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Gene Dx #360 (1120674) KCNH2 gene Long QT Syndrome (LQTS)
Test Code360
Alias/See Also
" Ventricular Fibrillation with Prolonged QT interval; Romano-Ward syndrome (RWS); Jervell and Lange-Nielsen
syndrome (JLNS)
"
syndrome (JLNS)
"
CPT Codes
81280x1
Preferred Specimen
2-5 mL Blood
Other Acceptable Specimens
Saliva: Can be used as an alternative to blood. Use a GeneDx saliva kit (others not accepted). To request a GeneDx saliva kit
Instructions
Ship overnight at ambient temperature
Transport Container
Lavender Top Tube
Transport Temperature
rooom temp
Specimen Stability
refrigerated for 7 days
Methodology
Next-gen Sequencing
Report Available
8-10 weeks
Clinical Significance
"Long QT syndrome (LQTS) is a cardiac disorder due to abnormal ion channel function characterized by prolongation of the QT
interval on ECG. 75% of cases of LQTS are due to known genetic causes. It is associated with increased risk for syncope
(unexplained fainting), ventricular arrhythmia and sudden cardiac death in young adults with normal heart structure. Sudden death is
the first and final symptom in 10-15% of individuals with this diagnosis. LQTS has an estimated prevalence greater than 1 in 3000
individuals,2 occurs in all ethnicities, and results in approximately 4000 deaths annually in the US.3
The diagnosis of LQTS is based on clinical history, ECG findings and family history. Typically, the disorder manifests in patients
younger than 40 years of age, and sometimes as early as infancy. Patients often have a history of syncope or palpitations in the
absence of any other causes, such as medications, structural heart abnormalities, myocardial ischemia, or electrolyte imbalances. The
circumstances under which syncope occurs (with exercise, with auditory stimulation, at rest) may further suggest a particular subtype
of LQTS. In some patients, syncope may be mistakenly diagnosed as seizures. LQTS may be present even in the absence of any
clinical symptoms, and in some patients sudden cardiac death occurs without any preceding symptoms and without an identifiable
cause at autopsy. Inherited LQTS may underlie up to 10-15% of sudden infant death syndrome (SIDS) cases.
Inheritance Pattern: LQTS is usually inherited in an autosomal dominant manner, and an affected individual with a disease-causing
mutation has a 50% chance of transmitting this mutation to a child. Rarely, autosomal recessive inheritance has been described
(JLNS).
Genetics:
LQTS is genetically heterogeneous with mutations in more than 12 genes being identified to date (KCNQ1, KCNH2, SCN5A,
ANK2, KCNE1, KCNE2, KCNJ2, CACNA1C,
CAV3,SCN4B, AKAP9, and SNTA1). Most of
the disease-associated mutations have been
found in genes encoding ion channel proteins in
the heart that are crucial for the regulation of the
heart beat. The majority of mutations identified
in individuals with LQTS are in the KCNQ1,
KCNH2 or SCN5A genes. Genotype-phenotype
correlations have identified some of the triggers
for malignant arrhythmias based on the gene
involved, for example, patients harboring a
KCNQ1 mutation (LQT1) have an increased risk
of cardiac events during exercise, while patients
with a KCNH2 mutation (LQT2) have an
increased risk of cardiac events triggered by
auditory stimulation, particularly during sleep. However, disease-causing mutations in LQTS have been reported to display
reduced penetrance and variable clinical expressivity even within families.
Reasons for Referral:
1. Confirmation of a clinical diagnosis in symptomatic patients
2. Risk assessment for asymptomatic family members of a proband with LQTS
3. Genetic counseling and recurrence risk calculation
4. Differentiation of hereditary LQTS from acquired (non-genetic) causes of LQTS.
5. Prenatal diagnosis in families with a known mutation
Genotype Gene Gene Name
LQT1 KCNQ1 KQT-like voltage-gated potassium channel 1
LQT2 KCNH2 Potassium channel, voltage-gated, H2
LQT3 SCN5A Alpha polypeptide of voltage-gated sodium channel type V
LQT4 ANK2 Ankyrin-B
LQT5 KCNE1 Voltage-gated potassium channel, Isk related subfamily, member 1
LQT6 KCNE2 Voltage-gated potassium channel, Isk related subfamily, member 2
LQT7 KCNJ2 Inwardly rectifying potassium channel
LQT8 CACNA1C Calcium channel, L type, alpha 1 polypeptide isoform
LQT9 CAV3 Caveolin 3
LQT10 SCN4B Sodium channel, voltage-gated, type IV beta subunit
LQT11 AKAP9 A-kinase anchor protein 9
LQT12 SNTA1 Syntrophin, alpha 1
Information Sheet: Long QT Syndrome (LQTS) Panel Page 2 of 2 © GeneDx Revision Date: 07/2012
"
interval on ECG. 75% of cases of LQTS are due to known genetic causes. It is associated with increased risk for syncope
(unexplained fainting), ventricular arrhythmia and sudden cardiac death in young adults with normal heart structure. Sudden death is
the first and final symptom in 10-15% of individuals with this diagnosis. LQTS has an estimated prevalence greater than 1 in 3000
individuals,2 occurs in all ethnicities, and results in approximately 4000 deaths annually in the US.3
The diagnosis of LQTS is based on clinical history, ECG findings and family history. Typically, the disorder manifests in patients
younger than 40 years of age, and sometimes as early as infancy. Patients often have a history of syncope or palpitations in the
absence of any other causes, such as medications, structural heart abnormalities, myocardial ischemia, or electrolyte imbalances. The
circumstances under which syncope occurs (with exercise, with auditory stimulation, at rest) may further suggest a particular subtype
of LQTS. In some patients, syncope may be mistakenly diagnosed as seizures. LQTS may be present even in the absence of any
clinical symptoms, and in some patients sudden cardiac death occurs without any preceding symptoms and without an identifiable
cause at autopsy. Inherited LQTS may underlie up to 10-15% of sudden infant death syndrome (SIDS) cases.
Inheritance Pattern: LQTS is usually inherited in an autosomal dominant manner, and an affected individual with a disease-causing
mutation has a 50% chance of transmitting this mutation to a child. Rarely, autosomal recessive inheritance has been described
(JLNS).
Genetics:
LQTS is genetically heterogeneous with mutations in more than 12 genes being identified to date (KCNQ1, KCNH2, SCN5A,
ANK2, KCNE1, KCNE2, KCNJ2, CACNA1C,
CAV3,SCN4B, AKAP9, and SNTA1). Most of
the disease-associated mutations have been
found in genes encoding ion channel proteins in
the heart that are crucial for the regulation of the
heart beat. The majority of mutations identified
in individuals with LQTS are in the KCNQ1,
KCNH2 or SCN5A genes. Genotype-phenotype
correlations have identified some of the triggers
for malignant arrhythmias based on the gene
involved, for example, patients harboring a
KCNQ1 mutation (LQT1) have an increased risk
of cardiac events during exercise, while patients
with a KCNH2 mutation (LQT2) have an
increased risk of cardiac events triggered by
auditory stimulation, particularly during sleep. However, disease-causing mutations in LQTS have been reported to display
reduced penetrance and variable clinical expressivity even within families.
Reasons for Referral:
1. Confirmation of a clinical diagnosis in symptomatic patients
2. Risk assessment for asymptomatic family members of a proband with LQTS
3. Genetic counseling and recurrence risk calculation
4. Differentiation of hereditary LQTS from acquired (non-genetic) causes of LQTS.
5. Prenatal diagnosis in families with a known mutation
Genotype Gene Gene Name
LQT1 KCNQ1 KQT-like voltage-gated potassium channel 1
LQT2 KCNH2 Potassium channel, voltage-gated, H2
LQT3 SCN5A Alpha polypeptide of voltage-gated sodium channel type V
LQT4 ANK2 Ankyrin-B
LQT5 KCNE1 Voltage-gated potassium channel, Isk related subfamily, member 1
LQT6 KCNE2 Voltage-gated potassium channel, Isk related subfamily, member 2
LQT7 KCNJ2 Inwardly rectifying potassium channel
LQT8 CACNA1C Calcium channel, L type, alpha 1 polypeptide isoform
LQT9 CAV3 Caveolin 3
LQT10 SCN4B Sodium channel, voltage-gated, type IV beta subunit
LQT11 AKAP9 A-kinase anchor protein 9
LQT12 SNTA1 Syntrophin, alpha 1
Information Sheet: Long QT Syndrome (LQTS) Panel Page 2 of 2 © GeneDx Revision Date: 07/2012
"
