Medical Policy

 

Subject: Genetic Testing of an Individual’s Genome for Inherited Diseases
Document #: GENE.00043 Publish Date:    04/24/2019
Status: Revised Last Review Date:    03/21/2019

Description/Scope

This document addresses the framework for consideration of genetic testing for any disease with an established genetic basis.

Notes:

Please refer to the documents indicated below for information regarding genetic testing for the following conditions (this is not an all-inclusive list of related genetic testing documents):

Genetic testing involves the analysis of an individual’s deoxyribonucleic acid (DNA), ribonucleic acid (RNA), chromosomes, genes, or gene products (such as enzymes and other proteins) to identify inherited or somatic (noninherited) genetic variations associated with health or disease.  The use of genetic testing information is being explored as a means to:

Genetic testing may be conducted by several methods.  Molecular genetic tests analyze single genes or short lengths of DNA to identify variations or mutations that lead to a genetic disorder. Chromosomal genetic tests examine whole chromosomes or long lengths of DNA to identify large genetic changes, such as an extra copy of a chromosome, that cause a genetic condition (karyotype).  Biochemical genetic tests or GEP measure the activity level or amount of specific proteins, metabolites or enzymes which may be indicative of changes to the DNA that result in a genetic disorder.

Genetic tests can be considered in four general categories: predictive, diagnostic, prognostic and therapeutic. Refer to the following chart and the Background/Overview section. 

 

Asymptomatic

Symptomatic

Predictive

Screening for risk
Presymptomatic: disease certain to develop

N/A

Predispositional: disease may develop
For example: BRCA for breast or ovarian cancer

N/A

Diagnostic

For example: cystic fibrosis, fragile X

Confirm suspected diagnosis
For example: achondroplasia

Prognostic

Understand likelihood of disease or condition occurrence or course (penetrance and heterogeneity)
For example: BRCA, cystic fibrosis

Understand course of disease or condition
For example: familial adenomatous polyposis (FAP)

Therapeutic, including but not limited to pharmacotherapeutic

Guide preventive treatment
For example: BRCA or FAP

Impact treatment planning
For example: cytochrome p450, BRCA or FAP

In addition to the general four classifications addressed above for testing the individual’s genome, genetic tests can also be done for two other genomic categories:

Pregnancy-related genetic testing (preconception, prenatal, pre-implantation, in vitro fertilization) is carried out prior to or during pregnancy for various indications, including but not limited to guiding reproductive decisions and as part of assistive reproductive procedures.  This includes carrier testing which is used to identify individuals who possess one copy of a gene mutation that, when present in two copies, result in a specific genetic disorder.  Having only one copy of the gene mutation does not place the individual being tested at increased risk of developing the disease, but will increase the risk of the individual having an affected child who will develop the disease and may necessitate pregnancy related genetic testing.  Genetic testing for pregnancy-related conditions is more specifically addressed in other documents, including but not limited to:

Somatic cell genetic testing involves the testing of tissue (most often cancerous tissue) for mutations that are not inherited.  This testing is generally done for diagnostic purposes or to assist in the selection of a cancer treatment.  Genetic testing for somatic cell mutations is addressed more specifically in other documents.

Position Statement

Medically Necessary:

Genetic testing of the individual’s genome for inherited diseases is considered medically necessary when all the following criteria (#I and #II) are met:

  1. The individual for whom the test is requested:
    1. Is asymptomatic but is judged to be at significant risk, as determined by the likelihood of future disease and burden of suffering, for a genetic disease (for example, based on family history); or
    2. Is currently symptomatic with suspicion of a known genetic disease; and
  2. All of the following criteria apply:
    1. A specific mutation, or set of mutations, has been established in the scientific literature to be reliably associated with the disease; and
    2. A biochemical or other test is identified but the results are indeterminate, or the genetic disorder cannot be identified through biochemical or other testing; and
    3. The genetic disorder is associated with a potentially significant disability or has a lethal natural history; and
    4. Results of the genetic test, whether affirmative or negative, will impact the clinical management (predictive, diagnostic, prognostic or therapeutic) of the individual.  For example, genetic test results will guide treatment decisions, surveillance recommendations or preventive strategies; and
    5. The findings of the genetic test will likely result in an anticipated improvement in net health outcomes; that is, the expected health benefits of the interventions outweigh any harmful effects (medical or psychological) of the intervention; and
    6. Genetic counseling, which encompasses all of the following components, has been performed:
      1. Interpretation of family and medical histories to assess the probability of disease occurrence or recurrence; and
      2. Education about inheritance, genetic testing, disease management, prevention and resources; and
      3. Counseling to promote informed choices and adaptation to the risk or presence of a genetic condition; and
      4. Counseling for the psychological aspects of genetic testing.

Investigational and Not Medically Necessary:

Genetic testing of the individual’s genome for inherited diseases in individuals not meeting the above criteria is considered investigational and not medically necessary, including, but not limited to, genetic testing for melanoma (hereditary), amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease) and ataxia telangiectasia.

Genetic testing of the individual’s genome for inherited diseases using panels of genes (with or without next generation sequencing), including but not limited to whole genome and whole exome sequencing, is considered investigational and not medically necessary unless all components of the panel have been determined to be medically necessary based on the criteria above.  However, individual components of a panel may be considered medically necessary when criteria above are met.

Rationale

Because of the rapidly evolving field of genetic testing, each genetic test must be carefully evaluated to determine whether or not the identified genetic mutation reliably identifies a genetic disorder, and that the results of the genetic test, whether affirmative or negative, will impact the predictive, diagnostic, prognostic or therapeutic management of the individual (for example, guide treatment decisions, surveillance recommendations or preventive strategies).  The results of genetic testing are also expected to improve net health outcomes, (that is, the anticipated health benefits of the interventions outweigh any harmful effects (medical or psychological) of the intervention).  Genetic testing may be employed to investigate malignant and non-malignant diseases.

Predictive Genetic Testing
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.

Adult-Onset Diabetes Mellitus
There has been a growing interest in the use of predictive genetic testing for adult-onset diabetes mellitus.  In a prospective cohort study, Talmud and colleagues (2010) assessed the performance of a panel of common single nucleotide polymorphisms (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 5535 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 adult-onset 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 based on the findings of the genetic test would improve outcomes, as compared with 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.

Cardiovascular 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.

Other Conditions
Researchers are exploring the use of commercial genetic testing for assessing disease risk for various 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. 

Diagnostic Genetic Testing
Diagnosis of a genetic disorder in asymptomatic individuals is closely related to predictive testing; in symptomatic individuals, diagnosis may typically be made using biochemical testing.  However, in some situations, genetic testing may be the method used to identify, confirm or rule out a condition in conjunction with clinical signs and symptoms. 

Testing for conditions listed in the table below without a check in the column for “May be Useful for Guiding Clinical Management” has not been shown to be useful in guiding clinical management.  In many cases this is because knowledge of the genetic status does not change management of the condition.  The following table lists commonly requested gene testing targets along with an assessment of whether or not they have been shown to be useful in guiding clinical management.

Gene

Condition

May be Useful for Guiding Clinical Management

Additional Information

ACADM

Medium-chain acyl-coenzyme A dehydrogenase (MCAD)

 

AFG3L2

Spinocerebellar ataxia Type 28 (SCA28)

 

 

AGL

Glycogen Storage Disease Type III

 

 

ANG

Amyotrophic lateral sclerosis

 

 

APTX

Ataxia with oculomotor apraxia Type 1

 

 

AR

Spinal and bulbar muscular atrophy (also known as Kennedy disease, X chromosome inactivation, X-linked spinal and bulbar muscular atrophy)

 

 

ARSA

Arylsulfatase A Deficiency

 

ASPA

Canavan disease

 

 

ATM

Ataxia telangiectasia

 

 

ATN1 (DRPLA)

Dentatorubral-Pallidoluysian atrophy (also known as hereditary sensory and autonomic neuropathy type 1 with dementia and hearing loss, hereditary sensory neuropathy type IE, Haw River Syndrome, and Naito-Oyanagi disease)

 

 

ATP7B

Wilson disease (hepatolenticular degeneration)

 

ATXN1

Spinocerebellar ataxia type 1 (SCA1)

 

 

ATXN10

Spinocerebellar ataxia type 10 (SCA10)

 

 

ATXN2

Spinocerebellar ataxia type 2 (SCA2)

 

 

ATXN3

Spinocerebellar ataxia type 3 (SCA3)

 

 

ATXN7

Spinocerebellar ataxia type 7 (SCA7)

 

 

ATXN8

(ATXN8OS)

Spinocerebellar ataxia type 8 (SCA8)  

 

 

BCKDHA

Maple Syrup Urine Disease type 1A

 

BCKDHB

Maple Syrup Urine Disease type 1B

 

BLM

Bloom’s syndrome

 

CACNA1A

Spinocerebellar ataxia type 6 (SCA6)

 

 

CDKN2A

Familial malignant melanoma

 

 

CFTR

Cystic fibrosis

 

CNBP

Myotonic dystrophy type 2

 

CSTB

Unverricht-Lundborg disease (ULD, EPM1)

 

 

DLD

Dihydrolipoamide dehydrogenase deficiency (E3-deficient maple syrup urine disease)

 

DBT

Maple Syrup Urine Disease type 2

 

DHCR7

Smith-Lemli-Opitz Syndrome (SLOS)

 

DMPK

Myotonic dystrophy type 1

 

EIF2B5

Childhood ataxia with central nervous system hypomyelination/Vvanishing white matter

 

 

ELP1 (IKBKAP)

Familial Dysautonomia

 

F5

Factor V Leiden thrombophilia

 

FANCC

Fanconi anemia type C

 

FUS

Amyotrophic lateral sclerosis

 

 

FXN

Friedreich ataxia (also known as Friedreich’s ataxia, FRDA)

 

 

G6PC

Glycogen storage disease type I (GSD I, Von Gierke disease)

 

GAA

Glycogen Storage Disease Type II (GSD II, Pompe disease)

 

GALT

Galactosemia

 

GBA

Gaucher disease

 

GBE1

Glycogen Storage Disease type IV

 

GJB2

Nonsyndromic Hearing Loss and Deafness, (DFNB1)

 

 

HBA1

Alpha-thalassemia

 

HBA2

Alpha thallasemia

 

HBB

Beta thalassemia

 

HBB

Sickle cell disease

 

HEXA

Tay-Sachs disease

 

 

HFE

Hemachromatosis

 

HTT

Huntington disease

 

 

ITPR1

Spinocerebellar ataxia type 15 (SCA15)

 

 

KCNC3

Spinocerebellar ataxia type 13

 

 

MECP2

Rett syndrome

 

 

MCOLN1

Mucolipidosis

 

 

OPTN

Amyotrophic lateral sclerosis

 

 

PABPN1

Oculopharyngeal muscular dystrophy (also known as OPMD)

 

 

PAH

Phenylalanine hydroxylase deficiency

 

PPP2R2B

Spinocerebellar ataxia type 12 (SCA12)

 

 

PRKCG

Spinocerebellar ataxia type 14 (SCA14)

 

 

PYGM

Glycogen storage disease type V GSD V)

 

RPE65

Hereditary retinal dystrophy

Also see MED.00120
Voretigene neparvovec-rzyl (Luxturna)

SERPINA1

Alpha-1 antitrypsin deficiency (AATD)

 

SETX

Ataxia with Oculomotor Apraxia Type 2

 

 

SIL1

Marinesco-Sjögren syndrome

 

 

SLC37A4

Glycogen Storage Disease type Ib

 

SMN-1

Spinal muscular atrophy

 

SMPD1

Acid Sphingomyelinase Deficiency (Niemann-Pick disease type B)

 

SNRPN

Prader-Willi syndrome

 

 

SOD1

Amyotrophic lateral sclerosis (ALS, Lou
Gehrig's disease)

 

 

SPTBN2

Spinocerebellar ataxia type 5 (SCA5)

 

 

TARDBP

Amyotrophic lateral sclerosis

 

 

TBP

Spinocerebellar ataxia type 17 (SCA17)

 

 

TGFBI

Corneal dystrophy

 

 

TTPA

Ataxia with vitamin E deficiency

 

UBE3A

Angelman syndrome

 

 

Whole Genome Sequencing
Whole genome sequencing (WGS), 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 single time.  WGS allows researchers to study the 98% of the genome that does not generally contain protein-coding genes.  In the clinical setting, this process frequently involves obtaining a DNA sample from the individual (typically from blood, saliva or bone marrow) 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 and the development or presence of disease.  The clinical role of WGS has yet to be established.  Research is still being done to determine if WGS can be used to accurately identify the presence of a disease, predict the development of a particular disease in asymptomatic individuals as well as how an individual might respond to pharmacological therapy.  It has been theorized that WGS might eventually improve clinical outcomes by preventing the development of disease.

Whole Exome Sequencing
It is estimated that most disease-causing mutations (around 85%) of clinically important sequence variants occur within the regions of the genome that encode proteins.  While similar to WGS, whole-exome sequencing (WES) reads only the parts of the human genome that encode proteins, leaving the other regions of the genome unread (Choi, 2009).  Since most of the errors that occur in DNA sequences that then lead to genetic disorders are located in the exons, sequencing of the exome is being explored as a more efficient method of analyzing an individual's DNA to discover the genetic cause of diseases or disabilities.  It has been theorized that sequencing of the human exome can be used to identify genetic variants in individuals to diagnose diseases without the high cost associated with WGS.

The American College of Medical Genetics and Genomics (ACMG, 2012) published a position statement addressing points to consider in the clinical application of genomic sequencing.  The policy statement:

Was developed primarily as an educational resource for clinical and laboratory geneticists to help them provide quality clinical and laboratory genetic services.  Adherence to these Points to Consider is voluntary and, in determining the relevance of and weight to be given to any specific point, the clinical and laboratory geneticist should apply his or her own professional judgment to the specific circumstances presented by the individual patient or specimen.

The document contains indications for whole genome and WES as both screening and diagnostic tools.  The ACMG states that clinical diagnostic testing using whole genome or WES is indicated for the following phenotypically affected individuals:

  1. The phenotype or family history data strongly implicate a genetic etiology, but the phenotype does not correspond with a specific disorder for which a genetic test targeting a specific gene is available on a clinical basis.
  2. A patient presents with a defined genetic disorder that demonstrates a high degree of genetic heterogeneity, making WES or WGS analysis of multiple genes simultaneously a more practical approach.
  3. A patient presents with a likely genetic disorder but specific genetic tests available for that phenotype have failed to arrive at a diagnosis.
  4. A fetus with a likely genetic disorder in which specific genetic tests , including targeted sequencing tests, available for that phenotype have failed to arrive at a diagnosis.
    1. Prenatal diagnosis by genomic (i.e., next-generation whole exome- or whole genome-) sequencing has significant limitations.  The current technology does not support short turn-around times which are often expected in the prenatal setting.  There are high false positive, false negative, and variants of unknown clinical significance rates.  These can be expected to be significantly higher than seen when array CGH is used in prenatal diagnosis (2012).

The ACMG document does not include references to peer reviewed literature in support of the recommendations made, or describe the process by which the recommendations were developed. 

The American College of Obstetricians and Gynecologists’ Committee on Genetics in collaboration with the Society for Maternal–Fetal Medicine published a Committee Opinion Summary which states “the routine use of whole-genome or whole-exome sequencing for prenatal diagnosis is not recommended outside of the context of clinical trials until sufficient peer-reviewed data and validation studies are published (Committee on Genetics, 2016).

WES and WGS present ethical questions about informing individuals about incidental findings that have clinical significance.  Ongoing discussions continue to explore whether or not, and how to inform individuals about medically relevant mutations in genes unrelated to the diagnostic question (i.e., mutations of unknown significance, non-paternity and sex chromosome abnormalities).  This type of information may not only affect the individual being tested, but may also implicate family members.  Also, in light of the small sample sizes and the limited number of studies exploring treatment outcomes, there may be safety considerations if a treatment decision is based on WES or WGS findings.

In 2016, the ACMG updated its recommendations for analyzing and reporting incidental or secondary findings from genome and exome sequencing in the clinical context.  The Working Group continues to recommended that clinical diagnostic laboratories conducting exome or genome sequencing report known pathogenic or expected pathogenic variants in a total of 59 medically actionable genes, even when unrelated to the primary medical reason for testing.  The conditions included for reporting were those that the Working Group and external reviewers considered most likely to be verifiable by other diagnostic methods and amenable to medical intervention.  A complete list of these specified conditions can be found in the ACMG document.  It should be noted that the ACMG clarified that the term “secondary” findings is preferred to the term “incidental” findings because “ these genes are intentionally being analyzed, as opposed to genetic variants found incidentally or accidentally”.  Conditions that were part of routine newborn screening were not addressed because they have their own assessment criteria and are applied in a specific public health framework.  The Working Group recommendations also do not address preconception sequencing, prenatal sequencing, newborn sequencing, or sequencing of healthy children and adults (Kalia, 2016).

A potential major indication of WES is the establishment of a molecular diagnosis in individuals with a phenotype that is suspicious for a genetic disorder or for individuals with known genetic disorders that have a large degree of genetic heterogeneity involving substantial gene complexity.  Such individuals may be left without a clinical diagnosis of their disorder, despite a lengthy diagnostic work-up involving a variety of traditional molecular and other types of conventional diagnostic tests.  For some of these individuals, WES, after initial conventional testing has failed to make the diagnosis, may return a likely pathogenic variant.

While some of the potential advantages of WES include the fact that it can be carried out more quickly than traditional genetic testing and it may be less expensive than some other tests (for example, WGS), it is not without limitations.  WES typically covers only 85-95% of the exome and has no, or limited coverage of other areas of the genome.  Areas of concern with this technology include: (1) gaps in the identification of exons prior to sequencing; (2) the need to narrow the large initial number of variants to manageable numbers without losing the likely candidate mutation; (3) difficulty identifying the potential causative variant when large numbers of variants of unknown significance are generated for each individual. It is more difficult to detect chromosomal changes, duplications, large deletions, rearrangements, epigenetic changes or nucleotide repeats from WES data compared with other genomic technologies (ACMG, 2012; Teer, 2010[a]; Teer, 2010[b]).

At this time, there are limitations to WES that prohibit its use in routine clinical care.  The limited experience with WES on a population level leads to gaps in understanding and interpreting ancillary information and variants of uncertain significance.  As a result, the risk/benefit ratio of WES testing is poorly defined.  Because the peer-reviewed literature on WES for clinical purposes consists primarily of case reports and small case series, the clinical applications of WES has yet to be established (Bilguvar, 2010; Choi, 2009; Clayton-Smith, 2011, Saitsu, 2011; Vissers, 2011).

Cytogenomic Microarray Analysis
Cytogenomic microarray analysis collectively describes two different laboratory techniques: array comparative genomic hybridization (aCGH) and single nucleotide polymorphism (SNP) arrays.  While both of these techniques detect copy number variants (CNVs), they identify different types of genetic variation.  aCGH allows the detection of gains and losses in DNA copy number across the entire genome without prior knowledge of specific chromosomal abnormalities.  SNP arrays allow genotyping based on allele frequency.  SNP arrays have additional oligonucleotide probes which analyze thousands of SNPs throughout the genome in order to identify deletions and duplications.  The use of cytogenomic microarray analysis is specifically addressed more fully in other documents, including but not limited to GENE.00021 Chromosomal Microarray Analysis (CMA) for Developmental Delay, Autism Spectrum Disorder, Intellectual Disability (Intellectual Developmental Disorder) and Congenital Anomalies.

Background/Overview

The term “genetic testing” encompasses various techniques used to analyze an individual’s DNA, RNA, chromosome, genes or gene products (such as enzymes) to detect gene variations associated with health and or specific diseases.  Genetic tests may be divided into four broad categories: predictive, diagnostic, prognostic and therapeutic. 

Predictive genetic testing (also known as susceptibility testing) is generally carried out in asymptomatic individuals 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 genetic test results replace the individual's prior risks based on family history or population data with risks based on genotype (NIH, 2005).  Predictive genetic testing can be further divided into two categories: presymptomatic and predispositional.  Presymptomatic predictive genetic testing confirms or denies the development of the disease in those at risk as the condition’s gene mutation is highly penetrant and there is little or no variable expression.  Predispositional predictive genetic tests provide information about an individual’s risk of developing a specific disorder in the future.  Predispositional predictive genetic testing is generally carried out for incompletely penetrant conditions and the results are not indicative of the inevitable occurrence of a condition or disease nor are they a guarantee that a disease will not develop in the future. 

Diagnostic genetic testing is used to identify or rule out a genetic or chromosomal disorder in individuals suspected of having a condition or disease.  Depending on the clinical circumstances, diagnostic genetic testing may be performed on symptomatic or asymptomatic individuals.  When performed in asymptomatic individuals, diagnostic genetic testing is generally performed as a screening test.  Genetic screening differs from genetic testing in that it targets general populations rather than individuals.  This document does not address genetic population screening.  When performed in symptomatic individuals, diagnostic genetic testing is generally performed to rule out or confirm the existence of a genetic condition that may be identifiable by biochemical or other diagnostic tests.  This confirmatory evidence should then assist with therapeutic interventions. 

Prognostic genetic testing is used to assess the risk of progression and course in an asymptomatic individual not yet diagnosed with a disease, and as a means to forecast whether an individual diagnosed with a disease will have a serious or benign course (prognostic).

Therapeutic genetic testing (including but not limited to pharmacotherapeutics) involves the identification of a genetic variant that affects the way an individual responds to a therapeutic intervention.  This application is often seen in the area of pharmacogenetic testing where genetic testing results are used to inform treatment decisions with regards to how an individual is expected to respond to drug therapy.  Genetic testing for pharmacotherapeutics is more specifically addressed in other documents.

Whole Genome Sequencing
Whole genome sequencing (WGS), 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 single time.  The role of WGS in the clinical setting has yet to be established. 

Whole Exome Sequencing
While similar to WGS, WES reads only the parts of the human genome that encode proteins.  Since most of the errors that occur in DNA sequences that then lead to genetic disorders are located in the exons, sequencing of the exome is being explored as a more efficient method of analyzing an individual's DNA to discover the genetic cause of diseases or disabilities.  Researchers are exploring various applications of WES including but not limited to determining if sequencing of the human exome can be used to identify genetic variants in individuals in order to diagnose diseases in individuals without the high cost associated with WGS.

Genetic Counseling
According to the National Society of Genetic Counselors (NSGC), genetic counseling is the process of assisting individuals to understand and adapt to the medical, psychological and familial ramifications of a genetic disease.  This process typically includes the guidance of a specially trained professional who:

  1. Integrates the interpretation of family and medical histories to assess the probability of disease occurrence or recurrence; and
  2. Provides education about inheritance, genetic testing, disease management, prevention and resources; and
  3. Provides counseling to promote informed choices and adaptation to the risk or presence of a genetic condition; and
  4. Provides counseling for the psychological aspects of genetic testing (NSGC, 2006).
Definitions

Amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease): A progressive neurodegenerative disorder that affects nerve cells in the spinal cord and brain which eventually results in paralysis and death. 

Ataxia telangiectasia: A rare, progressive, neurodegenerative childhood disease that affects the brain and other body systems.

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.

Exome: All the exons in a genome.

Exon: The portion of the genome that predominantly encodes protein.

Genome: An organism's entire set of DNA.

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.

Phenotype: The observable physical or biochemical characteristics of an organism, as determined by both genetic makeup and environmental influences.

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

Single-nucleotide polymorphisms (SNPs): DNA sequence variations that occur when a single nucleotide in the genome sequence is altered. 

Coding

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:

CPT

 

81187

CNBP (CCHC-type zinc finger nucleic acid binding protein) (eg, mytonic dystrophy type 2) gene analysis, evaluation to detect abnormal (eg, expanded alleles

81205

BCKDHB (branched-chain keto acid dehydrogenase E1, beta polypeptide) (eg, maple syrup urine disease) gene analysis, common variants (eg, R183P, G278S, E422X)

81209

BLM (Bloom syndrome, RecQ helicase-like) (eg, Bloom syndrome) gene analysis, 2281del6ins7 variant

81221

CFTR (cystic fibrosis transmembrane conductance regulator) (eg, cystic fibrosis) gene analysis; known familial variants

81222

CFTR (cystic fibrosis transmembrane conductance regulator) (eg, cystic fibrosis) gene analysis; duplication/deletion variants

81223

CFTR (cystic fibrosis transmembrane conductance regulator) (eg, cystic fibrosis) gene analysis; full gene sequence

81224

CFTR (cystic fibrosis transmembrane conductance regulator) (eg, cystic fibrosis) gene analysis; intron 8 poly-T analysis (eg, male infertility)

81234

DMPK (DM1 protein kinase) (eg, myotonic dystrophy type 1) gene analysis; evaluation to detect abnormal (expanded) alleles

81239

DMPK (DM1 protein kinase) (eg, myotonic dystrophy type 1) gene analysis; characterization of alleles (eg, expanded size)

81241

F5 (coagulation Factor V) (eg, hereditary hypercoagulability) gene analysis, Leiden variant

81242

FANCC (Fanconi anemia, complementation group C) (eg, Fanconi anemia, type C) gene analysis, common variant (eg, IVS4+4A>T)

81250

G6PC (glucose-6-phosphatase, catalytic subunit) (eg, Glycogen storage disease, Type 1a, von Gierke disease) gene analysis, common variants (eg, R83C, Q347X)

81251

GBA (glucosidase, beta, acid) (eg, Gaucher disease) gene analysis, common variants (eg, N370S, 84GG, L444P, IVS2+1G>A)

81256

HFE (hemochromatosis) (eg, hereditary hemochromatosis) gene analysis, common variants (eg, C282Y, H63D)

81257

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

81258

HBA1/HBA2 (alpha globin 1 and alpha globin 2) (eg, alpha thalassemia, Hb Bart hydrops fetalis syndrome, HbH disease), gene analysis; known familial variant

81259

HBA1/HBA2 (alpha globin 1 and alpha globin 2) (eg, alpha thalassemia, Hb Bart hydrops fetalis syndrome, HbH disease), gene analysis; full gene sequence

81260

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

81269

HBA1/HBA2 (alpha globin 1 and alpha globin 2) (eg, alpha thalassemia, Hb Bart hydrops fetalis syndrome, HbH disease), gene analysis; duplication/deletion variants

81330

SMPD1(sphingomyelin phosphodiesterase 1, acid lysosomal) (eg, Niemann-Pick disease, Type A) gene analysis, common variants (eg, R496L, L302P, fsP330)

81332

SERPINA1 (serpin peptidase inhibitor, clade A, alpha-1 antiproteinase, antitrypsin, member 1) (eg, alpha-1-antitrypsin deficiency), gene analysis, common variants (eg, *S and *Z)

81336

SMN1 (survival of motor neuron 1, telomeric) (eg, spinal muscular atrophy) gene analysis; full gene sequence

81337

SMN1 (survival of motor neuron 1, telomeric) (eg, spinal muscular atrophy) gene analysis; known familial sequence variant(s)

81361

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

81362

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

81363

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

81364

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

81412

Ashkenazi Jewish associated disorders (eg, 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

81434

Hereditary retinal disorders (eg, retinitis pigmentosa, Leber congenital amaurosis, cone-rod dystrophy), genomic sequence analysis panel, must include sequencing of at least 15 genes, including ABCA4, CNGA1, CRB1, EYS, PDE6A, PDE6B, PRPF31, PRPH2, RDH12, RHO, RP1, RP2, RPE65, RPGR, and USH2A

81479

Unlisted molecular pathology procedure [for example GBE1 (1,4-alpha-glucan branching enzyme 1) (eg. glycogen storage disease)]

81599

Unlisted multianalyte assay with algorithmic analysis

 

 

HCPCS

 

S3841

Genetic testing for retinoblastoma

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 diseases

S3850

Genetic testing for sickle cell anemia

S3853

Genetic testing for myotonic muscular dystrophy

 

 

ICD-10 Diagnosis

 

 

All diagnoses except preconception or prenatal testing diagnoses or those listed as investigational and not medically necessary

When services may also be Medically Necessary when criteria are met:

CPT

 

81400

Molecular pathology procedure, Level 1 (eg, identification of single germline variant [eg, SNP] by techniques such as restriction enzyme digestion or melt curve analysis) [when specified as the following]:

  • ACADM (acyl-CoA dehydrogenase, C-4 to C-12 straight chain, MCAD) (eg, medium chain acyl dehydrogenase deficiency), K304E variant
  • BCKDHA (branched chain keto acid dehydrogenase E1, alpha polypeptide) (eg, maple syrup urine disease, type 1A), Y438N variant
  • F5 (coagulation factor V) (eg, hereditary hypercoagulability), HR2 variant

81401

Molecular pathology procedure, Level 2 (eg, 2-10 SNPs, 1 methylated variant, or 1 somatic variant [typically using nonsequencing target variant analysis], or detection of a dynamic mutation disorder/triplet repeat) [when specified as the following]:

  • GALT (galactose-1-phosphate uridylyltransferase) (eg, galactosemia), common variants (eg, Q188R, S135L, K285N, T138M, L195P, Y209C, IVS2-2A>G, P171S, del5kb, N314D, L218L/N314D)
  • PYGM (phosphorylase, glycogen, muscle) (eg, glycogen storage disease type V, McArdle disease), common variants (eg, R50S, G205S)

81404

Molecular pathology procedure, Level 5 (eg, 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)  [when specified as the following]:

  • TTPA (tocopherol [alpha] transfer protein) (eg, ataxia), full gene sequence

81405

Molecular pathology procedure, Level 6 (eg, analysis of 6-10 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 11-25 exons, regionally targeted cytogenomic array analysis) [when specified as the following]:

  • ARSA (arylsulfatase A) (eg, arylsulfatase A deficiency), full gene sequence
  • BCKDHA (branched chain keto acid dehydrogenase E1, alpha polypeptide) (eg, maple syrup urine disease, type 1A), full gene sequence
  • DBT (dihydrolipoamide branched chain transacylase E2) (eg, maple syrup urine disease type 2), duplication/deletion analysis
  • DHCR7 (7-dehydrocholesterol reductase) (eg, Smith-Lemli-Opitz syndrome), full gene sequence

81406

Molecular pathology procedure, Level 7 (eg, analysis of 11-25 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 26-50 exons, cytogenomic array analysis for neoplasia)  [when specified as the following]:

  • ATP7B (ATPase, Cu++ transporting, beta polypeptide) (eg, Wilson disease), full gene sequence
  • BCKDHB (branched chain keto acid dehydrogenase E1, beta polypeptide) (eg, maple syrup urine disease, type 1B), full gene sequence
  • DBT (dihydrolipoamide branched chain transacylase E2) (eg, maple syrup urine disease, type 2), full gene sequence
  • DLD (dihydrolipoamide dehydrogenase) (eg, maple syrup urine disease, type III), full gene sequence
  • GAA (glucosidase, alpha; acid) (eg, glycogen storage disease type II [Pompe disease]), full gene sequence
  • GALT (galactose-1-phosphate uridylyltransferase) (eg, galactosemia), full gene sequence
  • PAH (phenylalanine hydroxylase) (eg, phenylketonuria), full gene sequence
  • PYGM (phosphorylase, glycogen, muscle) (eg, glycogen storage disease type V, McArdle disease), full gene sequence
  • RPE65 (retinal pigment epithelium-specific protein 65kDa) (eg, retinitis pigmentosa, Leber congenital amaurosis), full gene sequence
  • SLC37A4 (solute carrier family 37 [glucose-6-phosphate transporter], member 4) (eg, glycogen storage disease type Ib), full gene sequence

ICD-10 Diagnosis

 

 

All diagnoses except preconception or prenatal testing diagnoses

When services are Investigational and Not Medically Necessary:
For the procedure codes listed above when criteria are not met or for the diagnoses listed below, or for the codes listed below:

CPT

 

81402

Molecular pathology procedure, Level 3 (eg, > 10 SNP's 2-10 methylated variants, or 2-10 somatic variants [typically using non-sequencing target variant analysis], immunoglobulin and T-cell receptor gene rearrangements, duplication/deletion variants of 1 exon, loss of heterozygosity [LOH], uniparental disomy [UPD]) [when specified as the following]:

  • Uniparental disomy (UPD) (eg, Russell-Silver syndrome, Prader-Willi/Angelman syndrome), short tandem repeat (STR) analysis

81403

Molecular pathology procedure, Level 4 (eg, analysis of single exon by DNA sequence analysis, analysis of >10 amplicons using multiplex PCR in 2 or more independent reactions, mutation scanning or duplication/deletion variants of 2-5 exons)  [when specified as the following]:

  • ANG (angiogenin, ribonuclease, RNase A family, 5) (eg, amyotrophic lateral sclerosis), full gene sequence
  • KCNC3 (potassium voltage-gated channel, Shaw-related subfamily, member 3) (eg, spinocerebellar ataxia), targeted sequence analysis (eg, exon 2)

81404

Molecular pathology procedure, Level 5 (eg, 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)  [when specified as the following]:

  • CDKN2A (cyclin-dependent kinase inhibitor 2A) (eg, CDKN2A-related cutaneous malignant melanoma, familial atypical mole-malignant melanoma syndrome), full gene sequence
  • SOD1 (superoxide dismutase 1, soluble) (eg, amyotrophic lateral sclerosis), full gene sequence

81405

Molecular pathology procedure, Level 6 (eg, analysis of 6-10 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 11-25 exons, regionally targeted cytogenomic array analysis)  [when specified as the following]:

  • APTX (aprataxin) (eg, ataxia with oculomotor apraxia 1), full gene sequence
  • SIL1 (SIL1 homolog, endoplasmic reticulum chaperone [S. cerevisiae]) (eg, ataxia), full gene sequence
  • TARDBP (TAR DNA binding protein) (eg, amyotrophic lateral sclerosis), full gene sequence

81406

Molecular pathology procedure, Level 7 (eg, analysis of 11-25 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 26-50 exons, cytogenomic array analysis for neoplasia)  [when specified as the following]:

  • AFG3L2 (AFG3 ATPase family gene 3-like 2 [S. cerevisiae]) (eg, spinocerebellar ataxia), full gene sequence
  • EIF2B5 (eukaryotic translation initiation factor 2B, subunit 5 epsilon, 82kDa) (eg, childhood ataxia with central nervous system hypomyelination/vanishing white matter), full gene sequence
  • FUS (fused in sarcoma) (eg, amyotrophic lateral sclerosis), full gene sequence;
  • HEXA (hexosaminidase A, alpha polypeptide) (eg, Tay-Sachs disease), full gene sequence
  • OPTN (optineurin) (eg, amyotrophic lateral sclerosis), full gene sequence
  • PRKCG (protein kinase C, gamma) (eg, spinocerebellar ataxia), full gene sequence
  • SETX (senataxin) (eg, ataxia), full gene sequence
  • UBE3A (ubiquitin protein ligase E3A) (eg, Angelman syndrome), full gene sequence

81407

Molecular pathology procedure, Level 8 (eg, analysis of 26-50 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of >50 exons, sequence analysis of multiple genes on one platform) [when specified as the following]:

  • AGL (amylo-alpha-1, 6-glucosidase, 4-alpha-glucanotransferase) (eg, glycogen storage disease type III), full gene sequence
  • SPTBN2 (spectrin, beta, nono-erythrocytic 2) (eg, spinocerebellar ataxia), full gene sequence

81408

Molecular pathology procedure, Level 9 (eg, analysis of >50 exons in a single gene by DNA sequence analysis)  [when specified as the following]:

  • ATM (ataxia telangiectasia mutated) (eg, ataxia telangiectasia), full gene sequence
  • ITPR1 (inositol 1,4,5-triphosphate receptor, type 1) (eg, spinocerebellar ataxia), full gene sequence

ICD-10 Diagnosis

 

 

All diagnoses except preconception or prenatal testing diagnoses

When services are also Investigational and Not Medically Necessary:
For the following procedure codes; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

CPT

 

81173

AR (androgen receptor) (eg, spinal and bulbar muscular atrophy, Kennedy disease, X chromosome inactivation) gene analysis; full gene sequence

81174

AR (androgen receptor) (eg, spinal and bulbar muscular atrophy, Kennedy disease, X chromosome inactivation) gene analysis; known familial variant

81177

ATN1 (atrophin1) (eg, dentatorubral-pallidoluysian atrophy) gene analysis, evaluation to detect abnormal (eg, expanded) alleles

81178

ATXN1 (ataxin 1) (eg, spinocerebellar ataxia) gene analysis, evaluation to detect abnormal (eg, expanded) alleles

81179

ATXN2 (ataxin 2) (eg, spinocerebellar ataxia) gene analysis, evaluation to detect abnormal (eg, expanded) alleles

81180

ATXN3 (ataxin 3) (eg, spinocerebellar ataxia, Machado-Joseph disease) gene analysis, evaluation to detect abnormal (eg, expanded) alleles

81181

ATXN7 (ataxin 7) (eg, spinocerebellar ataxia) gene analysis, evaluation to detect abnormal (eg, expanded) alleles

81182

ATXN8OS (ataxin 8 opposite strand [non-protein coding]) (eg, spinocerebellar ataxia) gene analysis, evaluation to detect abnormal (eg, expanded) alleles

81183

ATXN10 (ataxin 10) (eg, spinocerebellar ataxia) gene analysis, evaluation to detect abnormal (eg, expanded) alleles

81184

CACNA1A (calcium voltage-gated channel subunit alpha1 A) (eg, spinocerebellar ataxia) gene analysis; evaluation to detect abnormal (eg, expanded) alleles

81185

CACNA1A (calcium voltage-gated channel subunit alpha1 A) (eg, spinocerebellar ataxia) gene analysis; full gene sequence

81186

CACNA1A (calcium voltage-gated channel subunit alpha1 A) (eg, spinocerebellar ataxia) gene analysis; known familial variant

81188

CSTB (cystatin B) (eg, Unverricht-Lundborg disease) gene analysis; evaluation to detect abnormal (eg, expanded) alleles

81189

CSTB (cystatin B) (eg, Unverricht-Lundborg disease) gene analysis; full gene sequence

81190

CSTB (cystatin B) (eg, Unverricht-Lundborg disease) gene analysis; known familial variant(s)

81200

ASPA (aspartoacylase) (eg, Canavan disease) gene analysis, common variants (eg, E285A, Y231X)

81204

AR (androgen receptor) (eg, spinal and bulbar muscular atrophy, Kennedy disease, X chromosome inactivation) gene analysis; characterization of alleles (eg, expanded size or methylation status)

81252

GJB2 (gap junction protein, beta 2, 26kDa, connexin 26) (eg, nonsyndromic hearing loss) gene analysis; full gene sequence

81253

GJB2 (gap junction protein, beta 2, 26kDa, connexin 26) (eg, nonsyndromic hearing loss) gene analysis; known familial variants

81254

GJB2 (gap junction protein, beta 6, 30kDa, connexin 30) (eg, nonsyndromic hearing loss) gene analysis, common variants (eg, 309kb [del(GJB6-D13S1830)] and 232kb [del(GJB6-D13S1854)])

81255

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

81271

HTT (huntingtin) (eg, Huntington disease) gene analysis; evaluation to detect abnormal (eg, expanded) alleles

81274

HTT (huntingtin) (eg, Huntington disease) gene analysis; characterization of alleles (eg, expanded size)

81284

FXN (frataxin) (eg, Friedreich ataxia) gene analysis; evaluation to detect abnormal (expanded) alleles

81285

FXN (frataxin) (eg, Friedreich ataxia) gene analysis; characterization of alleles (eg, expanded size)

81286

FXN (frataxin) (eg, Friedreich ataxia) gene analysis; full gene sequence

81289

FXN (frataxin) (eg, Friedreich ataxia) gene analysis; known familial variant(s)

81290

MCOLN1 (mucolipin 1) (eg, Mucolipidosis, type IV) gene analysis, common variants (eg, IVS3-2A>G, del6.4kb)

81302

MECP2 (methyl CpG binding protein 2) (eg, Rett syndrome) gene analysis; full sequence analysis

81303

MECP2 (methyl CpG binding protein 2) (eg, Rett syndrome) gene analysis; known familial variant

81304

MECP2 (methyl CpG binding protein 2) (eg, Rett syndrome) gene analysis; duplication/deletion variants

81312

PABPN1 (poly[A] binding protein nuclear 1) (eg, oculopharyngeal muscular dystrophy) gene analysis, evaluation to detect abnormal (eg, expanded) alleles

81331

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

81333

TGFBI (transforming growth factor beta-induced) (eg, corneal dystrophy) gene analysis, common variants (eg, R124H, R124C, R124L, R555W, R555Q)   

81343

PPP2R2B (protein phosphatase 2 regulatory subunit Bbeta) (eg, spinocerebellar ataxia) gene analysis, evaluation to detect abnormal (eg, expanded) alleles

81344

TBP (TATA box binding protein) (eg, spinocerebellar ataxia) gene analysis, evaluation to detect abnormal (eg, expanded) alleles

81410

Aortic dysfunction or dilation (eg, Marfan syndrome, Loeys Dietz syndrome, Ehler Danlos syndrome type IV, arterial tortuosity syndrome); genomic sequence analysis panel, must include sequencing of at least 9 genes, including FBN1, TGFBR1, TGFBR2, COL3A1, MYH11, ACTA2, SLC2A10, SMAD3, and MYLK

81411

Aortic dysfunction or dilation (eg, Marfan syndrome, Loeys Dietz syndrome, Ehler Danlos syndrome type IV, arterial tortuosity syndrome); duplication/deletion analysis panel, must include analyses for TGFBR1, TGFBR2, MYH11, and COL3A1

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)

81417

Exome (eg, unexplained constitutional or heritable disorder or syndrome); re-evaluation 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 exome (eg, parents, siblings)

81427

Genome (eg, unexplained constitutional or heritable disorder or syndrome); re-evaluation of previously obtained genome sequence (eg, updated knowledge or unrelated condition/syndrome)

81430

Hearing loss (eg, nonsyndromic hearing loss, Usher syndrome, Pendred syndrome); genomic sequence analysis panel, must include sequencing of at least 60 genes, including CDH23, CLRN1, GJB2, GPR98, MTRNR1, MYO7A, MYO15A, PCDH15, OTOF, SLC26A4, TMC1, TMPRSS3, USH1C, USH1G, USH2A, and WFS1

81431

Hearing loss (eg, nonsyndromic hearing loss, Usher syndrome, Pendred syndrome); duplication/deletion analysis panel, must include copy number analyses for STRC and DFNB1 deletions in GJB2 and GJB6 genes

81440

Nuclear encoded mitochondrial genes (eg, neurologic or myopathic phenotypes), genomic sequence panel, must include analysis of at least 100 genes, including BCS1L, C10orf2, COQ2, COX10, DGUOK, MPV17, OPA1, PDSS2, POLG, POLG2, RRM2B, SCO1, SCO2, SLC25A4, SUCLA2, SUCLG1, TAZ, TK2, and TYMP

81442

Noonan spectrum disorders (eg, 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, MAP2K1, MAP2K2, NRAS, PTPN11, RAF1, RIT1, SHOC2, and SOS1

81443

Genetic testing for severe inherited conditions (eg, cystic fibrosis, Ashkenazi Jewish-associated disorders [eg, 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 (eg, ACADM, ARSA, ASPA, ATP7B, BCKDHA, BCKDHB, BLM, CFTR, DHCR7, FANCC, G6PC, GAA, GALT, GBA, GBE1, HBB, HEXA, IKBKAP, MCOLN1, PAH)

81460

Whole mitochondrial genome (eg, Leigh syndrome, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes [MELAS], myoclonic epilepsy with ragged-red fibers [MERFF], neuropathy, ataxia, and retinitis pigmentosa [NARP], Leber hereditary optic neuropathy [LHON]), genomic sequence, must include sequence analysis of entire mitochondrial genome with heteroplasmy detection

81465

Whole mitochondrial genome large deletion analysis panel (eg, Kearns-Sayre syndrome, chronic progressive external ophthalmoplegia), including heteroplasmy detection if performed

81470

X-linked intellectual disability (XLID) (eg, syndromic and non-syndromic XLID); genomic sequence analysis panel, must include sequencing of at least 60 genes, including ARX, ATRX, CDKL5, FGD1, FMR1, HUWE1, IL1RAPL, KDM5C, L1CAM, MECP2, MED12, MID1, OCRL, RPS6KA3, and SLC16A2

81471

X-linked intellectual disability (XLID) (eg, syndromic and non-syndromic XLID); duplication/deletion gene analysis, must include analysis of at least 60 genes, including ARX, ATRX, CDKL5, FGD1, FMR1, HUWE1, IL1RAPL, KDM5C, L1CAM, MECP2, MED12, MID1, OCRL, RPS6KA3, and SLC16A2

81479

Unlisted molecular pathology procedure [when specified as diagnostic genetic testing using panels of genes (with or without next generation sequencing) not elsewhere specified]

81506

Endocrinology (type 2 diabetes), biochemical assays of seven analytes (glucose, HbA1c, insulin, hs-CRP, adiponectin, ferritin, interleukin 2-receptor alpha), utilizing serum or plasma, algorithm reporting a risk score
[PreDx Diabetes Risk Score™, Tethys Clinical Laboratory]

81599

Unlisted multianalyte assay with algorithmic analysis [when specified as  other MAAA test not meeting medical necessity criteria]

0012U

Germline disorders, gene rearrangement detection by whole genome next-generation sequencing, DNA, whole blood, report of specific gene rearrangement(s)
MatePair Targeted Rearrangements, Congenital, Mayo Clinic

 

 

HCPCS

 

S3800

Genetic testing for amyotrophic lateral sclerosis (ALS)

S3844

DNA analysis of the connexin 26 gene (GJB2) for susceptibility to congenital, profound deafness

 

 

ICD-10 Diagnosis

 

 

All diagnoses except preconception or prenatal testing diagnoses

References

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Government Agency, Medical Society, and Other Authoritative Publications:

  1. American College of Medical Genetics and Genomics. Position Statement. Points to consider in the clinical application of genomic sequencing. Genet Med. 2012; 14(8):759-761.
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  15. National Center for Biotechnology Information (NCBI). GeneReviews: Available at: https://www.ncbi.nlm.nih.gov/books/NBK1116/. Accessed on January 29, 2019.
    • Alpha-1 Antitrypsin Deficiency. Updated Jan 19, 2017.
    • Amyotrophic Lateral Sclerosis. Updated January 12, 2015.
    • Angelman Syndrome. Updated Dec 21, 2017.
    • Arylsulfatase A Deficiency. Updated Dec 14, 2017.
    • Bloom's Syndrome. Updated Apr 7, 2016.
    • Canavan Disease. Updated Sep 13, 2018.
    • Classic Galactosemia and Clinical Variant Galactosemia. Updated Mar 9, 22017.
    • Dihydrolipoamide Dehydrogenase Deficiency (DLD Deficiency). Initial posting July 17, 2014.
    • DRPLA. Updated June 9, 2016.
    • Factor V Leiden Thrombophilia. Updated January 4, 2018.
    • Familial Dysautonomia. Updated Dec 18, 2014.
    • Fanconi Anemia. Mar 8, 2018.
    • Friedreich Ataxia. Updated June 1, 2017.
    • Gaucher Disease. Updated Jun 2018.
    • Glycogen Storage Disease Type I (Von Gierke Disease). Updated November 2018.
    • Glycogen Storage Disease Type IV. Updated Jan 3, 2013.
    • HBA1 (Alpha-Thalassemia).  Updated December 29, 2016.
    • HFE Hemochromatosis. Updated December 6, 2018.
    • Hexosaminidase A Deficiency. Updated Aug 11, 2011.
    • Huntington Disease. Updated July 5, 2018.
    • Maple Syrup Urine Disease. Updated May 9, 2013.
    • MECP2-Related Disorders. Updated Jun 28 2012.
    • Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency. Updated Apr 20, 2000.
    • Myotonic Dystrophy type 1. Updated December 6, 2018.
    • Myotonic Dystrophy type 2. Updated July 3, 2013.
    • Nonsyndromic Hearing Loss and Deafness, DFNB1. Updated August 18, 2016.
    • Oculopharyngeal Muscular Dystrophy. Updated February 20, 2014.
    • Phenylalanine Hydroxylase Deficiency. Updated Jan 5, 2017.
    • Pompe Disease. Updated May 11, 2017.
    • Prader-Willi Syndrome. Updated December 14, 2017.
    • Sickle Cell Disease. Updated Aug 17 2017.
    • Smith-Lemli-Opitz Syndrome. Updated Jun 20, 2013.
    • Spinal and Bulbar Muscular Atrophy. Updated January 26, 2017.
    • Spinocerebellar Ataxia Type 1. Updated June 22, 2018.
    • Spinocerebellar ataxia Type 2. Updated November 12, 2015.
    • Spinocerebellar Ataxia Type 3. Updated September 24, 2015.
    • Spinocerebellar Ataxia Type 6. Updated July 18, 2013.
    • Spinocerebellar Ataxia Type 7. Updated December 20, 2012.
    • Spinocerebellar Ataxia Type 8. Updated April 3, 2014.
    • Spinocerebellar Ataxia Type 10. Updated September 20, 2012.
    • Spinocerebellar Ataxia Type 12. Updated November 17, 2011.
    • Spinocerebellar Ataxia Type 17. Updated May 17, 2012.
    • Unverricht-Lundborg Disease. Updated November 26, 2014.
    • Wilson Disease. Updated July 29, 2016.
  16. National Library of Medicine (NLM). Genetics Home Reference.
    • CDKN2A gene. Cyclin dependent kinase inhibitor 2A. Reviewed August 2018. Published January 29, 2019.
    • CFTR gene. Cystic fibrosis transmembrane conductance regulator. Reviewed January 2008. Published January 22, 2019. Available at: https://ghr.nlm.nih.gov/gene/CFTR. Accessed on January 29, 2019.
    • FANCC gene. FA complementation group C Reviewed January 2012. Published January 22, 2019. Available at: https://ghr.nlm.nih.gov/gene/FANCC. Accessed on January 29, 2019.
    • HBB gene. Hemoglobin subunit beta. Reviewed July 2015. Published January 29, 2019. Available at: https://ghr.nlm.nih.gov/gene/HBB. Accessed on January 29, 2019.
    • SMN1 gene. Survival of motor neuron 1, telomeric. Reviewed October 2018. Published January 29, 2019. Available at https://ghr.nlm.nih.gov/gene/SMN1. Accessed on January 29, 2019.
    • TGFBI gene. Transforming growth factor beta 1. Reviewed November 2017. Published January 29, 2019. Available at: https://ghr.nlm.nih.gov/gene/TGFBI. Accessed on January 29, 2019.
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  20. Stone EM, Aldave AJ, Drack AV, et al. Recommendations for genetic testing of inherited eye diseases: report of the American Academy of Ophthalmology task force on genetic testing. Ophthalmology. 2012; 119(11):2408-2410.
  21. Teutsch SM, Bradley LA, Palomaki GE, et al. The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Initiative: methods of the EGAPP Working Group. Genet Med. 2009; 11(1):3-14.
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    andgenetherapiesadvisorycommittee/ucm579300.pdf
    . Accessed on January 29, 2019.
  23. Yawn BP, John-Sowah J. Management of sickle cell disease: Recommendations from the 2014 Expert Panel Report. Am Fam Physician. 2015; 92(12):1069-1076. Available at: https://www.aafp.org/afp/2015/1215/p1069.html. Accessed on January 29, 2019.
  24. Zhu Y1, Shentu X, Wang W. The TGFBI R555W mutation induces a new granular corneal dystrophy type I phenotype. Mol Vis. 2011; 17:225-230.
Websites for Additional Information
  1. American Academy of Opthalmology. What Are Corneal Dystrophies? Available at: https://www.aao.org/eye-health/diseases/corneal-dystrophies. Accessed on January 29, 2019.
  2. Centers for Disease Control and Prevention (CDC). Public Health Genomics (NOPHG). Last updated June 21, 2018. Available at: http://www.cdc.gov/genomics. Accessed on January 29, 2019.
  3. Human Genome Project. Frequently asked questions about genetic testing. Last updated July 5, 2017. Available at: http://www.genome.gov/19516567#al-2. Accessed on January 29, 2019.
  4. National Library of Medicine (NLM). Genetic Conditions: Amyotrophic lateral sclerosis. Reviewed March 2016. Published January 29, 2019. Available at: http://ghr.nlm.nih.gov/condition=amyotrophiclateralsclerosis. Accessed on January 29, 2019.
  5. National Library of Medicine (NLM). Genetic Conditions: Ataxia-telangiectasia. Reviewed January 2013. Published January 29, 2019. Available at: http://ghr.nlm.nih.gov/condition/ataxia-telangiectasia. Accessed on January 29, 2019.
Index

CorusCAD
Diagnostic genetic test
Pharmacotherapeutic genetic test
Predictive genetic test
Prognostic genetic test
Therapeutic genetic test
Whole exome sequencing
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.

Document History

Status

Date

Action

Revised

03/21/2019

Medical Policy & Technology Assessment Committee (MPTAC) review. Information related to Corus® CAD deleted from this document and moved to GENE.00050 Gene Expression Profiling for Coronary Artery Disease. Updated Rationale, Coding, References, Websites for Additional Information and History sections.

Reviewed

01/24/2019

MPTAC review.

 

12/27/2018

Updated Coding section with 01/01/2019 CPT changes; added Tier 1 81336, 81337 for SMN1; added new Tier 1 codes to ‘may be medically necessary when criteria are met’ and Inv&NMN sections.

Reviewed

07/26/2018

MPTAC review. Updated Rationale, Coding, References and History sections.

 

12/27/2017

The document header wording updated from “Current Effective Date” to “Publish Date.” Updated Coding section with 01/01/2018 CPT changes; added codes 81258, 81259, 81269, and 81361-81364 replacing Tier 2 codes for these genes.

Reviewed

08/03/2017

Medical Policy & Technology Assessment Committee (MPTAC) review. Updated Rationale, References and History sections. Updated Coding section with 08/01/2017 CPT PLA code changes.

Revised

05/04/2017

MPTAC review. Updated the medically necessary statements to include criteria for genetic counseling. Updated Background/Overview, Definitions, Coding, References and History sections.

Reviewed

08/04/2016

MPTAC review. Updated formatting in Position Statement. Updated the Rationale, History and References sections.

 

01/01/2016

Updated Coding section with 01/01/2016 CPT changes; removed ICD-9 codes.

Revised

08/06/2015

MPTAC review. Position statement added which indicates the use of the Corus CAD test is considered investigational and not medically necessary. Updated the Rationale, References and History sections.

Revised

05/07/2015

MPTAC review. In bullet 1(a) of the medically necessary position statement, removed the words “late onset or slowly evolving”.  Removed references to deCODE tests from document. Updated the Description/Scope, Rationale, References and History sections.

New

02/05/2015

MPTAC review. Initial document development. This document subsumes two previous documents: GENE.00013 Diagnostic Genetic Testing of a Potentially Affected Individual (Adult or Child) and GENE.00015 Predictive Genetic Testing for Non-Malignant Diseases.