Commercial

Medical Policy

Title:

Genetic Testing for Congenital Long QT Syndrome (Independence Administrators)

Policy #:

06.02.31g

Policy

The Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member’s medical needs and condition.

This policy only applies to members for whom Independence Administrators serves as the claims administrator and whose group has not enrolled in the UM vendor program. For those groups who have been given the option to enroll in the UM vendor program, this policy is no longer applicable upon their renewal effective date. Individual member benefits must be verified before/prior to providing services.

The intent of this policy is to communicate the medical necessity criteria for genetic testing for congenital long QT syndrome (LQTS).

For information on policies related to this topic, refer to the Cross References section in this policy.

MEDICALLY NECESSARY

Genetic testing for congenital LQTS is considered medically necessary and, therefore, covered when ordered by a cardiologist, and when the individual having the genetic test meets any of the following criteria:

The individual has a prolonged QT interval on resting electrocardiogram (a corrected QTc) of greater than 440 msec without an identifiable external cause for the QTc prolongation (ie, electrolyte imbalance or certain medications).
The individual has a close relative (first-, second-, or third-degree relative) with a known LQTS mutation.
The individual has a close relative (first-, second-, or third-degree relative) diagnosed with LQTS by clinical means and whose genetic status is unavailable.
The individual has signs and/or symptoms indicating a moderate-to-high pretest probability of LQTS using the Schwartz criteria.
The individual has palpitations, syncope, dizziness with a history of a close relative (first-, second-, or third-degree relative) who experienced a sudden cardiac death.

EXPERIMENTAL/INVESTIGATIONAL

Genetic testing for congenital LQTS for all other indications is considered experimental/investigational and, therefore, not covered because the safety and/or effectiveness of this service cannot be established by review of the available published peer-reviewed literature.

REQUIRED DOCUMENTATION

The individual's medical record must reflect the medical necessity for the care provided. These medical records may include, but are not limited to: records from the professional provider's office, hospital, nursing home, home health agencies, therapies, and test reports.

The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the service.

Guidelines

It is recommended that the individual having genetic testing for congenital LQTS be seen by a cardiac electrophysiologist prior to the genetic testing.

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable benefit contract, genetic testing for congenital long QT syndrome is covered under the medical benefits of the Company’s products when the medical necessity criteria listed in the medical policy are met.

Description

Congenital long QT syndrome (LQTS) is an inherited disorder of the heart’s electrical system that is characterized by abnormal QT prolongation. Disruptions in the sodium and potassium ion channels lengthen the time of ventricular repolarization (displayed as the QT interval on an electrocardiogram). This delay increases the risk for arrhythmic events, such as ventricular tachycardia and torsades de pointes, that may lead to syncope and sudden cardiac death. Treatment modalities include beta blockers as first-line therapy, and pacemakers or implantable cardiac defibrillators (ICD) as second-line therapy.

A genetic basis for LQTS includes seven different variants, each corresponding to mutations in different genes, and has been identified as follows:

LQT1 is associated with mutations in the gene KNQ1, located on chromosome 11. LQT1 is responsible for approximately 50 percent of all LQTS. Arrhythmic events prompted by exercise occur most commonly in this subtype.
LQT2 is associated with mutations in the gene KCNH2, located on chromosome 7. LQT2 is seen in 45 percent of individuals with LQTS. Arrhythmic events are often precipitated by loud noises.
LQT3 is associated with mutations in the gene SCN5A, located on chromosome 3. This subtype is seen in 3 percent to 4 percent of individuals with LQTS.
LQT 4 - 7 involve KCN genes, located on chromosomes 21 and 17. These variants each account for less than 1 percent of LQTS.

It has been noted that typical ST-T-wave patterns are also suggestive of specific LQTS subtypes.

LQTS is one of the leading causes of sudden cardiac death in young adults. Congenital LQTS usually manifests before 40 years of age and should be suspected when there is a history of seizure, syncope, or sudden death in a child or young adult. Frequently, syncope or sudden death occurs during physical exertion or emotional excitement. In addition, LQTS may be considered when a long QT interval is observed on an EKG. Diagnostic criteria for LQTS focus on EKG findings, as well as clinical and family history. However, measurement of the QT interval is not well standardized, and in some cases, individuals may be considered borderline cases. The mortality of untreated individuals with LQTS is estimated at 1 percent to 2 percent per year, although this figure varies depending on the genotype.

Only a few laboratories in the United States perform genetic testing for congenital LQTS. For example, Transgenomic Inc offers the Familion® test, which performs an analysis of the genes responsible for subtypes LQT 1-5, and is offered in a variety of ways. For example, if a family member has been diagnosed with LQTS based on clinical characteristics, a complete analysis of all five genes can be performed to identify the specific mutation and subtype of LQTS. If a mutation is identified, additional family members can then undergo a focused genetic analysis for the identified mutation. If a specific type of LQTS is suspected based on EKG abnormalities, genetic testing can focus on the individual gene, as the pathophysiologic significance of each of the discrete mutations is an important aspect of genetic analysis.

After genetic analysis, the results are compared to the Transgenomic Inc Cardiac Ion Channel Variant Database. Specific mutations are pathophysiologically significant if they are repeatedly reported in other cases of known LQTS.

GeneDx, another laboratory offering LQTS testing, offers a LQTS panel in which the entire coding region of 10 genes (KCNQ1, KCNH2, SCN5A, ANK2, KCNE1, KCNE2, KCNJ2, CACNA1C, CAV3 and SCN4B) is sequenced using a solid-state sequencing-by-synthesis process that allows sequencing a large number of amplicons in parallel.

The John Welsh Cardiovascular Diagnostic Laboratory offers more limited LQTS testing, focusing only on mutations in KCNJ2 and CAVEOLIN (CAV3) sequencing. Individuals are tested by automatic fluorescent DNA sequencing.

Although the pathophysiologic significance of each of the discrete mutations is an important aspect of genetic analysis, there may be instances when the detected mutations are of unknown significance. Studies estimate that mutations are only identified in 60 percent to 70 percent of individuals with a clinical diagnosis of LQTS, indicating that the absence of a mutation does not imply the absence of LQTS. An additional complication resulting from genetic analysis is variable penetrance for the LQTS, as that penetrance may differ for the various subtypes. For example, approximately 50 percent of carriers of mutation never have symptoms. Recent analysis by molecular genetics has suggested that penetrance may be as low as 25 percent for some families. Therefore, the most informative result of testing occurs when a family member undergoes genetic testing for a specific genetic mutation that has been identified in symptomatic relatives known to have LQTS.

The true clinical sensitivity and specificity of genetic testing for LQTS cannot be determined with certainty as there is no independent gold standard for the diagnosis of LQTS. Nevertheless, data indicate that genetic testing will identify more individuals with possible LQTS than with clinical diagnosis alone.

References

Ackerman MJ, Priori SG, Willems, S, et al. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies: this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA). Europace. 2011; 13(8):1077-109.

Al-Khatib SM, LaPointe NM, Kramer JM, Califf RM. What clinicians should know about the QT interval. JAMA. 2003;289(16):2120-2128.

American College of Cardiology, American Heart Association Task Force, European Society of Cardiology. 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology committee for practice guidelines. J Am Coll Cardiol. 2006;48(5).

Amin AS, Giudicessi JR, Tijsen AJ, et al. Variants in the 3' untranslated region of the KCNQ1-encoded Kv7.1 potassium channel modify disease severity in patients with type 1 long QT syndrome in an allele-specific manner. Eur Heart J. 2012; 33(6):714-23.

Andersen J, Oyen N, Bjorvatn C, Gjengedal E. Living with long QT syndrome: a qualitative study of coping with increased risk of sudden death. J Genet Couns. 2008;17(5):489-498.

Barsheshet A, Goldenberg I, O-Uchi J, et al. Mutations in cytoplasmic loops of the KCNQ1 channel and the risk of life-threatening events: implications for mutation-specific response to beta-blocker therapy in type 1 long-QT syndrome. Circulation 2012; 125(16):1988-96.

Baylor College of Medicine (BCM). John Welsh cardiovascular diagnostic laboratory. [BCM Web site]. 11/29/2011. Available at: http://www.bcm.edu/pediatrics/cardiology/genetictesting-disease. Accessed August 20th, 2014.

BlueCross BlueShield Association (BCBSA) Technology Evaluation Center. Genetic Testing for Long QT Syndrome [technology assessment]. Assessment Program Volume 22, No.9. November 2007.

Costa J, Lopes CM, Barsheshet A, et al. Combined assessment of sex- and mutation-specific information for risk stratification in type 1 long QT syndrome. Heart Rhythm. 2012; 9(6):892-8.

Crotti L, Monti MC, Insolia R, et al. NOS1AP is a genetic modifier of the long-QT syndrome. Circulation. 2009; 120(17):1657-63.

Dalageorgou C, Ge D, Jamshidi Y, et al. Heritability of QT interval: how much is explained by genes for resting heart rate? J Cardiovasc Electrophysiol. 2008;19(4):386-391.

Eddy CA, MacCormick JM, Chung SK, et al. Identification of large gene deletions and duplications in KCNQ1 and KCNH2 in patients with long QT syndrome. Heart Rhythm. 2008;5(9):1275-1281.

GeneDX. Test information sheet. [GeneDx web site]. Available at: : http://www.genedx.com/test-catalog/disorders/long-qt-syndrome-lqts/. Accessed August 20th, 2014.

Hendriks KS, Hendriks MM, Birnie E, et al. Familial disease with a risk of sudden death: a longitudinal study of the psychological consequences of predictive testing for long QT syndrome. Heart Rhythm. 2008; 5(5):719-724.

Hofman N, Wilde AA, Kaab S, et al. Diagnostic criteria for congenital long QT syndrome in the era of molecular genetics: do we need a scoring system? Eur Heart J. 2007;28(5):575-580.

Jons C, Moss AJ, Lopes CM, et al. Mutations in conserved amino acids in the KCNQ1 channel and risk of cardiac events in type-1 long-QT syndrome. J Cardiovasc Electrophysiol. 2009; 20(8):859-65

Kapa S, Tester DJ, Salisbury BA, et al. Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants. Circulation. 2009; 120(18):1752-60.

Moss AJ, Zareba W, Hall WJ, et al. Effectiveness and limitations of beta-blocker therapy in congenital long QT syndrome. Circulation. 2000;101(6):616-623.

Park JK, Martin LJ, Zhang X, et al. Genetic variants in SCN5A promoter are associated with arrhythmia phenotype severity in patients with heterozygous loss-of-function mutation. Heart Rhythm 2012 [Epub ahead of print].

Priori SG, Napolitano C, Schwartz PJ, et al. Association of long QT syndrome loci and cardiac events among patients treated with beta-blockers. JAMA. 2004;292(11):1341-1344.

Priori SG, Napolitano C, Schwartz PJ. Low penetrance in the long-QT syndrome: clinical impact. Circulation. 1999;99(4):529-533.

Refsgaard L, Holst AG, Sadjadieh G, et al. High prevalence of genetic variants previously associated with LQT syndrome in new exome data. Eur J Hum Genet. 2012 [Epub ahead of print].

Sauer AJ, Moss AJ, McNitt S, et al. Long QT syndrome in adults. J Am Coll Cardiol. 2007;49(3):329-337.

Schwartz PJ, Moss AJ, Vincent GM, et al. Diagnostic criteria for the long QT syndrome. An update. Circulation.1993;88;782-784.

Schwartz PJ, Priori SG, Spazzolini C, et al. Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias. Circulation. 2001;103(1):89-95.

Scicluna BP, Wilde AW, Bezzina CR. The primary arrhythmia syndromes: same mutation, different manifestations. Are we starting to understand why? J Cardiovasc Electrophysiol. 2008;19(4):445-452.

Sen-Chowdhry S, McKenna WJ. Sudden cardiac death in the young: a strategy for prevention by targeted evaluation. Cardiology. 2006;105(4):196-206. Epub 2006 Feb 22.

Shimizu W, Moss AJ, Wilde AA, et al. Genotype-phenotype aspects of type 2 long QT syndrome. J Am Coll Cardiol. 2009; 54(22):2052-62.

Sy RW, Chattha IS, Klein GJ, et al. Repolarization dynamics during exercise discriminate between LQT1 and LQT2 genotypes. J Cardiovasc Electrophysiol. 2010 Apr 29 [epub ahead of print].

Sze E, Moss AJ, Goldenberg I, et al. Long QT syndrome in patients over 40 years of age: increased risk for LQTS-related cardiac events in patients with coronary disease. Ann Noninvasive Electrocardiol. 2008;13(4):327-331.

Tester DJ, Salisbury BA, Carr JL, et al. The effect of mutation class on QTc in unrelated patients referred for the Familion™ genetic test for long QT syndrome. Paper presented at: Heart Rhythm Society Meeting; May 11, 2007; Denver, CO.

Tester DJ, Will ML, Haglund CM, Ackerman MJ. Effect of clinical phenotype on yield of long QT syndrome genetic testing. J Am Coll Cardiol. 2006;47(4):764-768.

Transgenomic, Inc. FAMILION® Comprehensive Genetic Tests for Cardiac Syndromes. [Transgenomic, Inc. Web site]. Available at: http://labs.transgenomic.com/cardiology-familion. Accessed June 12, 2013.

Zareba W, Moss AJ, Daubert JP, et al. Implantable cardioverter defibrillator in high-risk long QT syndrome patients. J Cardiovasc Electrophysiol. 2003;14(4):337-341.

Zhang S, Yin K, Ren X, et al. Identification of a novel KCNQ1 mutation associated with both Jervell and Lange-Nielsen and Romano-Ward forms of long QT syndrome in a Chinese family. BMC Med Genet. 2008;9:24.

Coding

CPT Procedure Code Number(s)

0237U, 81413, 81414

ICD - 10 Procedure Code Number(s)

N/A

ICD - 10 Diagnosis Code Number(s)

I45.81 Long QT syndrome

THE FOLLOWING CODES ARE USED TO REPRESENT SIGNS AND SYMPTOMS

R55 Syncope and collapse

R42 Dizziness and giddiness

R00.2 Palpitations

R94.31 Abnormal electrocardiogram [ECG] [EKG]

Z82.41 Family history of sudden cardiac death

Z84.81 Family history of carrier of genetic disease

THE FOLLOWING CODES ARE USED TO REPRESENT GENETIC TESTING SCREENING

Z13.71 Encounter for nonprocreative screening for genetic disease carrier status

Z13.79 Encounter for other screening for genetic and chromosomal anomalies

HCPCS Level II Code Number(s)

G0452 Molecular pathology procedure; physician interpretation and report

Revenue Code Number(s)

N/A

MPMiscCodesNarrativesPub

Coding and Billing Requirements

Cross Reference

Policy History

Revisions From 06.02.31g:

03/04/2026	This policy has been reissued in accordance with the Company's annual review process.
03/05/2025	This policy has been reissued in accordance with the Company's annual review process.
04/17/2024	This policy has been reissued in accordance with the Company's annual review process.
04/05/2023	This policy has been reissued in accordance with the Company's annual review process.
07/01/2022	This policy has been reissued in accordance with the Company's annual review process. The following disclaimer language…: This policy only applies to members for whom Independence Administrators serves as the claims administrator and whose group has not enrolled in the UM vendor program. For those groups who have been given the option to enroll in the UM vendor program, this policy is no longer applicable upon their renewal effective date. Individual member benefits must be verified before/prior to providing services. … is replacing this disclaimer language…: This policy only applies to members for whom Independence Administrators serves as the claims administrator. For all other Independence members, refer to the policy entitled eviCore Lab Management Program.
06/01/2022	This policy has been reissued in accordance with the Company's annual review process.
03/24/2021	This policy has been reissued in accordance with the Company's annual review process.
01/01/2021	This version of the policy went through a code update process effective 01/01/2021, and procedure code 0237U was added to the policy.

Revisions From 06.02.31f:

03/25/2020	This policy has been reissued in accordance with the Company's annual review process.
05/08/2019	This policy has been reissued in accordance with the Company's annual review process.
08/29/2018	The policy has been reviewed and reissued to communicate the Company’s continuing position on Genetic Testing for Congenital Long QT Syndrome (Independence Administrators).

Effective 10/05/2017 this policy has been updated to the new policy template format.

Version Effective Date:

1/1/2021

Version Issued Date:

1/4/2021

Version Reissued Date:

3/4/2026