Predictive genetic testing (also known as susceptibility testing) is generally carried out in healthy or asymptomatic individuals, but is usually targeted at those who are considered to be at high risk for developing a disease due to a strong family medical history of the disorder, or other factors.  Predictive test results are not indicative of the inevitable occurrence of a disease or a guarantee that a disease will not develop.  Instead, predictive testing simply provides an estimated risk of the individual developing the disease in the future. 

Note:  This document is limited to predictive genetic testing for non-malignant diseases other than those addressed in other documents. Please refer to the documents indicated below for information regarding genetic susceptibility testing on the following conditions:

• GENE.00001 Genetic Testing for Cancer Susceptibility
• GENE.00002 Preimplantation Genetic Diagnosis Testing
• GENE.00007 Cardiac Ion Channel Genetic Testing
• GENE.00012 Preconceptional or Prenatal Genetic Testing of a Parent or Prospective Parent
• GENE.00013 Diagnostic Genetic Testing of a Potentially Affected Individual (Adult or Child)
• GENE.00016 Gene Expression Profiling as a Technique for Managing Colon Cancer
• GENE.00017 Genetic Testing for Diagnosis and Management of Hereditary Cardiomyopathies (including ARVD/C)

Medically Necessary:

In asymptomatic individuals who have no known risk for a specific late onset or slowly evolving genetic disorder*, predictive genetic testing for non-malignant diseases is considered medically necessary when the following criteria are met:

• The genetic disorder is associated with a potentially significant disability or has a lethal natural history; AND
• The risk of the significant disability or lethality from the genetic disorder cannot be identified through biochemical or other testing (e.g. serum cholesterol testing for familial hypercholesterolemia or ultrasound screening for aortic disease in Marfan's), AND
• A specific mutation, or set of mutations, has been established in the scientific literature to be reliably associated with the disease; AND
• The results of the genetic test could impact the medical management of the individual; AND
• The genetic test will likely result in an anticipated improvement in net health outcomes; AND
• Testing is accompanied by genetic counseling.

*If an asymptomatic individual has known risk for a specific late onset or slowly evolving genetic disorder, such as by family history, please see Gene.00013 Diagnostic Genetic Testing of a Potentially Affected Individual (Adult or Child).

Investigational and Not Medically Necessary:

Predictive genetic testing for non-malignant diseases is considered investigational and not medically necessary for all indications when the criteria listed above are not met, including but not limited to the PreDx Diabetes Risk Test™ , deCODE T2™, deCODE AF™, deCODE MI™, and the deCODE Glaucoma™ tests, as well as whole-genome sequencing in which an individual's entire DNA is sequenced.

Clinical Utility of Predictive Genetic Testing
Predictive genetic testing (also known as susceptibility testing) is generally carried out in healthy or asymptomatic individuals.  Predictive test results are not indicative of the inevitable occurrence of a disease or a guarantee that a disease will not develop.  Instead, predictive testing simply provides an estimated risk of the individual developing the disease in the future. 

One of the limitations of predictive genetic testing is the challenge in interpreting positive test results.  Some individuals who test positive for a disease-associated mutation may never develop the disease.  In order to be useful in the clinical setting, the results of predictive genetic testing should have a high positive predictive value and evidence should demonstrate that such results improve either disease prevention or management as compared with care without genetic testing.

There has been a growing interest in the use of predictive genetic testing for diabetes mellitus.  In a prospective cohort study, Talmud and colleagues (2010) assessed the performance of a panel of common SNPs (genotypes) associated with susceptibility to type 2 diabetes as well as two established phenotype-based risk models (the Cambridge type 2 diabetes risk score and the Framingham offspring study type 2 diabetes risk score) in estimating the absolute risk of type 2 diabetes.  Enrollment consisted of 5,535 initially healthy individuals (33% women, mean age 49 years) of whom 302 developed new onset type 2 diabetes over 10 years. The researchers concluded that the addition of genetic information to the phenotype-based risk models does not substantially improve the accuracy of risk estimation for the future development of type 2 diabetes.  

The incremental clinical utility of predictive genetic testing for diabetes mellitus, as compared with standard care, has not yet been demonstrated.  Even if genetic testing results indicate the individual to be at increased risk for the development of diabetes mellitus, it has not yet been confirmed that changing clinical management would improve outcomes, as compared with, say, assessing the family history of diabetes mellitus and encouraging the individual to maintain a healthy weight, maintain an exercise routine and make healthy dietary choices.  It also remains to be proven how many of the individuals who are believed to be at increased risk for the development of diabetes mellitus based on predictive genetic testing actually go on to develop the disease.

There has also been a growing interest in the use of predictive genetic testing for classifying the risk of cardiovascular disease.  Paynter and colleagues (2009) used a genetic variation at chromosome 9p21.3 to evaluate cardiovascular risk prediction in 22,129 white, female health professionals who were observed for a median of 10 years.  Consideration was also given to conventional risk factors-such as family history of early cardiovascular disease, cholesterol, smoking, blood pressure and C-reactive protein levels-with risk prediction using conventional risk factors alone.  The researchers concluded that adding genetic information to conventional risk factors did not improve the accuracy of classifying cardiovascular risk.

Palomaki and colleagues (2010) investigated the association between chromosome 9p21 single-nucleotide polymorphisms (SNPs) and heart disease.  The objective of the study was to perform a targeted systematic review of published literature for effect size, heterogeneity, publication bias, and strength of evidence and to consider whether testing for 9p21 SNPs would provide clinical utility.  Of the 22 articles analyzed, researchers were able to identify 47 distinct data sets on chromosome 9p21 SNPs and heart disease.  These included a total of 95,837 controls and 35,872 cases.  Individuals with two 9p21 at-risk alleles had a 25% increased risk of heart disease compared with individuals with only one at-risk allele.  The researchers concluded that there is a statistically significant association between 9p21 SNPs and heart disease which varies by age at disease onset, but the magnitude of the association was small.

The rapid increase in availability of commercial genetic testing for assessing disease risk has also led to tests for risk of glaucoma, atrial fibrillation, myocardial infarction, and other conditions in currently asymptomatic but perhaps higher risk individuals.  As yet, no clinical studies have definitively confirmed the incremental clinical utility of such testing, thus it is unknown whether making clinical management changes based on such testing alters outcome as compared with standard care of such individuals before as well as once such disease is diagnosed.

Classifications of Predictive Genetic Testing
Predictive genetic testing can be divided into two categories, presymptomatic and predispositional.  Presymptomatic tests are carried out to detect highly "penetrant" conditions.  In these instances, mutations strongly suggest the eventual development of the disease or symptoms, e.g., Huntington disease.  Predispositional tests are carried out for incompletely penetrant conditions.  Mutations suggest the probable (but not certain) development of disease or symptoms, e.g., Alzheimer's disease.

Genetic Testing versus Genetic Screening
According to the Task Force for Genetic Testing (Holtzman 1999), some predictive genetic testing falls under genetic screening which is defined as a search in a population for persons possessing certain genotypes that are associated with a disease or predisposed to a disease, may lead to the development of a disease in their descendants, or produce other variations not known to be associated with disease.  Genetic screening differs from genetic testing in that it targets general populations rather than individuals.  This document does not address genetic population screening.  

Whole Genome Sequencing
Whole genome sequencing, also known as full genome sequencing (FGS), complete genome sequencing, or entire genome sequencing is a laboratory procedure which seeks to determine an individual's entire DNA sequence, specifying the order of every base pair within the genome at a singe time.  In humans, this process involves obtaining a DNA sample from the individual (typically from saliva, bone marrow, epithelial cells, or hair) and sequencing an individual's entire chromosomal and mitochondrial DNA.  Because of the large volume of genomic data involved in this process, the genomic information is processed by and stored on microprocessors and computers.  Researchers continue to explore the relationship between mutations in the genomic material of asymptomatic individuals and the development of specific diseases.  The role of whole-genome sequencing in the clinical setting has yet to be established.  Research is still being done to determine if whole-genome sequencing can be used to not only accurately predict the development of a particular disease in asymptomatic individuals, but be used to either minimize the impact of or wholly avoid the development of the disease.

According to the Task Force on Genetic Testing (Holtzman 1999), the term "genetic testing" encompasses a host of techniques used to analyze the human DNA, RNA or protein to detect gene variations associated with specific diseases or conditions for clinical purposes.  Such purposes may include predicting the individual's risk of developing a disease, identifying carriers of a disease, establishing prenatal and clinical diagnosis or prognosis.

There has been growing interest in the use of predictive genetic testing to predict the development of conditions such as diabetes mellitus. Diabetes mellitus is a chronic, metabolic disorder of blood glucose metabolism.  Genes associated with the development of diabetes include but are not limited to TCF7L2, PPARG, FTO, KCNJ11, NOTCH2, WFS1, CDKAL1, IGF2BP2, SLC30A8, JAZF1, and HHEX genes.  Diabetes mellitus, if not adequately controlled, may lead to many complications including hypoglycemia, ketoacidosis, renal failure, blindness, heart disease, stroke, or amputation.  Management and treatment of diabetes mellitus typically includes assessing the individual for a family history of diabetes mellitus and obesity, encouraging the individual to maintain a healthy weight (exercise and dietary support), monitoring and controlling blood glucose levels, and if needed, diabetic medications (oral and insulin).  The clinical value of a genetic test to determine the risk of developing diabetes mellitus is of limited value at this time.  .

As mentioned above, whole genome sequencing is a laboratory procedure which seeks to determine an individual's entire DNA sequence, specifying the order of every base pair within the genome at a singe time.  Researchers are continuing to investigate the relationship between mutations in the genomic material of asymptomatic individuals and the development of specific diseases.  It has yet to be determined how the information obtained from whole-genome sequencing can influence the development of disease in asymptomatic individuals or impact the management of individuals in the clinical setting.

Chronic:  Recurring, long-lasting, without a cure.

Clinical utility: Measures the ability of the test to improve clinical outcomes.

DNA: (deoxyribonucleic acid): A type of molecule that contains the code for genetic information.

Genetic counseling: A process involving the guidance of a specially trained professional in the evaluation of family history, medical records, and genetic test results, in assessing the risk of genetic diseases, understanding the ramifications of diagnosis, and explanation of available treatment options available.

Genetic testing: A type of test that is used to determine the presence or absence of a specific gene or genetic alteration that may indicate an increased risk for developing a specific disease or disorder. Such testing is usually applied at a number of predetermined locations in genes where variation among individuals and groups is known to occur.

Genotype:The genetic structure (constitution) of an organism or cell. 

Mutation:  Permanent, structural change in the DNA.

Penetrant: The likelihood that a person carrying a particular variation of a gene will also have an associated trait.

Positive predictive value: Percentage of individuals with positive test results who are accurately diagnosed.

Whole genome sequencing: Unlike genetic testing, whole genome sequencing seeks to determine an individual's entire DNA sequence, specifying the order of every base pair within the genome.

The following codes for treatments and procedures applicable to this document are included below for informational purposes.  Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy.  Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services may be Medically Necessary when criteria are met:

When services are Investigational and Not Medically Necessary:
When the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

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Corus™ CAD
deCODE AF™
deCODE Glaucoma™
deCODE MI™
deCODE PrCa Test™
deCODE T2™
Gen-Probe PCA3 test
Illumina®
PreDx Diabetes Risk Test™
Whole genome sequencing

The use of specific product names is illustrative only.  It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.