of DNA testing for diagnosis, management, and genetic screening in long QT syndrome, hypertrophic cardiomyopathy, and Marfan syndrome. Editorial. Heart. 86:12-4. Available online. 2001. Accessed 5-13-14.

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Chapter Notes

Author History

Marielle Alders, PhD (2012-present)
Marcel MAM Mannens, PhD (2012-present)
G Michael Vincent, MD; University of Utah School of Medicine (2003-2012)

Revision History

  • 31 May 2012 (me) Comprehensive update posted live
  • 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
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