Test Catalog

Test ID: LQTGP    
Long QT Syndrome Multi-Gene Panel, Blood

Useful For Suggests clinical disorders or settings where the test may be helpful

Providing a comprehensive genetic evaluation for patients with a personal or family history suggestive of long QT syndrome (LQTS)

 

Establishing a diagnosis of a LQTS, in some cases, allowing for appropriate management and surveillance for disease features based on the gene involved

 

Identifying variants within genes known to be associated with increased risk for disease features and allowing for predictive testing of at-risk family members

Genetics Test Information Provides information that may help with selection of the correct genetic test or proper submission of the test request

This test includes next-generation sequencing and supplemental Sanger sequencing to evaluate the genes on this panel.

 

Prior Authorization is available for this assay; see Special Instructions.

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

Long QT syndrome (LQTS) is a genetic cardiac disorder characterized by QT prolongation and T-wave abnormalities on electrocardiogram (EKG), which may result in recurrent syncope, ventricular arrhythmia, and sudden cardiac death. Romano-Ward syndrome (RWS), which accounts for the majority of LQTS, follows an autosomal dominant inheritance pattern and is caused by pathogenic variants in genes that encode cardiac ion channels or associated proteins. The diagnosis of RWS is established by the prolongation of the QTc interval in the absence of other conditions or factors that may lengthen it, such as QT-prolonging drugs or structural heart abnormalities. Clinical factors such as a history of syncope and family history also contribute to the diagnosis of RWS.

 

RWS has an estimated prevalence of 1 in 3,000 individuals. Of the families who meet clinical diagnostic criteria for RWS, approximately 75% have known genetic causes, while approximately 25% have no detectable pathogenic variants in any of the genes known to cause RWS. Approximately 3% of RWS cases are the result of large deletions or duplications in KCNQ1 or KCNH2. Deletions/duplications have not been reported in the other genes implicated in RWS.

 

Only about half of the individuals with a pathogenic gene variant associated with RWS have symptoms, usually one to a few syncopal spells, and thus many patients with this condition unfortunately present with sudden cardiac death as their first symptom. Cardiac events may occur any time from infancy through adulthood, but are most common from the preteen years through the 20s. Additionally, RWS is believed to account for approximately 10% to 15% of sudden infant death syndrome (SIDS) cases. In some cases, LQTS may be associated with congenital profound bilateral sensorineural hearing loss, known as Jervell and Lange-Nielsen syndrome (JLNS). JLNS is inherited in an autosomal recessive inheritance pattern and is caused by homozygous or compound heterozygous pathogenic variants in either KCNQ1 or KCNE1.

 

Timothy syndrome (TS) is a multisystem disorder involving prolonged QT interval in association with congenital anomalies that may include hand/foot syndactly, structural heart defects, facial dysmorphology, and neurodevelopmental features. Ventricular tachyarrhythmia is the leading cause of death with an average age of death of 2.5 years. TS is inherited in an autosomal dominant manner and usually occurs as a result of a de novo heterozygous variant in the CACNA1C gene.

 

Management strategies for LQTS include pharmacologic therapies, implantable cardioverter defibrillators (ICD), or other surgical interventions, and lifestyle restrictions such as avoidance of competitive sports or other triggers for cardiac events. In some cases, knowledge of the LQTS genotype may assist in tailoring an individual’s treatment plan. For example, patients with an SCN5A pathogenic variant may not respond well to the typical first-line therapy of beta-blockers and may have a lower threshold for consideration of an ICD.

 

Genetic testing in LQTS is recommended and supported by multiple consensus statements to confirm the clinical diagnosis, assist with risk stratification, guide management, and identify at-risk family members. Even individuals with a normal QT interval may still be at risk for a cardiac event and sudden cardiac death and, thus, EKG analysis alone is insufficient to rule out the diagnosis and genetic testing is necessary to confirm the presence or absence of disease in at-risk family members. Pre- and posttest genetic counseling is an important factor in the diagnosis and management of LQTS and is supported by expert consensus statements.

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

An interpretive report will be provided.

Interpretation Provides information to assist in interpretation of the test results

Evaluation and categorization of variants is performed using the most recent published American College of Medical Genetics and Genomics (ACMG) recommendations as a guideline. Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.

 

Multiple in silico evaluation tools may be used to assist in the interpretation of these results. The accuracy of predictions made by in silico evaluation tools is highly dependent upon the data available for a given gene, and predictions made by these tools may change over time. Results from in silico evaluation tools should be interpreted with caution and professional clinical judgment.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

Clinical Correlations:

Some individuals who have involvement of 1 or more of the genes on the panel may have a variant that is not identified by the methods performed (eg, promoter variants, deep intronic variants). The absence of a variant, therefore, does not eliminate the possibility of long QT syndrome (LQTS) or a related disorder.

 

Test results should be interpreted in context of clinical findings, family history, and other laboratory data. Misinterpretation of results may occur if the information provided is inaccurate or incomplete.

 

If testing was performed because of a family history of LQTS or a related disorder, it is often useful to first test an affected family member. Identification of a pathogenic variant in an affected individual allows for more informative testing of at-risk individuals.

 

Technical Limitations:

Next-generation sequencing may not detect all types of genetic variants. Additionally, rare polymorphisms may be present that could lead to false-negative or false-positive results. If results do not match clinical findings, consider alternative methods for analyzing these genes, such as Sanger sequencing or large deletion/duplication analysis. If the patient has had an allogeneic blood or marrow transplant or a recent (ie, less than 6 weeks from time of sample collection) heterologous blood transfusion, results may be inaccurate due to the presence of donor DNA.

 

Reclassification of Variants Policy:

At this time, it is not standard practice for the laboratory to systematically review likely pathogenic variants or variants of uncertain significance that are detected and reported. The laboratory encourages health care providers to contact the laboratory at any time to learn how the status of a particular variant may have changed over time. Consultation with a genetics professional should be considered for interpretation of this result.

 

A list of benign and likely benign variants detected for this patient is available from the lab upon request.

 

Contact the laboratory if additional information is required regarding the transcript or human genome assembly used for the analysis of this patient's results.

Clinical Reference Recommendations for in-depth reading of a clinical nature

1. Online Mendelian Inheritance in Man. Retrieved June 2018. Available at www.omim.org/search?index=entry&sort=score+desc%2C+prefix_sort+desc&start=1&limit=10&search=Long+QT

2. Tranebjaerg L, Samson RA, Green GE: Jervell and Lange-Nielsen Syndrome. In GeneReviews. Edited by RA Pagon, MP Adam, HH Ardinger, et al: University of Washington, Seattle. 1993-2018. Updated 2017 Aug 17. Accessed June 2018. Available at www.ncbi.nlm.nih.gov/books/NBK1405/

3. Alders M, Bikker H, Christiaans I: Long QT Syndrome. In GeneReviews. Edited by RA Pagon, MP Adam, HH Ardinger, et al: University of Washington, Seattle. 1993-2018. 2003 Feb 20 (Updated 2018 Feb 8). Accessed June 2018. Available at www.ncbi.nlm.nih.gov/books/NBK1129/

4. Statland JM, Tawil R, Venance SL: Andersen-Tawil Syndrome. In GeneReviews. Edited by RA Pagon, MP Adam, HH Ardinger, et al: University of Washington, Seattle. 1993-2018. 2004 Nov 22 (Updated 2015 Sep 3). Accessed June 2018. Available at www.ncbi.nlm.nih.gov/books/NBK1264/

5. Napolitano C, Splawski I, Timothy KW, et al: Timothy Syndrome. In GeneReviews. Edited by RA Pagon, MP Adam, HH Ardinger, et al: University of Washington, Seattle. 1993-2018. 2006 Feb 15 (Updated 2015 Jul 16). Accessed June 2018. Available at www.ncbi.nlm.nih.gov/books/NBK1403/

6. Barc J, Briec F, Schmitt S, et al: Screening for copy number variation in genes associated with the long QT syndrome: clinical relevance. J Am Coll Cardiol 2011;57(1):40-47

7. Priori SG, Wilde AA, Horie M, et al: HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes. Heart Rhythm 2013;10:12:1932-1963

8. Ackerman MJ, Priori SG, Willems S, et al: HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies. Heart Rhythm 2011;8:1308-1339

9. Pazoki R, Wilde AA, Bezzina CR: Genetic basis of ventricular arrhythmias. Curr Cardiovasc Risk Rep 2010;4:454-460

10. Wilde AA: Is there a role for implantable cardioverter defibrillators in long QT syndrome? J Cardiovasc Electrophysiol 2002;13(Suppl 1):S110-S113

Special Instructions Library of PDFs including pertinent information and forms related to the test