CPT 0012U, 81415, 81416, 81417, 81425, 81426 - Whole Exome and Whole Genome Sequencing

Code Description CPT

0012U Germline disorders, gene rearrangement detection by whole genome next-generation sequencing, DNA, whole blood, report of specific gene rearrangement(s)

81415 Exome (eg, unexplained constitutional or heritable disorder or syndrome); sequence analysis 

81416 Exome (eg, unexplained constitutional or heritable disorder or syndrome); sequence analysis, each comparator exome (eg, parents, siblings) (List separately in addition to code for primary procedure)

81417 Exome (eg, unexplained constitutional or heritable disorder or syndrome); reevaluation of previously obtained exome sequence (eg, updated knowledge or unrelated condition/syndrome) 

81425 Genome (eg, unexplained constitutional or heritable disorder or syndrome); sequence analysis 

81426 Genome (eg, unexplained constitutional or heritable disorder or syndrome); sequence analysis, each comparator genome (eg, parents, siblings) (List separately in addition to code for primary procedure)

81427 Genome (eg, unexplained constitutional or heritable disorder or syndrome); reevaluation of previously obtained genome sequence (eg, updated knowledge or unrelated condition/syndrome)
 
81479 Unlisted molecular pathology code



Whole Exome and Whole Genome Sequencing for Diagnosis of Genetic Disorders


Introduction

Our DNA contains all of our genetic material, and makes us who we are. Our DNA contains about 20,000 genes which are packaged into 46 chromosomes (23 pairs). Genes are very important because they tell our cells how to make proteins. Although there are tens of thousands of genes, they make up only about 1% of our entire DNA. A large part of our DNA doesn’t code for any proteins. The protein-coding genes are also called “exomes”.

The entire collection of DNA is called the “whole genome”. If a person was only talking about the genes themselves that are contained within the whole genome, they are called the “whole exome”.

“Whole genome sequencing” is a test that looks at the entire genome, including parts of the DNA that don’t contain any genes. “Whole exome sequencing” is a test that only looks at the exomes, which is that part of the DNA that contains genes that code for proteins. As an analogyan entire football game would be your whole genome. Only the game highlights (1% of the game) would be the exomes. Whole genome sequencing would be like watching the entire football game from start to finish, while whole exome sequencing would be like watching only the game highlights the next day.
Whole genome and whole exome sequencing tests have been used to help diagnose genetic disorders in people. Whole genome sequencing is always considered to be investigational. Not enough good quality medical studies have been done to show that whole genome sequencing is reliable and helpful in diagnosing genetic conditions. However, whole exome sequencing may be medically necessary in some situations. This policy describes when whole exome sequencing may be medically necessary. 

Note:   The Introduction section is for your general knowledge and is not to be taken as policy coverage criteria. The rest of the policy uses specific words and concepts familiar to medical professionals. It is intended for providers. A provider can be a person, such as a doctor, nurse, psychologist, or dentist. A provider also can be a place where medical care is given, like a hospital, clinic, or lab. This policy informs them about when a service may be covered. 
Policy Coverage Criteria 

The policy statement is intended to address the use of whole exome and whole genome sequencing for the diagnosis of genetic disorders in patients with suspected genetic disorders and for population-based screening.

This policy does not address the use of whole exome and whole genome sequencing for preimplantation genetic diagnosis or screening, prenatal (fetal) testing, or testing of cancer cells.

Service Medical Necessity

Whole exome sequencing Whole exome sequencing may be considered medically necessary for the evaluation of unexplained congenital or neurodevelopmental disorders in children under the age of 18 when ALL of the following criteria are met: ? The patient has been evaluated by a clinician with expertise in
clinical genetics and counseled about the potential risks of genetic testing.
AND ? There is potential for a change in management and clinical

outcome for the individual being tested. AND ? A genetic etiology is felt to be the most likely explanation for
the patient’s signs and symptoms despite previous genetic testing (eg, chromosomal microarray analysis and/or targeted single-gene testing), OR when previous genetic testing has

Service Medical Necessity failed to yield a diagnosis, and the affected individual is faced with invasive procedures or testing as the next diagnostic step (eg, muscle biopsy).

Whole exome sequencing is considered investigational for the diagnosis of genetic disorders in all other situations.  Service Investigational
Whole genome sequencing Whole genome sequencing is considered investigational for the diagnosis of genetic disorders.
Whole exome sequencing Whole genome sequencing

Coding 

Whole exome sequencing and whole genome sequencing are considered investigational for screening of asymptomatic individuals for genetic disorders.

Whole Exome Sequencing (WES)

Whole Exome Sequencing (WES) is proven and medically necessary for diagnosing or evaluating a genetic disorder when the results are expected to directly influence medical management and clinical outcomes AND ALL of the following criteria are met:

** Clinical presentation is nonspecific and does not fit a well-defined syndrome for which a specific or targeted gene test is available. If a specific genetic syndrome is suspected, a single gene or targeted gene panel should be performed prior to determining if WES is necessary; and

 ** WES is ordered by a board-certified medical geneticist, neonatologist, neurologist, or developmental and behavioral pediatrician; and

** One of the following:

* The clinical presentation or clinical and family history strongly suggest a genetic cause for which a specific clinical diagnosis cannot be made with any clinically available targeted genetic tests; or

* There is a clinical diagnosis of a genetic condition where there is significant genetic heterogeneity and WES is a more practical approach to identifying the underlying genetic cause than are individual tests of multiple genes; or

* There is likely a genetic disorder and multiple targeted gene tests that have failed to identify the underlying cause.


Comparator (e.g., parents or siblings) WES is proven and medically necessary for evaluating a genetic disorder when the above criteria have been met and WES is performed concurrently or has been previously performed on the individual.

WES is unproven and not medically necessary for all other indications, including but not limited to the following:
** Screening and evaluating disorders in individuals when the above criteria are not met
 ** Prenatal genetic diagnosis or screening
** Evaluation of fetal demise
** Preimplantation Genetic Testing (PGT) in embryos
** Molecular profiling of tumors for the diagnosis, prognosis or management of cancer

Further studies are needed to evaluate the clinical utility of whole exome sequencing for other indications.



Whole Genome Sequencing (WGS)

Whole Genome Sequencing (WGS) is unproven and not medically necessary for screening and evaluating any genetic disorder. Although WGS has the potential to identify causal variants for a wide variety of conditions that may be missed with other technologies, as well as to identify predictive biomarkers, the information derived from WGS has not yet been translated into improved outcomes and changed medical management. Further studies are needed to establish the clinical utility of WGS.



DEFINITIONS

Comparator: A DNA sequence that is used to compare to the individual’s DNA sequence. This may be a parent or sibling of the individual, or non-cancerous tissue that is being compared to the individual’s tumor tissue (Thun et al., 2017).


Next Generation Sequencing (NGS): New sequencing techniques that can quickly analyze multiple sections of DNA at the same time. Older forms of sequencing could only analyze one section of DNA at once. Preimplantation Genetic Testing (PGT): A test performed to analyze the DNA from oocytes or embryos for human leukocyte antigen (HLA)-typing or for determining genetic abnormalities. These include:

* PGT-A: For aneuploidy screening (formerly PGS)
** PGT-M: For monogenic/single gene defects (formerly single-gene PGD)
**  PGT-SR: For chromosomal structural rearrangements (formerly chromosomal PGD)(Zegers-Hochschild et al., 2017)


Variant of Unknown Significance (VUS): A variation in a genetic sequence that has an unknown association with disease. It may also be called an unclassified variant. Whole Exome Sequencing (WES): About 1% of a person’s DNA makes protein. These protein making sections are called exons. All the exons together are called the exome. WES is a DNA analysis technique that looks at all of the exons in a person at one time, rather than gene by gene (U.S. National Library of Medicine, What are whole exome sequencing and whole genome sequencing? 2018).

Whole Genome Sequencing (WGS): WGS determines the sequence of all of the DNA in a person, which includes the protein making (coding) as well as non-coding DNA elements (U.S. National Library of Medicine, What are whole exome sequencing and whole genome sequencing? 2018).



Appropriate Use Criteria

Whole Exome Sequencing
Whole exome sequencing (WES) (81415 and 81416) is medically necessary for a phenotypicallyaffected individual when all of the following criteria are met: • Individual has been evaluated by a board-certified medical geneticist or other boardcertified specialist physician with specific expertise in the conditions being tested for and relevant genes



• WES results will directly impact clinical decision-making and/or clinical outcome

• A genetic etiology is the most likely explanation for the phenotype as demonstrated by the following:

• Multiple abnormalities affecting unrelated organ systems
or two of the following four criteria:

• Abnormality affecting a single organ system

• Significant intellectual disability or severe psychological/psychiatric disturbance (e.g. self-injurious behavior, reversed sleep-wake cycles)

• Family history strongly implicating a genetic etiology

• Period of unexplained developmental regression (unrelated to autism or epilepsy)

• No other causative circumstances (e.g. environmental exposures, injury, infection) can explain symptoms

• Clinical presentation does not fit a well-described syndrome for which single-gene or targeted panel testing is available

• The differential diagnosis list and/or phenotype warrant testing of multiple genes, and at least one of the following:

* WES is more practical than the separate single gene tests or panels that would be recommended based on the differential diagnosis
* WES results may preclude the need for multiple and/or invasive procedures, follow-up, or screening that would be recommended in the absence of testing