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Genetic Testing for Non-Cancerous Inheritable Diseases

Policy Number: MP-136

Latest Review Date: July 2019

Category: Laboratory

Policy Grade: D

DESCRIPTION OF PROCEDURE OR SERVICE:

A genetic disorder is a disease caused in whole or in part by a mutation of a gene. Genetic disorders can be passed on to family members who inherit the genetic abnormality. A number of disorders are caused by a mistake in a single gene. Genetic testing can be diagnostic, prenatal, presymptomatic, predispositional, and pharmacogenetic.

Genetic tests attempt to identify abnormalities in an individual’s genes, which include the presence or absence of key proteins whose production is directed by specific noncoding RNAs. These abnormalities in either the presence or absence of proteins could indicate an inherited disposition for a disorder.

Genetic testing includes gene, DNA or RNA testing and biochemical or protein testing. Gene tests are performed on DNA taken from blood, body fluids or tissues and examined for the abnormality. Abnormalities may be large or small involving either a piece of a chromosome or an entire chromosome may be missing or added. Genes may be amplified, over-expressed, inactivated or lost. In some instances, genes may become switched, transposed or discovered in the wrong location. Biochemical testing evaluates the presence or absence of key proteins and metabolites that may indicate abnormal or malfunctioning genes.

POLICY:

Genetic testing may be considered medically necessary when used to establish a molecular diagnosis of an inheritable disease when ALL of the following criteria are met:

  • The individual displays clinical features or is at direct risk of inheriting the mutation in question based on family history or ethnic background (e.g. Ashkenazi Jews); AND
  • The result of the test will directly impact the treatment or management of the individual or other family members; AND
  • After history, physical examination, pedigree analysis, genetic counseling, completion of appropriate conventional diagnostic studies, and a definitive diagnosis remains uncertain, genetic testing may be medically necessary for the following diagnoses (this list is not all inclusive):

Albinism

Hemoglobin S and/or C*

Alpha thalassemia*

Huntington’s disease

Angelman Syndrome

Kennedy Disease (SBMA)

Beta thalassemia*

Lowe Syndrome/Oculocerebrorenal dystrophy (OCRL)

Canavan Disease

MTHFR mutation

Classical Lissencephaly

Myotonic Dystrophy

Congenital Adrenal Hyperplasia

Niemann-Pick Disease

Dentatorubral-pallidoluysian atrophy

Prader-Willi Syndrome

Dystonias (i.e., Sandifer syndrome, stiff person syndrome, Isaac syndrome)

Prothrombin 20210A mutation

Factor V Leiden mutation

Sickle Cell Anemia

Friedreich’s ataxia

Spinal Muscular Atrophy

Gaucher Disease

Thanatophoric dysplasia (FGFR3Tay- Sachs disease)

Hemoglobin E thalassemia*

Von Hippel-Lindau Syndrome

*Electrophoresis is the appropriate initial laboratory test for individuals judged to be at-risk for a hemoglobin disorder.

Duchenne and Becker Muscular Dystrophy

Refer to Medical Policy #640, Genetic Testing for Duchenne and Becker Muscular Dystrophy

Facioscapulohumeral Muscular Dystrophy

Refer to Medical Policy #642, Genetic Testing for Facioscapulohumeral Muscular Dystrophy

Fanconi Anemia

Refer to Medical Policy #649, Genetic Testing for Fanconi Anemia

Fragile X

Refer to Medical Policy #606, Genetic Testing for FMR1 Variants (including Fragile X Syndrome)

Hereditary Hearing Loss

Refer to Medical Policy #643, Genetic Testing for Hereditary Hearing Loss

Inherited Peripheral Neuropathies (including Charcot-Marie-Tooth)

Refer to Medical Policy #595, Genetic Testing for the Diagnosis of Inherited Peripheral Neuropathies

Neurofibromatosis

Refer to Medical Policy #620, Genetic Testing for Neurofibromatosis

Rett Syndrome

Refer to Medical Policy #700, Genetic Testing for Rett Syndrome

*In the absence of specific information regarding advances in the knowledge of mutation characteristics for a particular disorder, the current literature indicates that genetic tests for each mutation need only be conducted once per lifetime of the patient.

*Testing should be performed in a setting that has adequately trained health care providers who can give appropriate pre-and post-test counseling and that has a qualified laboratory (See Key Points).

MEDICAL CRITERIA FOR DISEASE SPECIFIC GENETIC TESTING:

Genetic testing may be considered medically necessary when used to establish a molecular diagnosis of an inheritable disease when ALL of the following criteria are met:

  • The individual displays clinical features or is at direct risk of inheriting the mutation in question based on family history or ethnic background (e.g. Ashkenazi Jews); AND
  • The result of the test will directly impact the treatment or management of the individual or other family members; AND
  • After history, physical examination, pedigree analysis, genetic counseling, completion of appropriate conventional diagnostic studies, and a definitive diagnosis remains uncertain; AND
  • Follows individual criteria for specific disease/diagnosis listed below:

Cystic Fibrosis

Genetic testing for the cystic fibrosis gene may be considered medically necessary when one or more of the following criteria are met:

  • The baby has significantly elevated immuno-reactive trypsinogen (IRT); OR
  • The baby is considered to have a positive screen for CF (one or two gene mutations are identified) and may be an asymptomatic carrier of the CF gene; OR
  • Parents of a baby with a positive CF gene, to determine if they are CF gene carriers; OR
  • Adults with a family history of CF; OR
  • Partners of people with CF; OR
  • Individuals with a family history of congenital bilateral absence of the vas deferens.

Genetic testing for the cystic fibrosis gene for couples currently planning a pregnancy without any of the criteria listed above is considered not medically necessary (unless there is a contract benefit specific for cystic fibrosis routine screening).

Long QT Syndrome (LQTS)

Genetic testing for long QT syndrome (LQTS) may be considered medically necessary when one of the following criteria are met:

  • Individuals have a prolonged QTc interval (corrected QT interval) on resting electrocardiogram of ≥ 450 msec in males and ≥ 470 msec in females and do not have an identifiable external cause for QTc prolongation (such as heart failure, bradycardia, electrolyte imbalance, certain medications, or other medical conditions); or a Schwartz score of 2-3; OR
  • Individuals with a 1st degree relative (i.e., parents, full siblings, children) who have long QT syndrome or a defined LQT mutation; or whose genetic status is not known or unavailable.

AND

  • Testing is done for the following genes known to be associated with this condition: KCNQ1 (LQT1), KCNH2 (LQT2), SCN5A (LQT3), KCNE1 (LQT5), KCNE2 (LQT6); OR
  • Testing for Brugada Syndrome (SCN5A, LQT3) has been expanded to include six additional genes for a total of seven tested genes (GPD1L, CACNA1C, CACNB2, SCN1B, KCNE3, and SCN3B).

Polycystic Kidney Disease

Genetic testing for polycystic kidney disease may be considered medically necessary for patients younger than 30 years of age when one or more of the following criteria are met:

  • there are equivocal imaging results; OR
  • a definitive diagnosis is required (such as a potential living related donor).

CADASIL

Refer to Medical Policy #589, Genetic Testing of CADASIL Syndrome

Hereditary Pancreatitis

Refer to Medical Policy #590, Genetic Testing for Hereditary Pancreatitis

NON-COVERAGE INDICATIONS:

Genetic testing is considered investigational and not medically necessary for the following, including but not limited to:

  • ACE gene polymorphisms for the purpose of managing or treating diseases, including but not limited to cardiovascular disease, pulmonary disease, renal disease, diabetes mellitus and sarcoidosis
  • Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease
  • Autism
  • Glaucoma
  • Hypertrophic cardiomyopathy (HCM)
  • In-home or at-home genetics tests
  • Pierson syndrome, congenital nephrotic syndrome, for evaluating glomerular disease

Lactose Intolerance

Refer to Medical Policy #588, Genetic Testing for Lactase Insufficiency

Preimplantation Genetic Testing (PGS/PGD)

Refer to Medical Policy #593, Preimplantation Genetic Testing

Warfarin

Refer to Medical Policy #525, Genetic Testing for Warfarin Dose

Whole Exome and Whole Genome Sequencing (WES and WGS)

Genetic testing using expanded panels (non-targeted) of any type (i.e., molecular, next-generation sequencing, etc.) to establish a diagnosis of an inheritable disorder are considered investigational and not medically necessary.

Also, refer to Medical Policy #539, Whole Exome and Whole Genome Sequencing for Diagnosis of Genetic Disorders.

KEY POINTS:

Genetic disorders are grouped by geneticists into three categories: 1. Single gene disorders caused by a mistake in a single gene such as sickle cell disease, cystic fibrosis and Tay-Sachs disease. 2. Chromosome disorders caused by an excess or deficiency of the genes such as Down syndrome. 3. Multifactorial inheritance disorders caused by a combination of small variations in genes, sometimes combines with environmental factors such as heart disease, most cancers and Alzheimer’s disease.

There are also numerous types of genetic testing. These include: carrier identification as in sickle-cell and cystic fibrosis; prenatal diagnosis as in Down syndrome; newborn screening as in phenylketonuria; late-onset disorder as in cancer, heart disease and Huntington’s disease; and identification as in unique identification of an individual.

Many of the non-cancerous genetic disorders are autosomal recessive mutations. There must be two copies of the gene present for the disorder to occur. The genetic status of both parents and/or spouse of an affected individual needs to be evaluated before information regarding potential risks to siblings or offspring can be provided. Retinoblastoma, for example, may occur without a family history or sporadically or it can be inherited with a family history.

Competence for ordering genetic testing should be required before permitting providers from ordering predictive tests as needing stringent scrutiny or to counsel about them. Laboratories performing genetic testing should be certified under CLIA, the Clinical Laboratory Improvement Amendments of 1988.

**Genetic testing is contract dependent.

The following are critical issues that should be addressed when genetic testing is to be performed responsibly and effectively in the care of patients with a possible inherited genetic disorder predisposition:

  1. Counseling should be integrated into the role of the clinical medical geneticist.
    • During the evaluation and management or consultation of these patients, the following services should occur:
      • Documentation of a family history for the possible inherited disorder;
      • Counseling regarding familial disorder and options for prevention and early detection;
      • Recognition of those families for which genetic testing may serve as an aid in appropriate counseling.
  2. Counseling should be performed by a specialist who is appropriately sanctioned by a genetics credentialing organization (e.g. American Board of Genetic Counseling, Inc.) and who has been trained in the following:
    • Quantitative risk assessment;
    • Genetic testing;
    • Pre and post-test genetic counseling.
  3. Proper informed consent must be obtained. Basic elements for informed consent include the following:
    • Information on the specific test being performed.
    • Implication of a positive or negative test result.
    • Possibility that the test will not be informative.
    • Options for risk estimation without genetic testing.
    • Risk of passing a mutation or predisposition to children.
    • Technical accuracy of the test.
    • Fees involved in testing and counseling.
    • Risks of psychological distress.
    • Risks of insurance or employer discrimination.
    • Confidentiality issues.
    • Options and limitations of medical surveillance and screening following the testing.
  4. Indications for counseling and testing:
    • The patient has a strong family history of disorder (specific criteria is required for each genetic test to satisfy this requirement).
    • The test can be adequately interpreted.
    • Result will influence medical management of the patient and/or family member.
  5. Proper medical management, post-testing and counseling:
    • Discuss possible risks and benefits of early detection and treatment modalities that are presumed but unproven efficacy for individuals at the highest hereditary risk.
    • Encourage long-term research of outcome studies and/or cooperative studies or registries.

Amyotrophic lateral sclerosis (ALS)

Amyotrophic lateral sclerosis (ALS) sometimes called Lou Gehrig’s disease, is a rapidly progressive, invariably fatal neurological disease that attacks the nerve cells. This disease belongs to a group of disorders known as motor neuron disease, which are characterized by the gradual degeneration and death of motor neurons. As many as 20,000 Americans have ALS, and an estimated 5,000 people in the United States are diagnosed with the disease each year. ALS is one of the most common neuromuscular diseases worldwide, and people of all races and ethnic backgrounds are affected. In 90 to 95 percent of all ALS cases, the disease occurs apparently at random with no clearly associated risk factors. Patients do not have a family history of the disease, and their family members are not considered to be at increased risk for developing ALS. About five to 10 percent of all ALS cases are inherited. The familial form of ALS usually results from a pattern of inheritance that requires only one parent to carry the gene responsible for the disease. About 20 percent of all familial cases result from a specific genetic defect that leads to mutation of the enzyme known as superoxide dismutase 1 (SOD1). Research on this mutation is providing clues about the possible causes of motor neuron death in ALS. Not all familial ALS cases are due to the SOD1 mutation; therefore other unidentified genetic causes clearly exist.

Validation of the clinical use of any diagnostic test focuses on three main principles: 1) the technical feasibility of the test; 2) the diagnostic performance of the test, such as the sensitivity, specificity, PPV, and NPV in different populations and compared to the gold standard; 3) the clinical utility of the test, or how the results will be used to manage the patient.

The diagnostic performance is related to the interpretation of the results of the genetic analysis. The absence of an identified mutation does not imply absence of disease, since other mutations on different genes could potentially be involved. Also, the clinical significance of an identified mutation must be determined. The cardiac ion channel genes are quite large, and there may be numerous mutations discovered along the length. The discovered mutation can be compared to a growing database of known mutations, and if it is similar to one already identified in an affected patient, it is presumed that there is an increased risk that the mutation is pathogenic. However, there is varying penetrance of mutations and there is not necessarily a strong correlation between the genotype and the phenotype.

Angiotensin Converting Enzyme (ACE) Gene Polymorphism

The Angiotensin Converting Enzyme (ACE) insertion/deletion (I/D) polymorphism is one of the most widely studied genetic variants. It involves a 287-base pair insertion or deletion within intron 16 of the ACE gene. Although the clinical significance of this polymorphism remains controversial, the association with ACE enzymatic activity has consistently been demonstrated. Studies have shown that persons with the DD genotype have the highest ACE activity, heterozygotes (I/D) have intermediate levels and II genotype have the lowest levels of ACE activity. The relationship of the ACE gene I/D polymorphism has been explored in relation to numerous conditions including cardiovascular disease, (e.g., atherosclerosis, MI, CHF, HTN), stroke, pulmonary disease (e.g., pneumonia, ARDS), renal disease, sarcoidosis, diabetes, pancreatitis, ovarian disease, pediatric disease and others. The literature is replete with articles about the ACE gene polymorphisms and their relation to diseases and treatments.

Angiotensin-converting enzyme (ACE) inhibitors are widely used drugs for the treatment of hypertension, heart failure, and prevention of diabetic nephropathy. There is interest in these drugs because of a common polymorphism known to cause variations in serum ACE levels. The insertion/deletion (I/D) polymorphism has been noted to account for 47% of the variability in serum ACE levels. The DD genotype is seen in approximately one-third of the population. The I/D polymorphism has been studied as a risk factor for coronary artery disease; DD genotype may be a risk factor for myocardial infarction. The I/D polymorphism appears to be a strong predictor of ACE levels, which may be a predictor of cardiovascular outcomes, so interaction with ACE inhibitor treatment seems plausible. It is hypothesized that those with the DD genotype may be more responsive to ACE inhibitors. The ACE I/D polymorphism has also been studied in relation to other cardiovascular treatments, such as statins and beta blockers, with conflicting findings.

There are several published studies in the literature that investigate the interaction of ACE gene polymorphisms and pharmacogenomics interactions.

There are two recent reviews on the interaction of ACE gene polymorphisms and ACE inhibitor treatment. Scharplatz, et al (2005), reviewed 11 studies that examined the I/D polymorphism in relation to ACE inhibitor treatment. These studies had a wide variety of clinical indications and analyzed a variety of clinical endpoints and outcomes. The authors noted a trend toward better response to ACE inhibitors in Caucasian DD carriers. However, they noted the small number of studies and the lack of sufficient genetic data precluded drawing any convincing conclusions. Studies in Asian populations showed the opposite results, with DD carriers having worse outcomes with ACE inhibitor treatment.

Tsikouris and Peters (2007) published another review article that looked at ACE gene polymorphisms and ACE inhibitor therapy in patients with coronary artery disease. The authors evaluated 11 studies and reported the findings to be inconclusive and conflicting.

Arnett, et al (2005), reported on the GenHAT study that looked at ACE gene I/D polymorphism and pharmacogenomics interaction in 37,000 persons randomized to different classifications of hypertension medication. It was hypothesized those with the DD genotype randomized to ACE inhibitors would achieve superior outcomes compared to those assigned to other medications. They found that the ACE I/D polymorphism was not a predictor of any outcome, nor was there any interaction with the ACE inhibitor treatment. For one outcome, BP control, patients with the DD phenotype were less responsive to ACE inhibitors than other medications. The study cast doubts on the association between genotype and cardiovascular risk in general, and whether variations in serum ACE are associated with cardiovascular disease. The association between genotype and cardiovascular disease was inconsistent across studies, but a meta-analysis was consistent with a small effect.

Tascilar, et al (2009), reported on a study that looked at ACE I/D polymorphism in patients with large-vessel (n=97) and small-vessel (n=60) atherosclerotic stroke and in healthy subjects (n=85). The results showed a lack of association between stroke and ACE I/D polymorphism, and this did not change in the presence of traditional risk factors (hypertension, diabetes mellitus, smoking and dyslipidemia). The authors concluded that ACE I/D polymorphism did not predict the risk of stroke or hypertension in this population in Turkey.

The ACE gene polymorphism has also been studied in patients with sarcoidosis. The angiotensin-converting enzyme (ACE) is secreted by the epithelioid cells of sarcoid granulomas, and some patients with clinically active sarcoidosis exhibit elevated serum ACE levels. The serum ACE levels in normal and sarcoidosis patients are influenced by I/D polymorphism in the ACE gene. Average serum ACE levels are decreased in patients homozygous for the insertion (genotype II) and increased in patients without the insertion (genotype DD). This same pattern has been found in patients with sarcoidosis. An early report from Japan found an association of the D allele with the risk of sarcoidosis in females. However, most investigators could not confirm this finding. The ACE DD genotype has been found to be over-represented in African-American (AA) and in German patients with a family history of sarcoidosis.

Maliarik et al (1998) reported on the ACE gene polymorphism and sarcoidosis in African-Americans. They compared 183 AA cases and 111 control subjects. The results showed that in the risk for sarcoidosis was 1.3 for ID heterozygotes and 3.17 for DD homozygotes. The risk associated with DD homozygotes was even greater in AA with a positive family history. Further analyses of AA cases showed the ACE genotype was not associated with disease severity, extrathoracic involvement, or overall radiographic change two to four years after diagnosis. They concluded that the ACE genotype may play a more important role in sarcoidosis susceptibility and progression in AA than in Caucasians.

Pietinalho et al (1999) reported on the ACE genotype and prognosis in Finnish sarcoidosis patients. They looked at 59 Finnish sarcoidosis patients and 70 healthy control subjects and followed them for five years. The results showed that more patients with the DD genotype had a poor prognosis compared with patients with II homozygotes and ID heterozygotes, and the result was statistically significant. The authors noted that larger studies are warranted.

Levels of serum ACE are used to determine disease activity in sarcoidosis. However, serum ACE levels are influenced by the D/I polymorphism, so the sensitivity and specificity of this test for disease monitoring are limited.

Schena et al (2001) reported on the association of ACE gene polymorphism and IGA nephropathy in patients from Southern Italy. They evaluated 247 patients with IgAN and 205 healthy subjects and followed them for three years. The results showed no difference in the ACE I/D gene distribution between patients and controls and between patients with stable and those with deteriorating renal function.

van de Garde et al (2008) reported on a study that examined whether the ACE I/D polymorphism affects the risk and outcome of community-acquired pneumonia (CAP) in a Dutch white population. There were 200 patients with pneumonia and 200 control subjects. All patients were genotyped, and pneumonia severity and clinical outcome were compared between patients with II, ID and DD genotypes of the ACE gene. Pneumonia severity was assessed using the acute physiology score (APS). The results showed that the APS scores were not different between the genotype groups on any of the days, and all clinical outcomes were comparable between the three genotype groups on any of the days, and all clinical outcomes were comparable between the three genotype groups. The ACE I/D genotype distribution was identical for patients and control subjects. The ACE I/D polymorphism was not associated with risk and outcome of CAP in this population.

Autism

Research is ongoing to correlate clinical phenotypes with specific genetic profiles.

Miles and McCathren published an overview of autism. For individuals with secondary autism, genetic counseling is based on information relevant to the primary diagnosis. For idiopathic autism, the empiric aggregate risk to siblings is 4% for autism and an additional 4 to 6% risk for milder conditions, including language, social and psychiatric disorder. For families with two or more affected children, the recurrence risk approaches 35%. Male siblings of a proband (clinically affected individual through whom a family is found that can be used to study the genetics of a particular disorder) with essential autism have a 7% risk for autism and additional 7% risk for milder ASD. Female siblings of a proband with essential autism have a 1% risk for autism. The risk for a milder ASD spectrum disorder is unknown. The recurrence risk of ASD to siblings of a proband with complex autism is 1% for autism and an additional 2% for a milder ASD. Only about 3% of individuals with autism have a maternally inherited chromosomal duplication in the Prader-Willi syndrome/Angelman syndrome region of 15q11-q13. Children with Down syndrome have autism more commonly than expected.

Congenital Adrenal Hyperplasia (CAH)

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders caused by deficiency in one or more of the enzymes required for synthesis of cortisol, aldosterone, and sex steroids in the adrenal gland. There are at least five gene mutations associated with various forms of CAH. The most frequent form of CAH, 21-hydroxylase deficiency (21-OHD), is associated with gene mutations in CYP21A2 and accounts for 90% to 95% of all cases. Other gene mutations include CYP11B1, CYP17A1, HSD3B2 and STAR. Nimkarn and New (2009) reported that the most common form of CAH, 21-OHD, in its most severe form can cause genital ambiguity in females. Affected females experience virilization both physically and psychologically. Steroid 21-OHD can be diagnosed in utero through molecular genetic analysis of fetal DNA. Appropriate prenatal treatment by dexamethasone administration to the at-risk pregnant mother is effective in reducing genital virilization in the fetus, thus avoiding unnecessary genitoplasty in affected females. Current data from large human studies show that prenatal diagnosis and treatment are safe in the short term for both the fetus and the mother. Preliminary data from long-term studies support these results.

Congenital Nephrotic Syndrome

Pierson syndrome is a rare autosomal recessive condition defined by severe nephrosis presenting in early infancy accompanied by distinct ocular abnormalities. It is caused by mutations in the laminin B2 gene, LAMB2. Laminin B2 is part of a complex of glycoproteins in the renal glomerular basement membrane. Clinically, it is characterized by congenital nephrotic syndrome (CNS) that may progress to end-stage renal failure and ocular abnormalities including cataracts, anterior chamber and iris abnormalities, and progressive blindness due to retinal detachment.

Danderpani and Pollak (2006) published a review of the biologic and genetic complexity of the glomerular filtration barrier. They noted that there are several known congenital nephrotic syndrome genes and mutations in the same gene may lead to different phenotypes. The spectrum of genetic lesions underlying congenital nephrotic syndrome has yet to be fully defined. They noted that there is a large spectrum of inherited proteinuric disorders ranging from the relatively mild proteinuria and slowly progressive renal failure to severe congenital nephrosis. Further work is needed to define the precise downstream effects of these mutant or absent proteins to explain this variability. They noted that as our understanding of other genetic etiologies of nephrosis increased, so will our understanding of their prognostic and therapeutic implications. The authors noted that careful analysis of single gene disorders will continue to provide some informative insights into disease mechanisms. There is no current peer-reviewed literature that addresses changes in treatment options or outcomes for congenital nephrotic syndrome as a result of genetic testing.

Cystic Fibrosis

The Centers for Disease Control and Prevention (CDC) released recommendations for screening of newborns for cystic fibrosis (CF). The report also includes an evaluation of the benefits and risks of this type of screening program. Many states offer newborn screening for CF as part of the newborn testing programs.

Newborn screening for CF consists of multiple protocols and algorithms that all begin with measuring immunoreactive trypsinogen (IRT) in a dry blood heel-stick sample. Infants with elevated IRT values are referred for further testing. Depending on the state in which the testing is done, the next test following an elevated IRT may be a repeat IRT (IRT-repeat IRT protocol) or DNA analysis (IRT/DNA algorithm). Infants with an elevated repeat IRT or who have one or more cystic fibrosis transmembrane regulator (CFTR) mutations found on DNA analysis would then be referred for sweat testing.

Glaucoma

Alward, et al discussed the prevalence of variations in the myocilin gene in patients with primary open-angle glaucoma (POAG) in a study that included 779 patients and 524 with POAG. 3.2% had a disease-causing sequence (DCV) in the POAG group and 6.4% in the juvenile-onset group. None of these values were statistically significant. They concluded that for a genetic test to be useful, it must be able to identify subjects at risk in a population of disease carriers at a high rate. DCVs in the myocilin gene were found in only 3% of the glaucoma population with no differentiation between types. The authors concluded that screening for it would not help predict people at risk for glaucoma. More research on genetic testing for glaucoma is required before it can be an effective tool.

Cohen and Allingham in 2004 reviewed recent trends for patents with glaucoma. They stated some investigators have found that the myocilin gene may increase disease severity in patients with POAG, whereas others have not found this association. Genetic testing for glaucoma holds promise but currently available tests for disease related tests in patients with glaucoma or at risk for this disease remain controversial.

Mackey and Craig also wrote that to use DNA testing to identify individuals at high risk for glaucoma, it is necessary to have solid evidence with sensitivity and specificity parameters, genotype-phenotype correlations, and information on prevalence and penetrance. These data will have to be replicated in several studies using large, population-matched control groups.

There are complicated technical and ethical issues associated with preimplantation genetic diagnosis. Assisted reproductive techniques may be subject to specific contractual restriction.

Hypertrophic Cardiomyopathy (HCM)

Familial hypertrophic cardiomyopathy (HCM) is an inherited condition caused by a disease-associated variant in one or more of the cardiac sarcomere genes. Hypertrophic cardiomyopathy is associated with numerous cardiac abnormalities, the most serious of which is sudden cardiac death. The main feature of hypertrophic cardiomyopathy (HCM) is an excessive thickening of the heart muscle. Diagnosis of HCM is most often established when two- dimensional echocardiography detects left ventricular hypertrophy (LVH) in a non-dilated ventricle; it can also be established by pathognomonic histopathologic findings in cardiac tissue. HCM can occur without symptoms, but others may experience dyspnea, angina and palpitations. There is usually a gradual progression symptoms but can result in sudden death or severe heart failure may occur.

Genetic testing is now being considered by some an important part of diagnosis, particularly in familial HCM. The identification of gene mutations for HCM has led to the development of DNA-based testing of patients with HCM to aid diagnosis and management of patients. Per a review by uptodate.com the use of genetic testing still has issues that result in a poor recommendation. This article cites that all genes responsible for HCM have not yet been identified. In addition, among some genes that have been identified, the spectrum of possible disease-causing mutations is still incomplete. There is also evidence that some patients are compound heterozygotes (inherit two different mutations within a single HCM gene), double heterozygotes, or homozygotes. It is also noted that even in a known heterogeneity with clinical manifestations of a given mutation, the clinical course cannot be predicted with any degree of certainty. Rapid gene tests for HCM are also available that are capable of identifying some, but not all, genetic causes of the disease. There has not yet been a clear role defined by genetic testing and screening for HCM, and therefore this testing is not covered at this time.

Long QT Syndrome

Congenital long QT syndrome (LQTS) is an inherited disorder characterized by the lengthening of the repolarization phase of the ventricular action potential, resulting in prolongation of the QT interval. This leads to an increased risk for arrhythmic events, such as torsades de pointes, which may in turn result in syncope and sudden cardiac death. Management has focused on the use of beta-blockers as first-line treatment, with pacemakers or implantation cardioverter defibrillators (ICD) as second-line therapy.

Genetic testing for LQTS is recognized as an important research tool, but there is still discussion on whether the results can be used to improve patient management. At present, the initial treatment for LQTS is typically beta-blocker therapy, although this strategy has never been tested in controlled trials, and several authors caution that there is still a high rate of cardiac events in patients on beta-blocker therapy. Other treatment options include left-sided cardiac sympathetic denervation, pacemakers, or implantable cardioverter defibrillator (ICD). The bulk of the published literature consists of retrospective studies and there are no articles in which genotypic analysis was used in the management of the patient. Genetic testing has been used in several different clinical situations. It has been used in symptomatic patients with clinically diagnosed LQTS to determine the subtype. It has also been used in an asymptomatic family member who has a relative with LQTS with known genotype.

Congenital LQTS usually manifests itself before the age of 40 years, and may be suspected when there is a history of seizure, syncope, or sudden death in a child or young adult; this history may prompt additional testing in family members. It is estimated that more than one half of the 8,000 sudden unexpected deaths in children may be related to LQTS. The mortality of untreated patients with LQTS is estimated at 1%-2% per year, although this may vary with genotypes. Frequently, syncope or sudden death occurs during physical exertion or emotional excitement, and there has been some discussion about LQTS with regard to evaluation of adolescents for participation in sports. Also, LQTS may be considered when a long QT interval is incidentally observed on an EKG. Diagnostic criteria for LQTS have been established, and focus on EKG findings and clinical and family history. The corrected QT interval (QTc) is LQTS is usually > 0.46 sec in men and > 0.47 sec in women, although 1/3 of affected individuals may have QTc intervals that fall within the normal or non-diagnostic range. Typical ST-T wave patterns are also suggestive of specific subtypes.

The Schwartz criteria are commonly used as a diagnostic scoring system for LQTS. The most recent version of this scoring system is shown in the Table 1. A score of four or greater indicates a high probability that LQTS is present; a score of 2–3 an intermediate probability; and a score of one or less indicates a low probability of the disorder. Prior to the availability of genetic testing, it was not possible to test the sensitivity and specificity of this scoring system; therefore, the accuracy of this scoring system is ill-defined.

Table 1. Diagnostic Scoring System for LQTS

Criteria

Points

Electrocardiographic findings

*QTc >480 msec

3

*QTc 460-470 msec

2

*QTc <450 msec

1

History of torsades de pointes

2

T-wave alternans

1

Notched T-waves in three leads

1

Low heart rate for age

0.5

Clinical history

*Syncope brought on by stress

2

*Syncope without stress

1

*Congenital deafness

0.5

Family history

*Family members with definite LQTS

1

*Unexplained sudden death in immediate family members younger than 30 years of age

0.5

Currently, there are four recognized LQT syndromes: the Romano-Ward syndrome (RWS), Jervell and Lange-Nielsen syndrome (JLN), Andersen-Tarvil syndrome, and Timothy syndrome.

The RWS, (i.e., familial occurrence with AD inheritance, QT prolongation, and ventricular tachyarrhythmias) is the most common form and accounts for 85% of all LQTS cases. It is not associated with extracardiac manifestations, and may be difficult to detect clinically. Three phenotypes have been described and mutations in at least five different genes have been identified. The JLN syndrome (i.e., familial occurrence with AR inheritance) is associated with congenital deafness, marked QT prolongation, and ventricular arrhythmias.

In recent years, advances in molecular genetics and basic research have established that LQTS is an inherited disorder of cardiac ion channels. Abnormalities in the sodium and potassium channels that control the excitability of the cardiac myocytes leads to delayed repolarization of cardiac muscles, and prolongation of the QT interval on EKG. A genetic basis for LQTS has also emerged, with at least eight genes being associated with LQTS. Also, several hundred unique mutations have been identified within these genes. Some of the genotypic designations are as follows: LQT1 is the most common form and is associated with mutations in the gene KCNQI located on chromosome 11. It is responsible for about 45% of genotyped patients. The most common trigger for a cardiac event in these patients is exercise (particularly swimming), followed by emotional stress (fear, anger, or startle response). More than 80% of patients have a first cardiac event by age 20. Patients with LQT1 may be advised to minimize exercise. LQT2 is associated with mutations in the gene KCNH2 located on chromosome seven and accounts for 40% of genotyped patients. Arrhythmic events appear to be precipitated by auditory stimuli, and these patients may be advised to avoid clock alarms, etc. LQT3 is associated with mutations in the SCN5A located on chromosome three. This subtype is seen in 3%-4% of patients with LQTS. Most events in LQT3 patients occur during sleep or rest, suggesting they are at higher risk at slow heart rates. LQT3 variant is also known as the Brugada syndrome. LQT5 and seven involve KCN genes located on chromosomes 21 and 17. These variants each account for <1% of LQTS. LQT4 involves ANK genes on chromosome four. LQT8 involves LAC genes located on chromosome 12.

The Familion Test describes the analysis of the genes responsible for subtypes LQT 1-5. This test has been used in a variety of situations. If a person has been diagnosed with LQTS based on clinical characteristics, complete analysis of all five genes can be performed to identify the specific mutation and the subtype of LQTS. If a mutation is identified, then additional family members can undergo a focused genetic analysis for the identified mutation. If a specific type of LQTS is suspected based on the EKG abnormalities, and genetic testing can focus on the individual gene.

All of the LQTS genes are large, and genetic testing has revealed multiple different mutations along their length. The pathophysiologic significance of each of the discrete mutations is an important part of the interpretation of genetic analysis. Genaissance, the laboratory offering the Familion test, compares the results to the Genaissance Cardiac Ion Channel Variant Database, which includes data from over 750 individuals of diverse ethnic backgrounds. Therefore, the chance that a specific mutation is pathophysiologically significant is increased if it is the same mutation as that reported in several other cases of known LQTS. Some of the detected mutations may be of unknown significance. Also, the absence of a mutation does not imply the absence of LQTS. It is estimated that mutations are only identified in 60%-70% of patients with a clinical diagnosis. Another factor complicating interpretation of genetic analysis is the penetrance of a given mutation or the presence of multiple phenotypic expressions. For example, 50% of carriers of a mutation never have any symptoms.

PGxHealth Familion has published information that testing for Brugada syndrome (BrS) a member of the ion channel disease of LQTS. LQT3 is associated with mutations in the gene SCN5A located on chromosome three. This subtype is seen in 3%-4% of patients with LQTS. In this subtype, the majority of cardiac events occur during sleep. LQT3 variant is also known as the Brugada syndrome. The gene previously analyzed by the current test is SCN5A. PGxHealth has recommended an expansion of the FAMILION BrS test to include an additional six genes bringing the total number of tested genes to seven. These genes are recommended for inclusion due to their ability to identify additional patients with a high index of clinical suspicion for BrS. This will result in an increased sensitivity of the FAMILION BrS test to detect a disease-causing mutation in 25% to 40% of patients with a high index of clinical suspicion for BrS. In addition to the SCN5A gene, the expanded BrS tests will analyze the following genes: GPD1L, CACNA1C, CACNB2, SCN1B, KCNE3, and SCN3B. This expanded testing began on May 15, 2010.

There are many articles published in the peer-reviewed literature that discuss genetic testing for LQTS. Genetic testing has been used to establish a diagnosis of LQTS and to identify specific subtypes of LQTS and/or specific genetic mutations.

Zareda, et al (1998) looked at the genotypes of 246 patients with LQTS and determined the cumulative probability and lethality of cardiac events occurring from birth-age 40 years. The results showed the frequency of cardiac events was higher among subjects with mutations at the LQT1 locus (63%) or LQT2 locus (46%) than among subjects with mutations at the LQT3 locus (18%).

Schwartz, et al (2001) reported on the incidence of cardiac events in 670 LQTS patients with known genotype LQT 1-3. The results showed that patients with LQT1 had a lower cardiac event rate (28%) than LQT2 (40%) or LQT3 (49%).

Priori, et al (2003) looked at the risk of cardiac events based on genotype in 647 LQTS patients. The results showed that the incidence of a first cardiac event before age 40 and before therapy was lower in LQT1 patients (30%) than in LQT2 patients (46%) or LQT3 patients (42%).

Priori, et al (2004) reported on the incidence of cardiac events in 335 LQTS patients with known genotype, treated with beta-blockers. The results showed the incidence of cardiac events was lower in LQT1 patients (10%) than in LQT2 patients (23%) or LQT3 patients (32%).

Tester, et al (2006) looked at the sensitivity and specificity of genetic testing compared with clinical methods. They looked at 274 patients who had a LQTS mutation and compared the genetic diagnosis with the clinical diagnosis, defined as a Schwartz score of ≥ four. They reported a sensitivity of 72% and specificity of 57% for the genetic testing.

Hofman, et al (2007) looked at the sensitivity and specificity of various clinical methods used to make the diagnosis of LQTS, as compared with genetic testing. They looked at 513 relatives of 77 probands with known disease-causing mutation. The results showed the Schwartz criteria, using a score ≥ four, had 19% sensitivity and 99% specificity. The Keating criteria had a 36% sensitivity and 99% specificity. Analyzing the QTc duration alone, using a cutoff ≥ 430 msec, had 72% sensitivity and 86% specificity. They concluded that in genotyped families, genetic testing is the preferred diagnostic test.

Summary for Long QT genetic testing

A genetic mutation can be identified in approximately 70-75% of patients with LQTS. The majority of these are point mutations that are identified by gene sequencing analysis, however a small number are deletions/duplications that are best identified by chromosomal microarray analysis (CMA). The clinical validity of testing for point mutations by sequence analysis is high, while the clinical validity of testing for deletions/duplications by CMA is less certain.

The clinical utility of genetic testing for LQTS is high when there is a moderate to high pre-test probability of LQTS and when the diagnosis cannot be made with certainty by other methods. A definitive diagnosis of LQTS leads to treatment of LQTS with beta blockers in most cases, and sometimes to treatment with an ICD. As a result, confirming the diagnosis of LQTS will lead to a health outcome benefit by reducing the risk for ventricular arrhythmias and sudden cardiac death. The clinical utility of testing is also high for close relatives of patients with known LQTS, since these individuals should also be treated if they are found to have a pathologic LQTS mutation. Therefore, genetic testing for the diagnosis of LQTS may be medically necessary for the following individuals who do not have a clinical diagnosis of LQTS but who have: 1) a close relative (i.e., first-, second-, or third-degree relative) with a known LQTS mutation, 2) a close relative diagnosed with LQTS by clinical means whose genetic status is unavailable, or 3) signs and/or symptoms indicating a moderate-to-high pretest probability of LQTS. For all other indications, including prognosis and management of patients with known LQTS, genetic testing is considered investigational.

Lowe Syndrome

Wasserstein reports that in 1952, Lowe et al described an infant with congenital cataracts and mental retardation. When more patients were described, the phenotype was expanded to include the renal Fanconi syndrome, and the X-linked inheritance pattern was noted. The diagnostic triad of the oculocerebrorenal syndrome of Lowe (OCRL) includes congenital cataracts, neonatal or infantile hypotonia with subsequent mental impairment, and renal tubular dysfunction. OCRL is inherited in an X-linked fashion. Most patients are male, only a few females have been reported.

Dystonia refers to syndrome of involuntary sustained or spasmodic muscle contractions involving co-contraction of both the agonist and the antagonist. The movements are usually slow and sustained. They often occur in a repetitive and patterned manner, but they can be unpredictable and fluctuate. The frequent abnormal posturing and twisting can be painful and functionally disabling. Primary or idiopathic dystonia can manifest in a sporadic, autosomal dominant, autosomal recessive, or X-linked recessive manner. Heritable childhood-onset dystonia is particularly common among Ashkenazi Jewish people. Currently at least 12 types of dystonia can be distinguished on a genetic basis. Genetic screening for DYT gene abnormalities and genetic counseling is important for patients with an onset of primary dystonias at younger than 30 years or those who have an affected relative.

Polycystic Kidney Disease

Autosomal dominant polycystic kidney disease (ADPKD) is a common disorder, occurring in approximately one in every 400 to 1000 live births. Approximately 85% of families with ADPKD have an abnormality on chromosome 16 (PKD1 locus) that is tightly linked to the alpha-globin gene locus. The other patients have a different defect that involves a gene on chromosome 4 (the PDK2 locus).

Patients with PKD2 have a less severe phenotype than those with PKD1, but neither disorder is benign. Cysts occur later in PDK2 disease, as does end-stage renal disease. As a result, false negative results are more likely when screening young subjects with PKD2 disease.

The diagnosis of ADPKD relies principally upon imaging of the kidney. Ultrasonography is most commonly used as the imaging modality. Typical findings include large kidneys and extensive cysts scattered throughout both kidneys. Genetic testing may be needed in some cases for a definitive diagnosis.

The current methods used to perform genetic testing are linkage or sequence analysis of DNA.

Linkage analysis uses microsatellite markers that flank the PKD1 and PKD2 genes. The technique requires the accurate diagnosis in an adequate number of known family members (at least four) who are willing to be tested. Linkage analysis is therefore suitable in less than one-half of families.

Direct DNA analysis of the PKD1 and PKD2 genes is hampered by their immense size, complexity, and allelic heterogeneity. With both genes, mutation detection rates of approximately 65 to 70 percent have been reported with denaturing high-performance liquid chromatography (DHPLC). Direct sequencing is associated with rates of approximately 85 to 90 percent. However, whether a mutation is associated with pathogenicity is unclear since most changes are unique and missense changes in PKD1 constitute nearly one-third of all mutations.

A study by Zhao et al showed that a combined approach using both modalities may be most effective. Genetic linkage and direct DNA analysis was most effective among two prospective kidney donors with a positive family history and, the use of both linkage and DNA sequencing was required to definitively exclude the presence of ADPKD.

Thanatophoric Dysplasia (TD)

Thanatophoric dysplasia (TD) is a neonatal lethal short-limb dwarfism syndrome. TD is divided into Type I, characterized by micromelia with bowed face and, uncommonly the presence of cloverleaf skull deformity of varying severity; and Type II, characterized by micromelia with straight femurs and uniform presence of moderate-to-severe cloverleaf skull deformity. Other features common to the two subtypes of TD include short ribs, narrow thorax macrocephaly, distinctive facial features, brachydactyly, hypotonia, and redundant skin folds along the limbs. Most affected infants die of respiratory insufficiency shortly after birth. Diagnosis of TD is based on clinical examination and/or prenatal ultrasound examination and radiologic studies. Characteristic histopathology is also present. TD is considered an autosomal dominant disorder. FDFR3 is the only gene associated with TD. Approximately 99% of mutations causing TD can be identified through molecular genetic testing of FGFR3. TD I and TD II represent new mutations to normal parents. The recurrence risk is low. Because the mutated codons in TD are mutable for unknown reason and because of the theoretical risk of germ cell mosaicism, parents are offered prenatal diagnosis for subsequent pregnancies.

U.S. Preventive Services Task Force

Not applicable.

KEY WORDS:

Genetic test, Huntington’s disease, cystic fibrosis, Friedreich’s ataxia, Spinal Muscular Atrophy, Myotonic Dystrophy, Prader-Willi Syndrome, Angelman Syndrome, Canavan Disease, Hemoglobin S and /or C, Kennedy disease, SBMA, Dentatorubral-pallidoluysian atrophy, Classical Lissencephaly, Niemann-Pick disease, Tay-Sachs, Von Hippel-Lindau syndrome, Gaucher Disease, Retinoblastoma, Hemoglobin E thalassemia, Beta thalassemia, Alpha thalassemia, Albinism, Factor V Leiden mutation, Prothrombin 20210A mutation, Sickle cell anemia, mutation, DNA, congenital long QT syndrome, LQTS, glaucoma, OCRL, Lowe Syndrome, corrected QT interval (QTc), Romano Ward Syndrome (RWS), Jervell and Lange-Nielsen Syndrome (JLN), iron overload disorders, elevated transferrin-iron concentrations, elevated transferrin-iron levels, AmpliChip Cytochrome P450® Genotyping test, Helicobacter pylori (H. pylori), thanatophoric dysplasia, autism, Pierson Syndrome, Congenital Nephrotic Syndrome (CNS), angiotensin converting enzyme (ACE), gene polymorphisms, insertion (I), deletion (D), early onset myocardial infarction, congenital adrenal hyperplasia (CAH), HCM, Hypertrophic Cardiomyopathy, Familial HCM, Familial Hypertrophic Cardiomyopathy

APPROVED BY GOVERNING BODIES:

Appropriate lab competency for testing:

  • State license, Clinical Laboratory Improvement Amendments (CLIA) certification, American College of Medical Genetics/College of American Pathologist (ACMG/CAP) certification
  • Director and staff credentialed by the American Board of Medical Genetics (ABMG).
  • Credentialed by the American Board of Bioanalysis (ABB) and American Board of Histocompatibility and Immunogenetics (ABHI).

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits. Some contracts exclude genetic testing. Some genetic screening may be routine and contract benefits should be verified for routine services as in cystic fibrosis. Group specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply

FEP contracts: FEP does not consider investigational if FDA approved and will be reviewed for medical necessity. Special benefit consideration may apply. Refer to member’s benefit plan.

CURRENT CODING:

CPT codes:

81171

AFF2 (AF4/FMR2 family, member 2 [FMR2]) (e.g., fragile X mental retardation 2 [FRAXE]) gene analysis; evaluation to detect abnormal (e.g., expanded) alleles (Effective 01/01/2019)

81172

AFF2 (AF4/FMR2 family, member 2 [FMR2]) (e.g., fragile X mental retardation 2 [FRAXE]) gene analysis; characterization of alleles (e.g., expanded size and methylation status) (Effective 01/01/2019)

81173

AR (androgen receptor) (e.g., spinal and bulbar muscular atrophy, Kennedy disease, X chromosome inactivation) gene analysis; full gene sequence (Effective 01/01/2019)

81174

AR (androgen receptor) (e.g., spinal and bulbar muscular atrophy, Kennedy disease, X chromosome inactivation) gene analysis; known familial variant (Effective 01/01/2019)

81177

ATN1 (atrophin 1) (e.g., dentatorubral-pallidoluysian atrophy) gene analysis, evaluation to detect abnormal (e.g., expanded) alleles (Effective 01/01/2019)

81178

ATXN1 (ataxin 1) (e.g., spinocerebellar ataxia) gene analysis, evaluation to detect abnormal (e.g., expanded) alleles (Effective 01/01/2019)

81179

ATXN2 (ataxin 2) (e.g., spinocerebellar ataxia) gene analysis, evaluation to detect abnormal (e.g., expanded) alleles (Effective 01/01/2019)

81180

ATXN3 (ataxin 3) (e.g., spinocerebellar ataxia, Machado-Joseph disease) gene analysis, evaluation to detect abnormal (e.g., expanded) alleles (Effective 01/01/2019)

81181

ATXN7 (ataxin 7) (e.g., spinocerebellar ataxia) gene analysis, evaluation to detect abnormal (e.g., expanded) alleles (Effective 01/01/2019)

81182

ATXN8OS (ATXN8 opposite strand [non-protein coding]) (e.g., spinocerebellar ataxia) gene analysis, evaluation to detect abnormal (e.g., expanded) alleles (Effective 01/01/2019)

81183

ATXN10 (ataxin 10) (e.g., spinocerebellar ataxia) gene analysis, evaluation to detect abnormal (e.g., expanded) alleles (Effective 01/01/2019)

81184

CACNA1A (calcium voltage-gated channel subunit alpha1 A) (e.g., spinocerebellar ataxia) gene analysis; evaluation to detect abnormal (e.g., expanded) alleles (Effective 01/01/2019)

81185

CACNA1A (calcium voltage-gated channel subunit alpha1 A) (e.g., spinocerebellar ataxia) gene analysis; full gene sequence (Effective 01/01/2019)

81186

CACNA1A (calcium voltage-gated channel subunit alpha1 A) (e.g., spinocerebellar ataxia) gene analysis; known familial variant (Effective 01/01/2019)

81187

CNBP (CCHC-type zinc finger nucleic acid binding protein) (e.g., myotonic dystrophy type 2) gene analysis, evaluation to detect abnormal (e.g., expanded) alleles (Effective 01/01/2019)

81200

ASPA (aspartoacylase) (e.g. Canavan disease) gene analysis, common variants (e.g. E285A, Y231X)

81204

AR (androgen receptor) (e.g., spinal and bulbar muscular atrophy, Kennedy disease, X chromosome inactivation) gene analysis; characterization of alleles (e.g., expanded size or methylation status) (Effective 01/01/2019)

81205

BCKDHB (branched-chain keto acid dehydrogenase E1, beta polypeptide) (e.g. Maple syrup urine disease) gene analysis, common variants (e.g. R183P, G278S, E422X)

81209

BLM (Bloom syndrome, RecQ. helicase-like) (e.g. Bloom syndrome) gene analysis, 2281del6ins7 variant

81220

CFTR (cystic fibrosis transmembrane conductance regulator) (e.g. cystic fibrosis) gene analysis; common variants (e.g. ACMG/ACOG guidelines)

81221

CFTR (cystic fibrosis transmembrane conductance regulator) (e.g. cystic fibrosis) gene analysis; known familial variants

81222

CFTR (cystic fibrosis transmembrane conductance regulator) (e.g. cystic fibrosis) gene analysis; duplication/deletion variants

81223

CFTR (cystic fibrosis transmembrane conductance regulator) (e.g. cystic fibrosis) gene analysis; full gene sequence

81224

CFTR (cystic fibrosis transmembrane conductance regulator) (e.g. cystic fibrosis) gene analysis; intron 8 poly-T analysis (e.g. male infertility)

81234

DMPK (DM1 protein kinase) (e.g., myotonic dystrophy type 1) gene analysis; evaluation to detect abnormal (expanded) alleles (Effective 01/01/2019)

81239

DMPK (DM1 protein kinase) (e.g., myotonic dystrophy type 1) gene analysis; characterization of alleles (e.g., expanded size) (Effective 01/01/2019)

81240

F2 (prothrombin, coagulation factor II) (e.g. hereditary hypercoagulability) gene analysis, 20210G>A variant

81241

F5 (coagulation factor V) (e.g. hereditary hypercoagulability) gene analysis, Leiden variant

81250

G6PC (glucose-6-phosphatase, catalytic subunit) (e.g., glycogen storage disease, Type 1a, von Gierke disease) gene analysis, common variants (e.g., R83C, Q347X)

81251

GBA (glucosidase, beta, acid) (e.g., Gaucher disease) gene analysis, common variants (e.g., N370S, 84GG, l444P, IVS2+1G>A)

81255

HEXA (hexosaminidase A [alpha polypeptide]) (e.g., Tay-Sachs disease) gene analysis, common variants (e.g., 1278insTATC, 1421+1G>C, G269S)

81257

HBA1/HBA2 (alpha globin 1 and alpha globin 2) (e.g., alpha thalassemia, Hb Bart hydrops fetalis syndrome, HbH disease), gene analysis, for common deletions or variant (e.g., Southeast Asian, Thai, Filipino, Mediterranean, alpha3.7, alpha4.2, alpha20.5, and Constant Spring)

81258

HBA1/HBA2 (alpha globin 1 and alpha globin 2) (e.g., alpha thalassemia, Hb Bart hydrops fetalis syndrome, HbH disease), gene analysis; known familial variant (Effective 01/01/2018)

81259

HBA1/HBA2 (alpha globin 1 and alpha globin 2) (e.g., alpha thalassemia, Hb Bart hydrops fetalis syndrome, HbH disease), gene analysis; full gene sequence (Effective 01/01/2018)

81260

IKBKAP (inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase complex-associated protein) (e.g., familial dysautonomia) gene analysis, common variants (e.g., 2507+6T>C, R696P)

81269

HBA1/HBA2 (alpha globin 1 and alpha globin 2) (e.g., alpha thalassemia, Hb Bart hydrops fetalis syndrome, HbH disease), gene analysis; duplication deletion variants (Effective 01/01/2018)

81271

HTT (huntingtin) (e.g., Huntington disease) gene analysis; evaluation to detect abnormal (e.g., expanded) alleles (Effective 01/01/2019)

81274

HTT (huntingtin) (e.g., Huntington disease) gene analysis; characterization of alleles (e.g., expanded size) (Effective 01/01/2019)

81284

FXN (frataxin) (e.g., Friedreich ataxia) gene analysis; evaluation to detect abnormal (expanded) alleles (Effective 01/01/2019)

81285

FXN (frataxin) (e.g., Friedreich ataxia) gene analysis; characterization of alleles (e.g., expanded size) (Effective 01/01/2019)

81286

FXN (frataxin) (e.g., Friedreich ataxia) gene analysis; full gene sequence (Effective 01/01/2019)

81289

FXN (frataxin) (e.g., Friedreich ataxia) gene analysis; known familial variant(s) (Effective 01/01/2019)

81290

MCOLN1 (mucolipid 1) (e.g., Mucolipidosis, Type IV) gene analysis, common variants (e.g., IVS3-2A>G, del6.4kb)

81291

MTHFR (5,10-methylenetetrahydrofolate reductase) (e.g., hereditary hypercoagulability) gene analysis, common variants (e.g., 677T, 1298C)

81312

PABPN1 (poly[A] binding protein nuclear 1) (e.g., oculopharyngeal muscular dystrophy) gene analysis, evaluation to detect abnormal (e.g., expanded) alleles (Effective 01/01/2019)

81329

SMN1 (survival of motor neuron 1, telomeric) (e.g., spinal muscular atrophy) gene analysis; dosage/deletion analysis (e.g., carrier testing), includes SMN2 (survival of motor neuron 2, centromeric) analysis, if performed (Effective 01/01/2019)

81330

SMPD1 (sphingomyelin phosphodiesterase 1, acid lysosomal) (e.g., Niemann-Pick disease, type A) gene analysis, common variants (e.g., R496L, L302P, fsP330)

81331

SNRPN/UBE3A (small nuclear ribonucleoprotein polypeptide N and ubiquitin protein ligase E3A) (e.g., Prader-Willi syndrome and/or Angelman syndrome), methylation analysis

81333

TGFBI (transforming growth factor beta-induced) (e.g., corneal dystrophy) gene analysis, common variants (e.g., R124H, R124C, R124L, R555W, R555Q) (Effective 01/01/2019)

81336

SMN1 (survival of motor neuron 1, telomeric) (e.g., spinal muscular atrophy) gene analysis; full gene sequence (Effective 01/01/2019)

81337

SMN1 (survival of motor neuron 1, telomeric) (e.g., spinal muscular atrophy) gene analysis; known familial sequence variant(s) (Effective 01/01/2019)

81343

PPP2R2B (protein phosphatase 2 regulatory subunit Bbeta) (e.g., spinocerebellar ataxia) gene analysis, evaluation to detect abnormal (e.g., expanded) alleles (Effective 01/01/2019)

81344

TBP (TATA box binding protein) (e.g., spinocerebellar ataxia) gene analysis, evaluation to detect abnormal (e.g., expanded) alleles (Effective 01/01/2019)

81361

HBB (hemoglobin, subunit beta) (e.g., sickle cell anemia, beta thalassemia, hemoglobinopathy); common variant(s) (e.g., HbS, HbC, HbE)

81362

HBB (hemoglobin, subunit beta) (e.g., sickle cell anemia, beta thalassemia, hemoglobinopathy); known familial variant(s)

81363

HBB (hemoglobin, subunit beta) (e.g., sickle cell anemia, beta thalassemia, hemoglobinopathy); duplication/deletion variant(s)

81364

HBB (hemoglobin, subunit beta) (e.g., sickle cell anemia, beta thalassemia, hemoglobinopathy); full gene sequence

81403

Includes: PLN (phospholamban) (e.g., dilated cardiomyopathy, hypertrophic cardiomyopathy), full gene sequence

81405

Includes:

  • ACTC1 (actin, alpha, cardiac muscle 1) (e.g., familial hypertrophic cardiomyopathy), full gene sequence
  • MYL3 (myosin, light chain 3, alkali, ventricular, skeletal, slow) (e.g., familial hypertrophic cardiomyopathy), full gene sequence
  • MYL3 (myosin, light chain 3, alkali, ventricular, skeletal, slow) (e.g., familial hypertrophic cardiomyopathy), full gene sequence
  • TNNC1 (troponin C type 1 [slow]) (e.g., hypertrophic cardiomyopathy or dilated cardiomyopathy), full gene sequence
  • TNNI3 (troponin 1, type 3 [cardiac]) (e.g., familial hypertrophic cardiomyopathy), full gene sequence
  • TPM1 (tropomyosin 1 [alpha]) (e.g., familial hypertrophic cardiomyopathy), full gene sequence

81406

Includes: TNNT2 (troponin T, type 2 [cardiac]) (e.g., familial hypertrophic cardiomyopathy), full gene sequence

81407

Includes:

  • MYBPC3 (myosin binding protein C, cardiac) (e.g., familial hypertrophic cardiomyopathy), full gene sequence
  • MYH7 (myosin, heavy chain 7, cardiac muscle, beta) (e.g., familial hypertrophic cardiomyopathy, Liang distal myopathy), full gene sequence

81412

Ashkenazi Jewish associated disorders (e.g. Bloom syndrome, Canavan disease, cystic fibrosis, familial dysautonomia, Fanconi anemia group C, Gaucher disease, Tay-Sachs disease) genomic sequence analysis panel, must include sequencing of at least 9 genes, including ASPA, BLM, CFTR, FANCC, GBA, HEXA, IKBKAP, MCOLN1, and SMPD1

81437

hereditary neuroendocrine tumor disorders (e.g., medullary thyroid carcinoma, parathyroid carcinoma, malignant pheochromocytoma or paraganglioma); genomic sequence analysis panel, must include sequencing of at least 6 genes, including MAX, SDHB, SDHC, SDHD, TMEM127, and VHL

81438

duplication/deletion analysis panel, must include analyses for SDHB, SDHC, SDHD, and VHL

81439

Hereditary cardiomyopathy (e.g., hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy), genomic sequence analysis panel, must include sequencing of at least 5 cardiomyopathy-related genes (e.g., DSG2, MYBPC3, MYH7, PKP2, TTN)

81442

Noonan spectrum disorders (e.g., Noonan syndrome, cardio-facio-cutaneous syndrome, Costello syndrome, LEOPARD syndrome, Noonan-like syndrome), genomic sequence analysis panel, must include sequencing of at least 12 genes, including BRAF, CBL, HRAS, KRAS, MAP2K2, NRAS PTPN11, RAF1, RIT1, SHOC2, and SOS1

81443

Genetic testing for severe inherited conditions (e.g., cystic fibrosis, Ashkenazi Jewish-associated disorders [e.g., Bloom syndrome, Canavan disease, Fanconi anemia type C, mucolipidosis type VI, Gaucher disease, Tay-Sachs disease], beta hemoglobinopathies, phenylketonuria, galactosemia), genomic sequence analysis panel, must include sequencing of at least 15 genes (e.g., ACADM, ARSA, ASPA, ATP7B, BCKDHA, BCKDHB, BLM, CFTR, DHCR7, FANCC, G6PC, GAA, GALT, GBA, GBE1, HBB, HEXA, IKBKAP, MCOLN1, PAH) (Effective 01/01/2019)

81479

Unlisted molecular pathology procedure

81599

Unlisted multianalyte assay with algorithmic analysis

HCPCS:

S3800

Genetic testing for amyotrophic lateral sclerosis (ALS)

S3842

Genetic testing for von Hippel-Lindau disease

S3845

Genetic testing for alpha-thalassemia

S3846

Genetic testing for hemoglobin E beta-thalassemia

S3849

Genetic testing for Niemann-Pick disease

S3850

Genetic testing for sickle cell anemia

S3853

Genetic testing for myotonic muscular dystrophy

S3861

Genetic testing, sodium channel, voltage-gated, type V, alpha subunit (SCN5A) and variants for suspected Brugada syndrome

S3865

Comprehensive gene sequence analysis for hypertrophic cardiomyopathy analysis

S3866

Genetic analysis for a specific gene mutation for hypertrophic cardiomyopathy (HCM) in an individual with a known HCM mutation in the family

PREVIOUS CODING:

81280

Long QT Syndrome gene analyses (e.g., KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, KCNJ2, CACNA1C, CAV3, SCN4B, AKAP, SNTA1, and ANK2); full sequence analysis (deleted 1/1/2017)

81281

Long QT Syndrome gene analyses (e.g., KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, KCNJ2, CACNA1C, CAV3, SCN4B, AKAP, SNTA1, and ANK2); known familial sequence variant (deleted 1/1/2017)

81282

Long QT Syndrome gene analyses (e.g., KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, KCNJ2, CACNA1C, CAV3, SCN4B, AKAP, SNTA1, and ANK2); duplication/deletion variants (deleted 1/1/2017)

81404

Molecular pathology procedure, Level 5 (e.g., analysis of 2-5 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 6-10 exons, or characterization of a dynamic mutation disorder/triplet repeat by Southern blot analysis) includes – HBA1/HBA2 (alpha globin 1 and alpha globin 2) (e.g. alpha thalassemia), duplication/deletion analysis. – HBB (hemoglobin, beta, Beta-Globin) (e.g. thalassemia), full gene sequence

REFERENCES:

  1. 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). Heart Rhythm. Aug 2011;8(8):1308-1339.
  2. Adams PC. The modern diagnosis and management of haemochromatosis. Alliment Pharmacol Ther. 2006; 23(12):1681-9
  3. Agerholm-Larsen B, et al. ACE gene polymorphism in cardiovascular disease: Meta analyses of small and large studies in whites. Arteriosclerosis, Thrombosis and Vascular Biology, February 2000; 20(2): 484-49
  4. Albanese A, Barnes MP, et al. A systematic review on the diagnosis and treatment of primary (idiopathic) dystonia and dystonia plus syndromes: Report of an EFNS/MDS-ES Task Force. European Journal of Neurology 2006; 13: 433-444.
  5. Al Khatib SM. What clinicians should know about the QT interval? JAMA, April 2003; 289(16): 2120-2127.
  6. Alia P, et al. Association between ACE gene I/D polymorphism and clinical presentation and prognosis of sarcoidosis. Scandinavian Journal Clinical Laboratory Investigations 2005; 65(8): 691-697.
  7. American Academy of Pediatrics. Identifying infants and young children with developmental disorders in the medical home: An algorithm for developmental surveillance and screening. Pediatrics, July 2006, Vol. 118, No. 1.
  8. American Academy of Pediatrics. Committee on Children with Disabilities. The Pediatrician’s role in the diagnosis and management of autistic spectrum disorder in children. Pediatrics, May 2001, Vol. 107, No. 5.
  9. American College of Obstetricians and Gynecologists. ACOG Committee Opinion No. 430: preimplantation genetic screening for aneuploidy. Obstet Gynecol 2009; 113(3):766-7.
  10. The American College of Obstetricians and Gynecologists. ACOG News Release: Ob-Gyns offering large-scale cystic fibrosis screening, December 12, 2001, www.acog.org/from_home/publications/press_releases/nr12-12-01-2.cfm.
  11. Arnett DK, et al. Pharmacogenetic association of the angiotensin-converting enzyme insertion/deletion polymorphism on blood pressure and cardiovascular risk in relation to antihypertensive treatment: the Genetics of hypertension-associated treatment (Gen HAT) study. Circulation, June 2005; 111(25): 3374-3383.
  12. Athena Diagnostics, Inc. CADASIL. NeuroCAST Sessions. Worcester, MA; Athena; 2002. Available at www.neurocast.com/site/content/sessions_12_200.asp. Accessed June 2010.
  13. Authors/Task Force m, Elliott PM, Anastasakis A, et al. 2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: The Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC). Eur Heart J. Oct 14 2014;35(39):2733-2779.
  14. Behr E, et al. Cardiological assessment of first-degree relatives in sudden arrhythmic death syndrome. Lancet, November 2003; 362(9394): 1457-1459.
  15. Biller H, et al. Genotype-corrected reference values for serum angiotensin-converting enzyme. European Respiratory Journal, December 2006; 28(6): 1085-1090.
  16. Biros E, Cooper M, Palmer LJ et al. Association of an allele on chromosome 9 and abdominal aortic aneurysm. Atherosclerosis 2010; 212(2):539-42.
  17. Blue Cross Blue Shield Association. Special Report: Cardiovascular pharmacogenomics. Technology Evaluation Center (TEC) Assessment Program, November 2007, Vol. 22, No. 7.
  18. Cao, Antonio, Rosatelli, Maria Cristina, Monni, Giovanni, and Galanello, Renzo. Screening for thalassemia: A model of success, Obstetrics and Gynecology Clinics, June 2002, Vol. 29, No. 2.
  19. Centers for Disease Control and Prevention (CDC). CDC releases recommendations for state newborn screening programs for cystic fibrosis. American Family Physician, April 2005, Vol. 71, Issue 8.
  20. Chiang CE. Congenital and acquired long QT syndrome. Current concepts and management. Cardiology Review, July 2004; 12(4): 222-234.
  21. Ching LK and Tan EC. Congenital long QT syndromes: Clinical features, molecular genetics, and genetic testing. Expert Review Mol Diagnosis, May 2006; 6(3): 365-374.
  22. Choi G, et al. Spectrum and frequency of cardiac channel defects in swimming-triggered arrhythmia syndromes. Circulation, October 2004; 110(15): 2119-2124.
  23. Choi HJ, et al. Variable phenotype of Pierson Syndrome. Pediatric Nephrology, June 2008; 23(6): 995-1000.
  24. Cohen, JG, Dryja, TP, Davis, KB, Diller, LR, and Li, FP. RB1 genetic testing as a clinical service: A follow-up study, Medical and Pediatric Oncology, October 2001; 37(4): 372-378.
  25. Cohen CS and Allingham RR. The dawn of genetic testing for glaucoma, Current Opinion in Ophthalmology, April 2004; 15(2): 75-9.
  26. Collins KK and Van Hare GF. Advances in congenital long QT syndrome. Current Opinions in Pediatrics, October 2006; 18(5); 497-502.
  27. Concolino P, Mello E, et al. Molecular diagnosis of congenital adrenal hyperplasia due to 21-hydroxylase deficiency: an update of new CYP21A2 mutations. Clin Chem Lab Med, 2010 Aug;48(8):1057-62
  28. Dandapani SV, et al. The glomerular filter: Biologic and genetic complexity. Kidney International 2006; 70: 980-982.
  29. Dandona S, et al. Gene Dosage of the Common Variant Predicts Severity of Coronary Artery Disease. J AM Coll Cardiol 2010; 56: 479-486.
  30. Daubert JP, et al. Role of implantable cardioverter defibrillator therapy in patients with long QT syndrome. American Heart Journal, April 2007, Vol. 153, Issue 4, Suppl 1.
  31. de Kok JB, Verhaegh GW, et al. DD3(PCA3), a very sensitive and specific marker to detect prostate tumors. Cancer Res, May 29002; 62(9): 2695-8. (Abstract)
  32. Destace A, Brique S and Sablonniare B. [Genetic dystonia]. Presse Med 1999; 28(6): 298-305.
  33. doeGenomes.org, Human Genome Project Information. Gene testing, www.ornl.gov/TechResources/Human_Genome/medicine/genetest.html.
  34. Dorostkar PC, et al. Long term follow-up in patients with long QT syndrome treated with beta-blockers and continuous pacing. Circulation, December 1999; 100(24): 2431-2436.
  35. Earthtimes.org. New genomic test for coronary artery disease now available at The Heart & Vascular Center of Arizona. www.earthtimes.org/articles/printpressstory.php?news=1050021. November 2009.
  36. Eggenberger E Golnik K, Lee A, et al. Prognosis of ischemic internuclear ophthalmoplegia, Ophthalmology, September 2002, Vol. 109, No. 9.
  37. Excellus Blue Cross Blue Shield, Medical Policy. Genetic testing for specific diseases, February 2003.
  38. Eye Cancer Network: Conditions. Retinoblastoma Genetics, www.eyecancer.com/conditions/retinal%20tumors/retinog.html.
  39. Fan XH, et al. Polymorphisms of angiotensin-converting enzyme (ACE) and ACE2 are not associated with orthostatic blood pressure dysregulation in hypertensive patients. Acta Pharmacologica Sinica, August 2009.
  40. The Federal Trade Commission. At-home genetic tests: A healthy dose of skepticism may be the prescription. www.ftc.gov/bcp/edu/pubs/consumer/health/hea02.htm.
  41. Filipek PA, Accardo PJ, Ashwal, et al. Practice parameter: Screening and diagnosis of autism. Report of the Quality Standards Subcommittee of the American Academy of Neurology and the Child Neurology Society. Neurology 2000; 55(4): 468-479.
  42. Fontenot A, et al. Pathogenesis of sarcoidosis. UpToDate.com, May 2009, www.uptodate.com.
  43. Fuessel S, Sickert D, Meye A, Klenk U, et al. Multiple tumor marker analyses (PSA, hK2, PSCA, trp-p8) in primary prostate cancers using quantitative RT-PCR. Int J Oncol, July 2003; 23(1): 221-228. (Abstract)
  44. Gene Tests, www.genetests.org.
  45. Gene Reviews. Thanatophoric Dysplasia. www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=td.
  46. Genes and Disease from the National Center for Biotechnology Information. Von Hippel-Lindau syndrome.
  47. Genes and Disease from the National Center for Biotechnology Information. Niemann-Pick disease.
  48. Genes and Disease from the National Center for Biotechnology Information. Anemia, sickle cell, www.ncbi.nlm.nih.gov/books.
  49. Genetics Home Reference. Canavan disease, www.ghr.nlm.nih.gov/condition=canavandisease.
  50. Genetics Home Reference. Genetic Testing, www.ghr.nlm.nih.gov/ghr/info/genetic_testing.
  51. Genetics Home Reference. Thanatophoric dysplasia. ghr.nlm.nih.gov/condition=thanatophoricdysplasia.
  52. Genetic Science Learning Center at the Eccles Institute of Human Genetics, University of Utah. Genetic Testing of Newborn Infants: Sickle cell disorder, gslc.genetics.utah.edu/units/newborn/infosheets/sicklecelldisorder.cfm.
  53. Goldenberg I, et al. QT interval: How to measure it and what is “normal”. Journal of Cardiovascular Electrophysiology 2006; 17(3): 333-336.
  54. Goldman: Cecil Textbook of Medicine, 22nd edition. Long QT Syndrome.
  55. Grosse SD, Boyle CA, Botkin JR, Comeau AM, Kharrazi M, Rosenfeld M, et al. Newborn screening for cystic fibrosis: Evaluation of benefits and risks and recommendations for state newborn screening programs. MMWR Recomm Rep, October 2004; 53(RR-13): 1-36.
  56. Grundfast, Kenneth M., Siparsky, Nicole, and Chuong, Diana. Syndromic and other congenital anomalies of the head and neck, Orlaryngologic Clinics of North America, December 2000, Vol. 33, No. 6.
  57. Herman GE, Henninger N, Ratliff-Schaub K, Patore M, et al. Genetic testing in autism: How much is enough? Genet Med, May 2007; 9(5): 268-274.
  58. Hessels D, Klein Gunnewiek JM, et al. DD3 (PCA3)-based molecular urine analysis for the diagnosis of prostate cancer. Eur Urol, July 2003; 44(1): 8-15; discussion 15-6.
  59. Hirsh J, Guyatt G, Albers GW, et al. Antithrombotic and thrombolytic therapy. Chest 2008; 133: 110S-112S.
  60. Hofman N, et al. Diagnostic criteria for congenital long QT syndrome in the era of molecular genetics: Do we need a scoring system? European Heart Journal, March 2007; 28(5): 575-580.
  61. Hoffman: Hematology: Basic Principles and Practice, 4th edition. Iron Overload.
  62. Ingles, JJ, Goldstein, JJ, Thaxton, CC, Caleshu, CC, Corty, EE, Crowley, SS, Dougherty, KK, Harrison, SS, McGlaughon, JJ, Milko, LL, Morales, AA, Seifert, BB, Strande, NN, Thomson, KK, van Tintelen, JJ, Wallace, KK, Walsh, RR, Wells, QQ, Whiffin, NN, Witkowski, LL, Semsarian, CC, Ware, JJ, Hershberger, RR, Funke, BB. Evaluating the Clinical Validity of Hypertrophic Cardiomyopathy Genes. Circ Genom Precis Med, 2019 Jan 27.
  63. Kagan M, et al. A milder variant of Pierson syndrome. Pediatric Nephrology, February 2008; 23(2): 323-327.
  64. Khan IA. Long QT syndrome: Diagnosis and management. American Heart Journal, January 2002, Vol. 143, Issue 1.
  65. King TE, et al. Clinical manifestations and diagnosis of sarcoidosis. UpToDate.com, May 2009, www.uptodate.com.
  66. Kujovich, Jody L. and Goodnight, Scott H. Factor V Leiden thrombophilia, Gene Reviews, www.geneclinics.org/profiles/factor-v-leiden/details.html.
  67. Landers KA, et al. Use of multiple biomarkers for a molecular diagnosis of prostate cancer. Int J Cancer 2005; 114(6): 950-956. (Abstract)
  68. Lederle FA, Johnson GR, Wilson SE et al. The aneurysm detection and management study screening program: validation cohort and final results. Aneurysm Detection and Management Veterans Affairs Cooperative Study Investigators. Arch Intern Med 2000; 160(10):1425-30.
  69. Libby: Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine, 8th edition.
  70. Lintas C and Persico AM. Autistic phenotypes and genetic testing: State-of-the-art for the clinical geneticist. J Med Genet, published online August 26, 2008; doi:10.1136/jmg.2008.060871.
  71. Locati EH, et al. Age- and sex- related differences in clinical manifestations in patients with congenital long-QT syndrome: Findings from the International LQTS Registry. Circulation, June 1998; 97(22): 2237-2244.
  72. Lonstein JE, Carlson JM. The prediction of curve progression in untreated idiopathic scoliosis during growth. J Bone Joint Surg Am 1984; 66(7):1061-71.
  73. Mackey David A and Craig Jamie E. Predictive DNA testing for glaucoma: Reality in 2003, Ophthalmology Clinics of North America, December 2003, Vol. 16, No. 4.
  74. Maitland-van der Zee AH, et al. Absence of an interaction between the angiotensin-converting enzyme insertion-deletion polymorphism and pravastatin on cardiovascular disease in high-risk hypertensive patients: the Genetics of hypertension-associated treatment (GenHAT) study. American Heart Journal, January 2007; 153(1): 54-58.
  75. Maitland-van der Zee AH, et al. Pharmacogenetics of response to statins: Where do we stand? Current Atherosclerosis Rep, May 2005; 7(3): 204-208.
  76. Maliarik MJ, et al. Angiotensin-converting enzyme gene polymorphism and risk of sarcoidosis. American Journal Respiratory Critical Care Medicine 1998; 158: 1566-1570.
  77. Maron BJ, et al. Recommendations and considerations related to preparticipation screening for cardiovascular abnormalities in competitive athletes: 2007 update: A scientific statement from the American Heart Association Council on Nutrition, Physical Activity, and Metabolism: Endorsed by the American College of Cardiology Foundation. Circulation, March 2007; 115(112).
  78. Maron, BB, Udelson, JJ, Bonow, RR, Nishimura, RR, Ackerman, MM, Estes, NN, Cooper, LL, Link, MM, Maron, MM. Eligibility and Disqualification Recommendations for Competitive Athletes With Cardiovascular Abnormalities: Task Force 3: Hypertrophic Cardiomyopathy, Arrhythmogenic Right Ventricular Cardiomyopathy and Other Cardiomyopathies, and Myocarditis: A Scientific Statement From the American Heart Association and American College of Cardiology. J. Am. Coll. Cardiol., 2015 Nov 7;66(21).
  79. Maron, BB, Zipes, DD, Kovacs, RR. Eligibility and Disqualification Recommendations for Competitive Athletes With Cardiovascular Abnormalities: Preamble, Principles, and General Considerations: A Scientific Statement From the American Heart Association and American College of Cardiology. Circulation, 2015 Dec 2;132(22).
  80. Marre M, et al. Relationships between angiotensin I converting enzyme polymorphism, plasma levels, and diabetic retinal and renal complications. Diabetes, diabetes.diabetesjournals.org.
  81. Matejas V, et al. A syndrome comprising childhood-onset glomerular kidney disease and ocular abnormalities with progressive loss of vision is caused by mutated LAMB2. Nephrology Dialysis Transplant 2006; 21: 3283-3286.
  82. McGrath DS, et al. Ace gene I/D polymorphism and sarcoidosis pulmonary disease severity. American Journal Respiratory Critical Care Medicine, July 2001; 164(2): 197-201.
  83. Medica I, et al. Role of genetic polymorphisms in ACE and TNF alpha gene in sarcoidosis: A meta-analysis. Journal of Human Genetics 2007; 52(10): 836-847.
  84. Medical News Today. CardioDx completes validation study of first-of-its-kind genomic test for coronary artery disease. www.medicalnewstoday.com/printerfriendlynews.php?newsid=161839. August 26, 2009.
  85. Migdalovich D, Moss AJ, Lopes CM et al. Mutation and gender specific risk in type-2 long QT syndrome: Implications for risk stratification for life-threatening cardiac events in patients with long QT syndrome. Heart Rhythm 2011; March 24 [Epub ahead of print].
  86. Miles JH and McCathren RB. Autism overview. GeneReviews, NCBI Bookshelf, December 2005. www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=autism-overview. Accessed December 9, 2008.
  87. Moberg-Wolff Elizabeth, et al. Dystonias. www.emedicine.com/pmr/topic235.htm.
  88. Moller CC, et al. The genetic basis of human glomerular disease. Advanced Chronic Kidney Disease, April 2006; 13(2): 166-173.
  89. Moss AJ, et al. Effectiveness and limitations of beta-blocker therapy in congenital long-QT syndrome. Circulation, February 2000; 101(16): 616-623.
  90. Napolitano C, et al. Genetic testing in the long QT syndrome: Development and validation of an efficient approach to genotyping in clinical practice. JAMA, December 2005; 294(23): 2975-2980.
  91. National Human Genome Research Institute. Learning about Sickle-cell Disease, www.genome.gov/page.cfm?pageID=10001219.
  92. National Human Genome Research Institute. Frequently asked questions about genetics, www.genome.gov/page.cfm?pageID=10001191.
  93. National Human Genome Research Institute. A brief primer on genetic testing, January 2003, www.genome.gov/page.cfm?pageID=10506784.
  94. National Institute of Health. Researching disease: Dr. Roscoe Brady and Gaucher disease, www.history.nih.gov/exhibits/gaucher/full-text.html.
  95. National Institute of Neurological Disorders and Stroke. NINDS Gaucher’s Disease Information Page, www.ninds.nih.gov/health_and_medical/disorders/gauchers_doc.htm.
  96. National Institute of Neurological Disorders and Stroke. NINDS von Hippel-Lindau Disease Information Page, May 2002, www.ninds.nih.gov/health_and_medical/disorders/vonhippe_doc.htm
  97. National Tay-Sachs & Allied Disease Association, Inc. Tay-Sachs Disease (Classical Infantile Form), www.ntsad.org/pages/t-sachs.htm.
  98. Nimkarn S, New MI. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency: A paradigm for prenatal diagnosis and treatment. Ann N Y Acad Sci, 2010 Mar; 1192: 5-11.
  99. Nimkarn S, New MI. Prenatal diagnosis and treatment of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Mol Cell Endocrinol 2009 Mar 5; 300(1-2):192-6.
  100. Ogilvie J. Adolescent idiopathic scoliosis and genetic testing. Curr Opin Pediatr 2010; 22(1):67-70.
  101. Oruc N, et al. Angiotensin-converting enzyme gene DD genotype neither increases susceptibility to acute pancreatitis nor influences disease severity. HBP (Oxford) 2009; 11(1): 45-49.
  102. Ott P. Electrocardiographic markers of sudden death. Cardiology Clinics, August 2006, Vol. 24, Issue 3.
  103. Ou, Judy I., Wheeler, Sharon M., and O’Brien, Joan M. Posterior pole tumor update, Ophthalmology Clinics of North America, December 2002, Vol. 15, No. 4.
  104. Pakakasama, Samart and Tomlinson, Gail E. Genetic predisposition and screening in pediatric cancer, Pediatric Clinics of North America, December 2002, Vol. 49, No. 6.
  105. Park: Pediatric Cardiology for Practitioners, 4th edition. Long QT syndrome.
  106. Peters BJ, et al. Genetic determinants of response to statins. Expert Review Cardiovascular Therapeutics, August 2009; 7(8): 977-983.
  107. Peterson LE, Nachemson AL. Prediction of progression of the curve in girls who have adolescent idiopathic scoliosis of moderate severity. Logistic regression analysis based on data from The Brace Study of the Scoliosis Research Society. J Bone Joint Surg Am 1995; 77(6):823-7.
  108. PGxHealth, New Haven, CT. www.pgxhealth.com/genetictests/familion/physicians/howitworks.cfm.
  109. Phillips KA, et al. Cost-effectiveness analysis of genetic testing for familial long QT syndrome in symptomatic index cases. Heart Rhythm, December 2005, Vol. 2, No. 12, pp. 1294-1300.
  110. Pierson Syndrome. Online Mendelian Inheritance in Man. www.ncbi.nlm.nih.gov/entrez/dispomim.cg1?id=609049.
  111. Pietinalko A, et al. The angiotensin-converting enzyme DD gene is associated with poor prognosis in Finnish sarcoidosis patients. European Respiratory Journal 1999; 13: 723-726.
  112. Priori SG, et al. Association of long QT syndrome loci and cardiac events among patients treated with beta-blockers. JAMA, September 2004; 292(11): 1341-1344.
  113. Priori SG, et al. Risk stratification in the long QT syndrome. NEJM, May 2003; 348(19): 1866-1874.
  114. Rallidis LS, et al. Lack of association of angiotensin-converting enzyme insertion/deletion polymorphism and myocardial infarction at very young ages. Biomarkers, September 2009; 14(6): 401-405.
  115. Schalken JA, Hessels D, Verhaegh G. New targets for therapy in prostate cancer: Differential display code 3 (DD3(PCA3)), a highly prostate cancer-specific gene. Urology, November 2003; 62 (5 Suppl 1): 34-43. (Abstract)
  116. Scharplatz M, et al. Does the angiotensin-converting enzyme (ACE) gene insertion/deletion polymorphism modify the response to ACE inhibitor therapy? A systematic review. Current Control Trials Cardiovascular Medicine, October 2005; 6: 16.
  117. Schena FP, et al. ACE gene polymorphism and IgA nephropathy: An ethnically homogeneous study and a meta-analysis. Kidney International 2001; 60: 732-740.
  118. Schenk-Braat EA and Bangma CH. [The search for better markers for prostate cancer than prostate-specific antigen]. Ned Tijdschr Geneeskd, June 2006; 150(23): 1286-1290. (Abstract)
  119. Schmidt U, Fuessel S, Koch R, et al. Quantitative multi-gene expression profiling of primary prostate cancer. The Prostate, vol. 66, Issue 14, pp. 1521-1534.
  120. Schrier SL, Bacon BR. Pathophysiology and diagnosis of iron overload syndromes. patients.uptodate.com. Accessed April 2008.
  121. Schürmann M, et al. Angiotensin-converting enzyme ACE gene polymorphisms and familial occurrence of sarcoidosis. Journal of Internal Medicine 2001; 249(1): 77-83.
  122. Schürmann M, et al. Genetics of sarcoidosis. Clinics in Chest Medicine, September 2008, Vol. 29, Issue 3.
  123. Schwartz PJ, et al. Genotype-phenotype correlation in the long-QT syndrome: Gene-specific triggers for life-threatening arrhythmias. Circulation, January 2001; 103(1): 89-95.
  124. Schwartz PJ, et al. The Jewell- and Lange-Nielsen syndrome: Natural history, molecular basis, and clinical outcome. Circulation, February 2006; 113(6): 783-790.
  125. Sharma S, Gao X, Londono D et al. Genome-wide association studies of adolescent idiopathic scoliosis suggests candidate susceptibility genes. Hum Mol Genet 2011; 20(7):1456-66.
  126. Shimizu W, et al. Mutation site-specific differences in arrhythmic risk and sensitivity to sympathetic stimulation in the LQT1 form of congenital long QT syndrome: Multicenter study in Japan. JACC, July 2004; 44(1): 117-125.
  127. Somerville J. Modern diagnosis and evaluation of long QT syndrome. Cardiosource, American College of Cardiology 2006.
  128. Studdy PR, et al. Serum angiotensin converting enzyme in sarcoidosis-its value in present clinical practice. Annals of Clinical Biochemistry 1989; 26(Pt 1): 13-18.
  129. Su, Q. and Zhang, C. Progress in researches on the molecular genetics of facioscapulohumeral muscular dystrophy. Zhonghua Yi Xue Yi Chuan Xue Za Zhi, October 2001; 18(5): 398-401.
  130. Tan HL, et al. Genotype-specific onset of arrhythmias in congenital long-QT syndrome: Possible therapy implications. Circulation, November 2006; 114(20): 2096-2103.
  131. Tan KJ, Moe MM, Vaithinathan R et al. Curve progression in idiopathic scoliosis: follow-up study to skeletal maturity. Spine (Phila Pa 1976) 2009; 34(7):697-700.
  132. Tascilar N, et al. Angiotensin-converting enzyme insertion/deletion polymorphism has no effect on the risk of atherosclerotic stroke or hypertension. Journal Neurology Science, July 2009.
  133. Tester DJ, et al. Effect of clinical phenotype on yield of long QT syndrome genetic testing. Journal of American College of Cardiology, February 2006; 47(4): 764-768.
  134. Tinzl M, Marberger M, Horvath S and Chypre C. DD3PCA3 RNA analysis in urine—a new perspective for detecting prostate cancer. Eur Urol, August 2004; 46(2): 182-186; discussion 187. (Abstract)
  135. Torres VE and Bennett WM. Diagnosis of and screening for autosomal dominant polycystic kidney disease. UpToDate.com. Accessed October 14, 2008.
  136. Tsikouris JP, et al. Pharmacogenomics of renin angiotensin system inhibitors in coronary artery disease. Cardiovascular Drugs Therapy 2007; 21(2): 121-132.
  137. Upadhyaya, M. and Cooper, D.N. Molecular diagnosis of facioscapulohumeral muscular dystrophy. Expert Rev Mol Diagn, March 2002; 2(2): 160-71.
  138. Van DeVoorde R, et al. Pierson Syndrome: A novel cause of congenital nephrotic syndrome. Pediatrics 2006; 118: e501-e505.
  139. van de Garde EMW, et al. Angiotensin-converting enzyme insertion/deletion polymorphism and risk and outcome of pneumonia. Chest, January 2008, Vol. 133, Issue 1.
  140. Vegter S, et al. Cost-effectiveness of ACE inhibitor therapy to prevent dialysis in nondiabetic nephropathy: Influence of the ACE insertion/deletion polymorphism. Pharmacogenetic Genomics, August 2009.
  141. Wasserstein Melissa. Oculocerebrorenal dystrophy (Lowe Syndrome), www.emedicine.com/ped/topic1329.htm.
  142. Ward K, Ogilvie JW, Singleton MV et al. Validation of DNA-based prognostic testing to predict spinal curve progression in adolescent idiopathic scoliosis. Spine (Phila Pa 1976) 2010; 35(25):E1455-64.
  143. Weinstein SL, Dolan LA, Cheng JC et al. Adolescent idiopathic scoliosis. Lancet 2008; 371(9623):1527-37.
  144. Wynne-Davies R. Familial (idiopathic) scoliosis. A family survey. J Bone Joint Surg Br 1968; 50(1):24-30.
  145. Zareba W, et al. Implantable cardioverter defibrillator in high-risk long QT syndrome patients. Journal of Cardiovascular Electrophysiology, April 2003; 14(4): 337-341.
  146. Zareba W, et al. Influence of genotype on the clinical course of the long QT syndrome: International Long-QT Syndrome Registry Research Group. NEJM, October 1998; 339(14): 960-965.
  147. Zhang L. Spectrum of ST-T wave patterns and repolarization parameters in congenital long-QT syndrome: ECG findings identify genotypes. Circulation, December 2000; 102(23): 2849-2855.
  148. Zhao X, Paterson AD, Zahirieh A, et al. Molecular diagnostics in autosomal dominant polycystic kidney disease: Utility and limitations. Clin J Am Soc Nephrol 2008; 3: 146.
  149. Zipes: Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine, 7th edition. Long QT syndrome.

POLICY HISTORY:

Medical Policy Group, September 2003 (1)

Medical Policy Administration Committee, September 2003

Available for comment October 20-December 3, 2003

Medical Policy Group, March 2005 (1)

Medical Policy Group, July 2005 (1)

Medical Policy Administration Committee, July 2005

Available for comment August 6-September 19, 2005

Medical Policy Group, January 2006 (1)

Medical Policy Administration Committee, January 2006

Available for comment January 28-March 13, 2006

Medical Policy Group, April 2006 (1)

Medical Policy Administration Committee, May 2006

Available for comment, May 5-June 19, 2006

Medical Policy Group, August 2006 (1)

Medical Policy Administration Committee, August 2006

Available for comment August 17-October 2, 2006

Medical Policy Group, December 2006 (3)

Medical Policy Administration Committee, January 2007

Available for comment January 6-February 19, 2007

Medical Policy Group, May 2007 (1)

Medical Policy Administration Committee, May 2007

Available for comment May 8-June 21, 2007

Medical Policy Group, July 2007 (1)

Medical Review Committee, July 2007

Medical Review Committee, August 2007

Medical Policy Administration Committee, August 2007

Available for comment September 5-October 19, 2007

Medical Policy Group, December 2007 (3)

Medical Policy Administration Committee, January 2008

Available for comment January 5-February 20, 2008

Medical Policy Group, April 2008 (2)

Medical Policy Administration Committee, May 2008

Available for comment, May 3-June 16, 2008

Medical Policy Group, August 2008 (1)

Medical Policy Administration Committee, August 2008

Available for comment August 13-September 26, 2008

Medical Policy Group, October 2008 (3)

Medical Policy Administration Committee November 2008

Available for comment November 8-December 22, 2008

Medical Policy Group, January 2009 (1)

Medical Policy Administration Committee, February 2009

Available for comment January 17-March 2, 2009

Medical Policy Group, February 2009 (1)

Medical Policy Administration Committee, March 2009

Available for comment March 4-April 17, 2009

Medical Policy Group, May 2009 (3)

Medical Policy Administration Committee, May 2009

Available for comment May 11-June 24, 2009

Medical Policy Group, September 2009 (3)

Medical Policy Administration Committee, October 2009

Available for comment October 2-November 16, 2009

Medical Policy Group, January 2010 (1)

Medical Policy Administration Committee, January 2010

Available for comment January 26-March 11, 2010

Medical Policy Group, June 2010 (2)

Medical Policy Administration Committee, June 2010

Available for comment June 18-August 2, 2010 Added coverage for CADASIL and Key Points for CADASIL and H pylori

Medical Policy Group, July 2010 (1)

Medical Policy Administration Committee, August 2010

Available for comment August 6-September 18, 2010

Medical Policy Group, December 2010 (1): update to warfarin testing Key Points

Medical Policy Group, February 2011: Comment added to Policy section

Medical Policy Administration Committee, February 2011

Available for comment February 24 through April 11, 2011

Medical Policy Group, April 2011 (1): update to Policy, Key Points, Key Words and References for PRSS1 and entire policy reformatted

Medical Policy Administration Committee, April 2011

Available for comment April 13 – May 30, 2011

Medical Policy Group, April 2011 (1): Update to Policy, Key Points, Key Words and References for Congenital Adrenal Hyperplasia

Medical Policy Administration Committee, June 2011

Available for comment June 8 – July 25, 2011

Medical Policy Group, July 2011 (1): Clarification of policy statement related to Preimplantation genetic testing, remains investigational; Update to Key points and References related to preimplantation genetic testing and Long QT syndrome

Medical Policy Administration Committee, August 2011

Medical Policy Group, September 2011 (1): Update to Key Points and References related to CADASIL

Medical Policy Group, December 2011: (1): Added 2012 Code updates

Medical Policy Group, February 2012: (3): 2012 Code Updates: Deleted ‘S’ codes effective 4/1/12

Medical Policy Group, December 2012 (3): 2013 Coding Updates: Added codes 81161, 81252, 81253, 81254, 81324, 81325, 81326, 81404, 81479 and 81599; Deleted Codes 83890-83914; and Moved codes 84999, 88299, and 99199 to Previous Codes effective 01/01/2013.

Medical Policy Group, February 2013 (1): Added MTHFR mutation to coverage criteria effective 01/01/2013

Medical Policy Group, January 2014 (1): Removed all aspects of 9p21 genotyping related to cardiovascular disease or aneurysm and created new policy #542; Removed all aspects of HLA-DQ testing related to celiac disease and created new policy #545; no other changes noted to policy

Medical Policy Group, February 2014 (1): Removed all aspects of genetic testing for hereditary hemochromatosis and created new policy #546; no other changes noted to policy

Medical Policy Group, April 2014 (1): Removed all aspects of genetic testing to predict coronary artery disease (Corus CAD) and created new policy #549; removed all aspects of genetic testing for adolescent idiopathic scoliosis (AIS) and created new policy #547; no other changes to policy

Medical Policy Group, November 2014: 2015 Annual Coding update. Added codes 81430 and 81431 to current coding; updated code 81404. Moved deleted HCPCS code S3855 to previous coding.

Medical Policy Group, January 2015: Updated description for CPT code 81404

Medical Policy Group, November 2015: 2016 Annual Coding Update. Added CPT code 81412, 81437, 81438, 81442 to current coding.

Medical Policy Group, February 2016 (3): Removed all aspects of genetic testing of CADASIL syndrome now in a separate policy #589

Medical Policy Group, February 2016 (3): Removed all aspects of genetic testing for Hereditary Pancreatitis now in a separate policy #590

Medical Policy Group, February 2016 (3): Removed all aspects of genetic testing for Lactase Insufficiency now in a separate policy #588

Medical Policy Group, February 2016 (3): Removed all aspects of Preimplantation genetic testing now in a separate policy #593

Medical Policy Group, February 2016 (3): Removed all aspects of genetic testing for Warfarin dosing now in a separate policy #525

Medical Policy Group, February 2016 (3): Removed all aspects of genetic testing for Neurofibromatosis now in a separate policy #620

Medical Policy Group, June 2017 (3): Removed all aspects of genetic testing for Hereditary Hearing Loss now in a separate policy #643

Medical Policy Group, June 2017 (3): Removed all aspects of genetic testing for Facioscapulohumeral Muscular Dystrophy now in a separate policy #642

Medical Policy Group, June 2017 (3): Removed all aspects of genetic testing for Duchenne Muscular Dystrophy now in a separate policy #640; removed all deleted codes effective 1/1/13 and prior

Medical Policy Administration Committee, July 2017

Medical Policy Group, August 2017 (3): Removed previous coding section and code S3855 – this code is represented appropriately in medical policy #011 Genetic Testing for Alzheimer Disease

Medical Policy Group, December 2017: Annual Coding Update 2018. Added new CPT codes 81258, 81259, 81269, and 81361-81364 effective 1/1/18 to the Current Coding Section. Created Previous Coding section and moved 81404 to this section.

Medical Policy Group, January 2018 (3): Removed current coding 81242 for Fanconi anemia and placed in separate policy #649

Medical Policy Group, January 2018 (3): Removed all aspects of genetic testing for FMR1 variants (i.e., Fragile X syndrome) and placed in separate policy #606; removed current coding 81243 & 81244 for FMR1 testing and added to #606

Medical Policy Group, January 2018 (3): Removed all aspects of genetic testing for Rett syndrome and placed in separate policy #700; removed current coding 81302, 81303, 81304 and added to #700

Medical Policy Group, January 2018 (3): Removed genetic testing information current coding 81324, 81325, 81326 for PMP22 testing related to inherited peripheral neuropathies; this testing is addressed specifically in policy #595

Medical Policy Group, January 2018 (3): Clarified policy statement sections adding cross-references to #649, #606, #700, #595; added clarification statement for genetic testing using expanded panels (non-targeted) of any type (i.e., molecular, next-generation sequencing, etc.) to establish a diagnosis of an inheritable disease as being considered investigational and not medically necessary; added cross-reference to #539

Medical Policy Group, December 2018: 2019 Annual coding Update. Added CPT codes 81171, 81172, 81173, 81174, 81177, 81178, 81179, 81180, 81181, 81182, 81183, 81184, 81185, 81186, 81187, 81204, 81234, 81239, 81271, 81274, 81284, 81285, 81286, 81289, 81312, 81329, 81333, 81336, 81337, 81343, 81344, 81443 to the Current coding section.

Medical Policy Group, April 2019 (9): 2019 Updates to Key Points and References related to Inherited Hypertrophic Cardiomyopathy. Moved codes 81280, 81281, 81282 to previous coding section. Added codes 81403, 81405, 81406, 81407, 81439 to current coding section. Added key words: HCM, Hypertrophic Cardiomyopathy, Familial HCM, Familial Hypertrophic Cardiomyopathy. No change to policy statement.

Medical Policy Group, July 2019 (9): 2019 Updates to Key Points related to Genetic Testing for Alpha-Thalassemia. No change to policy statement.


This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.