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Clinical Policy Title: Genetic testing for rare diseases

Clinical Policy Number: 02.01.09

Effective Date: January 1, 2016

Initial Review Date: October 16, 2013

Most Recent Review Date: October 19, 2016

Next Review Date: October 2017

Related policies:

CP# 02.01.01 Maternal genetic testing

CP# 02.01.02 Genetic testing for breast and ovarian cancer

CP# 02.01.03 Array comparative genomic hybridization testing

CP# 02.01.13 Pharmacogenetic testing for warfarin

CP# 02.01.07 Genetic testing for cystic fibrosis

CP# 02.01.08 Familial polyposis gene testing

CP# 02.01.10 Colaris test for Lynch syndrome

CP# 02.01.11 Afirma gene expression classifier for indeterminate thyroid nodules

CP# 02.01.12 Corus coronary artery disease (CAD) for genomic expression

CP# 02.01.14 Gene expression profile testing for breast cancer

CP# 05.01.04 Molecular analysis for targeted therapy of non-small cell lung cancer

ABOUT THIS POLICY: Keystone First has developed clinical policies to assist with making coverage determinations. Keystone First’s clinical policies are based on guidelines from established industry sources, such as the Centers for Medicare & Medicaid Services (CMS), state regulatory agencies, the American Medical Association (AMA), medical specialty professional societies, and peer-reviewed professional literature. These clinical policies along with other sources, such as plan benefits and state and federal laws and regulatory requirements, including any state- or plan-specific definition of “medically necessary,” and the specific facts of the particular situation are considered by Keystone First when making coverage determinations. In the event of conflict between this clinical policy and plan benefits and/or state or federal laws and/or regulatory requirements, the plan benefits and/or state and federal laws and/or regulatory requirements shall control. Keystone First’s clinical policies are for informational purposes only and not intended as medical advice or to direct treatment. Physicians and other health care providers are solely responsible for the treatment decisions for their patients. Keystone First’s clinical policies are reflective of evidence-based medicine at the time of review. As medical science evolves, Keystone First will update its clinical policies as necessary. Keystone First’s clinical policies are not guarantees of payment.

Coverage policy

Keystone First considers the once-per-lifetime use of genetic testing for rare disease to be clinically

proven and, therefore, medically necessary when the following criteria are met:

Policy contains:

Inherited breast, ovarian, colorectal

cancers.

Cardiomyopathies, channelopathies.

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The test results will directly impact management (i.e., as a result of the test, effective

treatment may be offered that will alter the course of disease or outcomes).

The test is an analytically and clinically valid test (i.e., supported by peer-reviewed published

research).

The test results will be discussed with the patient or guardian (including the limitations of

the testing method, the risks and benefits of either continuing or stopping the therapy

based on the test, and current cancer management guidelines).

There is a care-coordinating, multidisciplinary team available for genetic and behavioral

counseling for a tiered evaluation, which includes (a.) a primary care provider and (b.) a

geneticist (who is a physician or a licensed genetic counselor). If access to a genetic

counselor or medical geneticist is not possible, genetic counseling may be initiated by a

physician with relevant genetic expertise.

The patient or guardian has a desire for engagement with the integrated multidisciplinary

team that is documented in the clinical record.

Consideration has been given to standard diagnostic evaluation and use of tiered panel or

targeted test sequence for minimal number of genes to establish the diagnosis.

The genetic test includes, but is not limited to, testing for any of the disorders listed below

where there is a family history or defined high risk:

Huntington’s disease.

HFE-associated hemochromatosis.

Heritable cancers — breast, ovarian, colorectal, or myeloproliferative.

Cardiomyopathy.

Channelopathy.

Hemoglobinopathy — sickle cell or thalassemia.

Hemophilia.

Duchenne muscular dystrophy.

Mitochondrial disease.

Chondrodystrophy.

Fragile X.

Down syndrome.

Limitations:

All other uses of once-per-lifetime genetic testing for rare disease are not medically necessary.

Note: The following CPT/HCPCS codes are not listed in the Pennsylvania Medicaid fee schedule:

81265 - Comparative analysis using Short Tandem Repeat (STR) markers: patient and comparative

specimen (e.g., pre-transplant recipient and donor germline testing, post transplant non-hematopoietic

recipient germline and donor testing, twin zygosity testing or maternal cell contamination of fetal cells.

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81401 - HTT (huntingtin) (eg, Huntington disease), evaluation to detect abnormal (eg, expanded) alleles

81479 - Unlisted molecular pathology procedure.

Alternative covered services:

Laboratory evaluation with karyotyping, fluorescence in situ hybridization (FISH) assay.

Clinical evaluation by an appropriately trained in-network provider and standard laboratory

testing.

Background

Genetic testing for mutations in the human chromosome is used to determine whether an individual has

an increased risk for disease, including cancer, and in many cases to establish with certainty the medical

diagnosis (e.g., persons at high risk of inherited illness but whose genotype by traditional investigative

methods is inconclusive). Children who inherit mutations are at increased risk of congenital disorders,

treatable illnesses, and early onset of cancers, and carry these proclivities into adulthood. Adults with

genetic code derangements can be predictably counseled regarding risk and causes of morbidity and

mortality.

Genetic testing (or genomic testing as it is sometimes called) includes a variety of laboratory tests

(analysis of deoxyribonucleic acid [DNA], ribonucleic acid [RNA], and genes or gene products) performed

to diagnose disease, assist in treatment decisions, predict future disease, identify carriers of disease, and

conduct prenatal testing.

Searches

Keystone First searched PubMed and the databases of:

UK National Health Services Center for Reviews and Dissemination.

Agency for Healthcare Research and Quality’s National Guideline Clearinghouse and other

evidence-based practice centers.

The Centers for Medicare & Medicaid Services (CMS).

We conducted searches on October 4, 2016. Search terms were: "genetic testing (MeSH)," "genomic

tests (MeSH)," and "rare diseases (MeSH)."

We included:

Systematic reviews, which pool results from multiple studies to achieve larger sample sizes and

greater precision of effect estimation than in smaller primary studies. Systematic reviews use

predetermined transparent methods to minimize bias, effectively treating the review as a

scientific endeavor, and are thus rated highest in evidence-grading hierarchies.

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Guidelines based on systematic reviews.

Economic analyses, such as cost-effectiveness, and benefit or utility studies (but not simple cost

studies), reporting both costs and outcomes — sometimes referred to as efficiency studies —

which also rank near the top of evidence hierarchies.

Findings

There is a great deal of evidence regarding genetic testing for diagnosis, but the vast majority of it has

been done in the closed cohort of risk-dense individuals (infants, children, and adults) in whom the

presumptive diagnosis has been made but not confirmed by karyotype or other laboratory assessment.

As such, the evidence can lead to an overestimate of risk attributable entirely due to the high

concentration of mutations in this group of people. Moreover, there are doubtless mutations that lead

to disease that have yet to be discovered or imagined, leading to the potential of false-negative results

due to undetected mutations.

Evidence regarding the impact of genetic testing on clinical decision-making is limited, although the

available data suggest that a positive genetic test can induce people to participate in surveillance

programs or to elect a primary prevention strategy (such as surgery or chemoprevention). In addition,

even those with negative tests may benefit from a higher level of understanding and awareness of

disease for which they face risk, leading to earlier diagnosis and greater survival.

Policy updates:

Okazaki (2016) studied next-generation sequencing (NGS) using the TruSight® one gene panel for the

diagnosis of Mendelian disorders in 17 families and 20 patients. The authors detected causative

mutations in six (35 percent) of 17 families. In particular, 11 (65 percent) of the families had syndromic

diagnosis and six (35 percent) had no syndromic diagnosis before NGS testing. The number of positive

diagnoses was five (45 percent) of 11 in the syndromic group and one (17 percent) of six among patients

of the no syndromic diagnosis group. Diagnostic yields were higher than in previous reports of whole

exome sequencing (WES).

Daoud (2016) conducted a pilot project in which the authors assessed the feasibility of NGS as a tool to

improve the diagnosis of rare diseases in newborns in the neonatal intensive care unit (NICU). Subjects

were retrospectively identified and newborns and infants prospectively recruited. Blood samples were

evaluated using the MiSeq® sequencing platform. Of 20 newborns studied, eight received a diagnosis on

the basis of NGS (40 percent) as varied as renal tubular dysgenesis, SCN1A-related encephalopathy

syndrome, myotubular myopathy, FTO deficiency syndrome, cranioectodermal dysplasia, congenital

myasthenic syndrome, autosomal dominant intellectual disability syndrome type 7, and Denys-Drash

syndrome.

NGS offers an opportunity to locate mutations associated with genetic and infectious diseases, as well as

tumorigenesis. Carrigan (2016) presented results from the Target 5000 project, a NGS study aimed at

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identifying causative mutations in inherited retinal degenerations (IRDs). DNA samples were sequenced

using a capture panel consisting of all coding exons for genes previously implicated in retinopathies.

Candidate mutations were identified in 57 percent of pedigrees, many of which were novel and

previously unreported mutations identified in the IRD cohort, as were new ocular disease phenotypes

associated with genes previously implicated in other retinal disorders.

Pellicani (2016) reviewed the main clinical effects of ion channel mutations associated with migraine

headaches and presented convincing evidence of an increasing and evolving use of genetic analysis in

migraine research. The authors also showed how novel information in rare monogenic forms of migraine

might help to clarify the disease mechanisms in the general population of migraineurs.

Simeoni (2016) studied inherited bleeding, thrombotic, and platelet disorders (BPDs) with a high-

throughput sequencing platform targeting 63 genes relevant for BPDs. The platform identified single-

nucleotide variants, short insertions and deletions, and large copy number variants (though not

inversions), resulting in an average of 5.34 candidate variants per individual. The authors sequenced 159

and 137 samples, respectively, from cases with and without previously known causal variants. Among

the latter group, 61 cases had clinical and laboratory phenotypes indicative of a particular molecular

etiology, whereas the remainder had an uncertain etiology. A molecular diagnosis was reached in 56 of

61 and eight of 76 cases, respectively.

Pangalos (2016) reported an expanded exome sequencing-based test, coupled to a bioinformatics-

driven prioritization algorithm, targeting gene disorders presenting with abnormal prenatal ultrasound

findings. The authors applied the testing strategy to14 euploid fetuses, from 11 ongoing pregnancies

and three products of abortion, all with various abnormalities or malformations detected through

prenatal ultrasound examination. WES was followed by variant prioritization, utilizing a custom Fetalis

algorithm targeting 758 genes associated with genetic disorders. A definitive or highly likely diagnosis

was made in six of 14 cases (43 percent), among them Ellis-van Creveld syndrome, Ehlers-Danlos

syndrome and Nemaline myopathy, citrullinemia, Noonan syndrome, and PROKR2-related Kallmann

syndrome. In eight ongoing pregnancy cases, a ZIC1 variant of unknown clinical significance was

detected in one case, while in seven cases testing did not reveal any pathogenic variants. The authors

concluded the expanded targeted exome sequencing-based approach provided strong evidence of a

definite and beneficial increase in prenatal diagnosis.

A contemporary review (Hussein, 2015) sought evidence of efficacy of pre-conception testing for

thalassemia, sickle cell disease, cystic fibrosis, and Tay-Sachs disease in couples at genetic risk of the

conditions before pregnancy. The available evidence (mostly nonrandomized studies of limited power)

was insufficient to make a recommendation regarding the practice.

A study of the efficacy of screening the newborn population with genetic testing for homocysteinuria

failed to identify sufficient evidence to support a variance from the routine chemical testing (i.e., serum

methionine) that is now a legally mandated standard practice nationwide.

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Summary of clinical evidence:

Citation Content, Methods, Recommendations

Okazaki (2016) Clinical Diagnosis of Mendelian Disorders Using a Comprehensive Gene-Targeted Panel Test for Next-Generation Sequencing

Key points:

NGS using the TruSight one gene panel for the diagnosis of Mendelian disorders in 17 families and 20 patients was evaluated.

The authors detected causative mutations in six (35 percent) of 17 families.

In particular, 11 (65 percent) of the families had syndromic diagnosis and six (35 percent) had no syndromic diagnosis before NGS testing.

The number of positive diagnoses was five (45 percent) of 11 in the syndromic group and one (17 percent) of six among patients in the non-syndromic diagnosis group.

Diagnostic yields were higher than in previous reports of WES.

Daoud (2016) Next-generation sequencing for diagnosis of rare diseases in the neonatal intensive care unit

Key points:

Pilot project assessed the feasibility of NGS as a tool to improve the diagnosis of rare diseases in newborns in the NICU.

Subjects were retrospectively identified and newborns and infants prospectively recruited.

Blood samples were evaluated using the MiSeq sequencing platform.

Of 20 newborns studied, eight received a diagnosis on the basis of NGS (40 percent) as varied as renal tubular dysgenesis, SCN1A-related encephalopathy syndrome, myotubular myopathy, FTO deficiency syndrome, cranioectodermal dysplasia, congenital myasthenic syndrome, autosomal dominant intellectual disability syndrome type 7, and Denys-Drash syndrome.

Carrigan (2016) Panel-Based Population Next-Generation Sequencing for Inherited Retinal Degenerations.

Key points:

Narrative review presented results from the Target 5000 project, an NGS study of causative mutations in IRDs.

DNA samples were sequenced using a capture panel consisting of all coding exons for genes previously implicated in retinopathies.

Candidate mutations were identified in 57 percent of pedigrees, many of which were novel and previously unreported mutations identified in the IRD cohort, as were new ocular disease phenotypes associated with genes previously implicated in other retinal disorders.

Pellacani (2016) The Revolution in Migraine Genetics: From Aching Channels Disorders to a Next-Generation Medicine

Key points:

Narrative review of the effects of ion channel mutations associated with migraine headaches.

Presented convincing evidence of an increasing and evolving use of genetic analysis in migraine research.

The authors also showed how novel information in rare monogenic forms of migraine might help to clarify the disease mechanisms in the general population of migraineurs.

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Simeoni (2016) A high-throughput sequencing test for diagnosing inherited bleeding, thrombotic, and platelet disorders

Key points:

Project studied inherited BPDs with a high-throughput sequencing platform.

The platform identified single-nucleotide variants, short insertions and deletions, and large copy number variants (though not inversions), resulting in an average of 5.34 candidate variants per individual.

The authors sequenced 159 and 137 samples, respectively, from cases with and without previously known causal variants.

Among the latter group, 61 cases had clinical and laboratory phenotypes indicative of a particular molecular etiology, whereas the remainder had an uncertain etiology.

A molecular diagnosis was reached in 56 of 61 and eight of 76 cases, respectively.

Pangalos (2016) First applications of a targeted exome sequencing approach in fetuses with ultrasound abnormalities reveals an important fraction of cases with associated gene defects

Key points:

Reported an expanded exome sequencing-based test, coupled to a bioinformatics-driven prioritization algorithm.

The authors applied the testing strategy to14 euploid fetuses, from 11 ongoing pregnancies and three products of abortion.

WES was followed by variant prioritization, utilizing a custom Fetalis algorithm targeting 758 genes associated with genetic disorders.

A definitive or highly likely diagnosis was made in six of 14 cases (43 percent), among them Ellis-van Creveld syndrome, Ehlers-Danlos syndrome and Nemaline myopathy, citrullinemia, Noonan syndrome, and PROKR2-related Kallmann syndrome.

In eight ongoing pregnancy cases, a ZIC1 variant of unknown clinical significance was detected in one case, while in seven cases testing did not reveal any pathogenic variants.

The authors concluded the expanded targeted exome sequencing-based approach provided strong evidence of a definite and beneficial increase in prenatal diagnosis.

Hussein (2015) Preconception risk assessment for thalassemia, sickle cell disease, cystic fibrosis, and Tay-Sachs disease

Key points:

Systematic review of 13 randomized controlled trials (RCTs) looked for evidence of efficacy of pre-conception testing for thalassemia, sickle cell disease, cystic fibrosis, and Tay-Sachs disease in couples at genetic risk of the conditions before pregnancy.

Authors concluded the research evidence for policy recommendations is limited to nonrandomized studies.

Further evaluation from additional controlled studies is needed before definitive statements of clinical efficacy can be made about pre-conception testing.

Walters (2015) Newborn screening for homocystinuria

Key points:

Searched for evidence indicating newborn population screening with genetic tests for homocysteinuria can prevent or reduce the severity of disease.

No studies were identified for inclusion in the review.

The authors were unable to draw any conclusions based on controlled studies and deferred recommendation for its routine clinical practice.

Berardelli (2013) EFNS/MDS-ES recommendations for the diagnosis of Parkinson’s disease

Key points:

Concluded that the diagnosis of Parkinsonism is still largely based on the correct identification of its clinical features.

Genetic testing recommended for the diagnosis of Parkinsonism on an individual basis.

Family history and age of onset were determined to be key indicators of likelihood of disease.

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Lala (2013) Genetic testing in patients with acute coronary syndrome undergoing percutaneous coronary intervention: a cost-effectiveness analysis

Key points:

Examined the cost effectiveness of genetic testing in acute coronary syndrome (ACS) patients undergoing percutaneous interventions.

Specifically evaluated the routine CYP2C19*2 genotype-guided strategy of anti-platelet therapy in ACS patients undergoing interventions.

Results indicated genetic testing yields similar outcomes to empiric therapy, but at marginally lower cost and greater effectiveness.

Walsh (2013) Fetal aneuploidy detection by maternal plasma DNA sequencing: a technology assessment

Key points:

Fetal aneuploidy detection by maternal plasma DNA sequencing for trisomies 21, 18, and 13 for Down, Edwards, and Patau syndromes, respectively.

Improvement of net health outcomes criterion met for trisomies 21 and 18 in high-risk women.

Djalalov (2012) Genetic testing in combination with preventive donezepil treatment for patients with amnestic mild cognitive impairment: an exploratory economic evaluation of personalized medicine

Key points:

Exploratory economic analysis of the value of genetic testing for amnestic cognitive impairment.

Evaluated the genetic screening for apolipoprotein €4 allele.

Based on the available evidence, the authors concluded testing may be economically advantageous, but more research is needed.

Hilgart (2012) Cancer genetic risk assessment for individuals at risk of familial breast cancer

Key points:

Systematic review of eight RCTs, including 1,973 subjects, evaluated the benefit of genetic risk assessment in individuals at risk of familial breast cancer.

Authors found favorable outcomes for patients after risk assessment for familial breast cancer.

However, there were too few papers to make any significant conclusions about how best to deliver cancer genetic risk-assessment services.

Norman (2012) Cost-effectiveness of carrier screening for cystic fibrosis in Australia

Key points:

Evaluated the cost-effectiveness of carrier screening for cystic fibrosis in Australia.

Screening reduced the annual incidence of cystic fibrosis births from 34/100,000 to 14/100,000.

Authors concluded carrier screening was likely to reduce incidence of disease and be a cost-saving measure.

Royal Australian College of General Practitioners (2012) Genetic counseling and testing

Key points:

Examined genetic counseling and testing as a preventive measure in general practice.

Found benefit in genetic tests of pregnant women, couples planning pregnancy, neonates, and individuals known to be at increased risk for genetically determined diseases.

Specific cohorts identified as “at risk” included patients with a familial history of breast and ovarian cancers, colon cancer, familial hypercholesterolemia, cystic fibrosis, Down syndrome, hereditary hemochromatosis, hemoglobinopathies, thalassemias, and Fragile X syndrome.

Weissman (2012) Identification of individuals

Key points:

Examined the benefit of genetic testing in identifying hereditary nonpolyposis colorectal

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at risk for Lynch syndrome using targeted interventions and genetic testing

cancer (Lynch syndrome).

Specified immuno-histochemical and DNA testing parameters to diagnosis the disease.

Identified false positive and false negative test results as potential hazards.

Ackerman (2011) HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies

Key points:

Consensus statement from American Heart Rhythm Society and European Heart Rhythm Association on cardiac channelopathies and cardiomyopathies.

Panel recommended genetic testing only for index cases when clinical suspicion is high and result will influence management.

Albanese (2011) EFNS guidelines on diagnosis and treatment of primary dystonias

Key points:

Guidelines for the diagnosis and treatment of primary dystonias.

Reiterated that the diagnosis of dystonia is clinical, and genetic testing is confirmatory after clinical diagnosis established.

Genetic testing for primary dystonia is not recommended for asymptomatic individuals.

Berg (2011) Routine testing for Factor V Leiden (R506Q) and prothrombin (20210G>A) mutations in adults with a history of idiopathic venous thromboembolism and their adult family members

Key points:

Guidelines on the routine genetic testing for Factor V Leiden (R506Q) and prothrombin (20210G>A) mutations in adults with a history of idiopathic venous thromboembolism (VTE) and their adult family members.

Guidelines do not recommend routine genetic screening of adults with idiopathic VTE.

There is insufficient evidence to recommend genetic testing for asymptomatic family members of patients with known VTE, nor for counseling about prophylactic antithrombotic therapy.

The group noted that anticoagulation in these individuals was likely to create more harm than benefit.

Gersh (2011) ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy

Key points:

Guidelines for diagnosis and treatment of hypertrophic cardiomyopathy.

Recommended routine screening of first-degree relatives with or without genetic tests for familial inheritance as part of evaluation of hypertrophic cardiomyopathy.

Recommended routine genetic counseling as part of evaluation of hypertrophic cardiomyopathy.

Goldman (2011) Genetic counseling and testing for Alzheimer’s disease

Key points:

Guidelines identify those individuals likely to benefit from genetic counseling and testing for Alzheimer’s disease.

Offers an algorithmic pedigree analysis and risk assessment for Alzheimer’s of early or late onset.

AUA (2010) The optimal evaluation of the infertile male: AUA best practice statement.

Key points:

Guidelines for the evaluation of the infertile male.

Authors found insufficient evidence to make a recommendation for genetic testing.

Burgunder (2010) EFNS guidelines on the molecular diagnosis of channelopathies, epilepsies, migraine, stroke, and dementias

Key points:

Evaluated genetic testing for the molecular diagnosis of channelopathies, epilepsies, migraine, stroke, and dementias.

Found sufficient available evidence that thorough clinical and electrophysiological investigation leads to informed choices of genetic tests for channelopathies (i.e., periodic paralysis).

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Evidence supported electrophysiologic testing to establish muscular dystonia phenotype as a guide to informed choice of molecular genetic testing for these conditions.

Authors concluded that, “Molecular investigations are possible and may help in some cases to diagnose the condition, but cannot be considered routine procedure with the large number of mutations in different genes.” They give one exception: severe myoclonic epilepsy of infancy in which SCN1A mutations are found in 80 percent of those tested.

Bushby (2010) Diagnosis and management of Duchenne muscular dystrophy

Key points:

Guidelines for the diagnosis and management of Duchenne muscular dystrophy (DMD).

Genetic testing for mutation is necessary to confirm diagnosis.

Testing should be performed by a neuromuscular specialist, with support from geneticist and genetic counselors.

Palomaki (2010) Use of Genomic Profiling to Assess Risk for Cardiovascular Disease (CVD) and Identify Individualized Prevention Strategies

Key points:

Genomic profiling to assess cardiovascular risk results is a small improvement at best.

Authors found insufficient evidence to recommend it as a routine screening practice for cardiovascular risk.

Gasser (2010) EFNS guidelines on the molecular diagnosis of ataxias and spastic paraplegias

Key points:

Guidelines for the molecular diagnosis of ataxias and spastic paraplegias.

Authors found moderate-to-good evidence to support genetic testing for diagnosis of hereditary spastic paraplegias and hereditary ataxias (i.e., autosomal dominant and autosomal recessive cerebellar ataxias).

Lees (2010) Neonatal screening for sickle cell disease

Key points:

Searched for evidence indicating newborn population screening with genetic tests for sickle cell anemia can reduce the adverse effects of the disease.

No studies were identified for inclusion in the review.

The authors were unable to draw any conclusions based on controlled studies and deferred recommendation for its routine clinical practice.

Glossary

Acute coronary syndrome — Any group of symptoms related to coronary artery obstruction: most

commonly pressure-like chest pain, often radiating to the left arm or jaw; associated with nausea and

sweating; diagnosed by characteristic electrocardiogram patterns.

Alzheimer’s disease — Named for the German psychiatrist who described it in the early 20th century,

Alzheimer’s disease is the most common form of dementia. It usually occurs in people over age 65,

although an early onset type can be diagnosed much earlier. Diagnosis by standardized memory and

thinking tests is usually sufficient, although it is sometimes supplemented by brain scans. Causation and

risk factors (including any genetic component) and prevention remain incompletely defined. No

treatments to stop or reverse disease progression are yet available.

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Cardiomyopathy — Literally, “disease of the heart muscle,” cardiomyopathy refers to deteriorated

heart function for any reason and ultimately results in heart failure. The most common form is dilated

cardiomyopathy. The cardiomyopathies are diagnosed by symptoms and electrocardiogram. Specific

causes, including any genetic contributors, are not always well-defined, although coronary artery

disease should be ruled out.

Channelopathy — Disease of the ion-channel sub-units of cell membranes or of the proteins that

regulate them. Channelopathies may be congenital/genetic or acquired. Those involving skeletal muscle

result in forms of paralysis.

Duchenne muscular dystrophy — Recessive, X-linked disease found in one of 3,600 boys before age 6

years and producing muscle degeneration eventually leading to death. Females may be carriers, but

rarely show symptoms. Genetic testing in symptomatic boys (muscle weakness in legs and pelvis, low

endurance and difficulty with stairs) confirms diagnosis. Leg braces may assist walking initially, but most

patients become wheelchair-dependent. Mean life expectancy is 25 years of age.

Fragile X — The second most common form of intellectual delay (after Down syndrome) and the most

common inherited form, Fragile X results from a dynamic mutation in a gene on the long arm of the X

chromosome. Various strategies are used for prenatal screening.

Genetic testing — A variety of laboratory tests (analysis of DNA, RNA, genes, or gene products)

performed to diagnose disease, assist in treatment decisions, predict future disease, and identify

carriers of disease.

Hereditary nonpolyposis colorectal cancer — Also known as Lynch syndrome, hereditary non-polyposis

colorectal cancer, familial adenomatous polyposis (FAP), attenuated familial polyposis (AFAP), inherited

mutation-associated polyposis (MAP), and adenomatous polyposis coli (APC), this condition is no longer

considered an exclusively autosomal dominant syndrome, since some patients show autosomal

recessive inheritance due to mutations in the same gene (MUTYH).

Mitochondrial diseases — A group of diseases caused by dysfunctional mitochondria, the subcellular

organelles responsible for energy production. Approximately 15 percent of the group is related to

mutations in mitochondrial DNA. These disorders include mitochondrial myopathies; diabetes mellitus

and deafness; Leber’s hereditary neuropathy; Wolff-Parkinson-White syndrome; Leigh syndrome;

neuropathy, ataxia, retinitis pigmentosa, and ptosis (NARP); myoneurogenic gastrointestinal

encephalopathy (MNGIE); myoclonic epilepsy with ragged red fibers (MERRF); mitochondrial myopathy,

encephalomyopathy, lactic acidosis, and stroke-like symptoms (MELAS); and others. Symptoms include

poor growth, muscle weakness and loss of coordination; visual and hearing problems; learning

disabilities; and dysfunction in other organs or systems. Approximately 1 in 4,000 U.S. children are

affected. Treatment options are limited.

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Parkinson’s disease — A degenerative disease of the central nervous system resulting from dopamine-

generating cell death in a region of the mid-brain, causing characteristic clinical motor problems initially,

then eventually cognitive and behavioral ones. Many risk factors have been investigated, but no single

causative exposure or agent has been established. Diagnosis is clinical, and treatment with dopamine

agonists, MAO-B inhibitors, surgery, or rehabilitation is variably effective in compensating for deficits.

Sickle-cell disease — An inherited blood disorder characterized by rigid, abnormally shaped red blood

cells that can “log jam” at narrow or branch points in the vascular system, resulting in various acute and

chronic complications and shortened life expectancy. A mutation in the gene controlling hemoglobin

production produces co-dominant inheritance. Individuals with a single copy (carriers) of the gene have

both normal and abnormal hemoglobins, and experience symptoms only in certain circumstances (e.g.,

oxygen deprivation or severe dehydration). Individuals with two copies of the mutated gene are more

likely to experience painful vaso-occlusive crises that can lead to tissue or organ damage.

X-linked hemophilia (hemophilia A and B) — X-linked recessive bleeding disorders caused by

deficiencies in factors VIII and IX. Affected males are symptomatic with a range of clinical severities,

while females usually are asymptomatic carriers. Worldwide incidence is 1 in 5,000 newborn males for

hemophilia A and 1 in 30,000 for hemophilia B. Patients and families experience uncertain and excessive

bleeding episodes, transfusion-associated infection risks, frequent outpatient visits or hospitalizations,

financial and quality-of-life costs, and emotional burdens.

References

Professional society guidelines/other:

American Urological Association Education and Research Inc. The optimal evaluation of the infertile

male: AUA best practice statement. Linthicum, MD: American Urological Association Education and

Research Inc.; 2010.

Association of Comprehensive Cancer Centres (ACCC). Hereditary colorectal cancer. Amsterdam: NL:

ACCC; 2009.

Hayes Inc., Hayes Medical Technology Report. Genetic Testing for Susceptibility to Breast Cancer.

Lansdale, PA: Hayes Inc.; January 2008.

New Zealand Guidelines Group (NZGG). Management of early breast cancer. Wellington, NZ: NZGG;

2009: 149 – 59.

Royal Australian College of General Practitioners (RACGP). Genetic counseling and testing. In: Guidelines

for preventive activities in general practice, eighth edition. East Melbourne, AU: RACGP; 2012: 14 – 16.

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Sturgeon CM, Diamandis EP (eds). Use of tumor markers in testicular, prostate, colorectal, breast, and

ovarian cancers. Washington, DC: National Academy of Clinical Biochemistry of the American

Association for Clinical Chemistry; 2009.

Peer-reviewed references:

Ackerman MJ, Priori SG, Willems S, et al. HRS/EHRA expert consensus statement on the state of genetic

testing for the channelopathies and cardiomyopathies. Heart Rhythm. 2011; 8(8): 1308 – 1339.

Albanese A, Asmus F, Bhatia KP, et al. EFNS guidelines on diagnosis and treatment of primary dystonias.

Eur J Neurol. 2011; 18(1): 5 – 18.

Berardelli A, Wenning GK, Antonini A, et al. EFNS/MDS-ES recommendations for the diagnosis of

Parkinson’s disease. Eur J Neurol. 2013; 20(1): 16 – 34.

Berg AO, Botkin J, Calone N, et al. Evaluation of Genomic Applications in Practice and Prevention

(EGAPP) Working Group. Routine testing for Factor V Leiden (R506Q) and prothrombin (20210G>A)

mutations in adults with a history of idiopathic venous thromboembolism and their adult family

members. Genet Med. 2011; 13(1): 67-76. doi: 10.1097/GIM.0b013e3181fbe46f.

Burgunder JM, Finisterer J, Szolnoki Z, et al. European Federation of Neurological Societies. EFNS

guidelines on the molecular diagnosis of channelopathies, epilepsies, migraine, stroke, and dementias.

Eur J Neurol. 2010; 17(5): 641 – 648.

Bushby K, Finkel R, Birnkrant DJ, et al. DMD Care Considerations Working Group. Diagnosis and

management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial

management. Lancet Neurol. 2010; 9(1): 77 – 93.

Carrigan M, Duignan E, Malone CPG, et al. Panel-Based Population Next-Generation Sequencing for

Inherited Retinal Degenerations. Scientific Reports. 2016;6:33248.

Daoud H, Luco S, Li R, et al. Next-generation sequencing for diagnosis of rare diseases in the neonatal

intensive care unit. CMAJ. 2016 Aug 9; 188(11): E254–E260.

Djalalov S, Yong J, Beca J, et al. Genetic testing in combination with preventive donezepil treatment for

patients with amnestic mild cognitive impairment: an exploratory economic evaluation of personalized

medicine. Mol Diagn Ther. 2012; 16(6): 389 – 399.

Finsterer J, Harbo HF, Baets J, et al. European Federation of Neurological Sciences (EFNS) guidelines on

the molecular diagnosis of mitochondrial disorders. Eur J Neurol. 2009; 16(12): 1255 – 1264.

13

Gasser T, Baets J, van Broeckhoven C, et al. EFNS guidelines on the molecular diagnosis of ataxias and

spastic paraplegias. Eur J Neurol. 2010; 17(2): 179 – 88.

Gersh BJ, Maron BJ, Bonow RO, et al. 2011 American College of Cardiology Foundation/American Heart

Association (ACCF/AHA) guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: a

report of the ACCF/AHA Task Force on Practice Guidelines. J. Am. Coll. Cardiol. 2011; 58(25): e212 –

e260.

Goldman JS, Hahn SE, Catania JW, et al. American College of Medical Genetics and the National Society

of Genetic Counselors. Genetic counseling and testing for Alzheimer disease. Genet Med. 2011; 13(6):

597 – 605.

Hilgart JS, Coles B, Iredale R. Cancer genetic risk assessment for individuals at risk of familial breast

cancer. Cochrane Database of Systematic Reviews 2012, Issue 2. Art. No.: CD003721. DOI:

10.1002/14651858.CD003721.pub3.

Hussein N, Weng SF, Kai J, Kleijnen J, Qureshi N. Preconception risk assessment for thalassaemia, sickle

cell disease, cystic fibrosis and Tay-Sachs disease. Cochrane Database Syst Rev. 2015, Issue 8. Art. No.:

CD010849. DOI: 10.1002/14651858.CD010849.pub2.

Kornman LH, Nisbet DL, Liebelt J. Preconception and antenatal screening for the fragile site on the X-

chromosome. Cochrane Database Syst Rev. 2003, Issue 1. Art. No.: CD001806. DOI:

10.1002/14651858.CD001806.

LaLa A, Berger S, Sharma G, Hochman JS, Braithwaite RS, Ladapo A. Genetic testing in patients with

acute coronary syndrome undergoing percutaneous coronary intervention: a cost-effectiveness analysis.

Thromb Haemost. January 2013; 11(1): 81 – 91. doi: 10.1111/jth.12059.

Lees C, Davies SC, Dezateux C. Neonatal screening for sickle cell disease. Cochrane Database Syst Rev.

2000, Issue 1. Art. No.: CD001913. DOI: 10.1002/14651858.CD001913.

Lindenfeld J, Albert NM, Boehmer JP, et al. Genetic evaluation of cardiomyopathy: HFSA 2010

comprehensive heart failure practice guideline. J Card Fail. 2010; 16(6): e180 – e194.

Norman R, van Gool K, Hall J, Delatycki M, Massie J. Cost-effectiveness of carrier screening for cystic

fibrosis in Australia. J Cyst Fibros. 2012; 11(4): 281 – 287.

Okazaki T, Murata M, Kai M, et al. Clinical Diagnosis of Mendelian Disorders Using a Comprehensive

Gene-Targeted Panel Test for Next-Generation Sequencing. Yonago Acta Med. 2016 Jun; 59(2): 118–

125.

Palomaki GE, Melillo S, Neveux L, et al. Evaluation of Genomic Applications in Practice and Prevention

(EGAPP) Working Group. Use of Genomic Profiling to Assess Risk for Cardiovascular Disease (CVD) and

14

Identify Individualized Prevention Strategies. Genet Med. December 2010; 12(12): 772 – 784. doi:

10.1097/GIM.0b013e3181f8728d.

Pangalos C, Hagnefelt B, Lilakos K, Konialis C. First applications of a targeted exome sequencing

approach in fetuses with ultrasound abnormalities reveals an important fraction of cases with

associated gene defects.

PeerJ. 2016; 4: e1955.

Pellacani S, Sicca F, Di Lorenzo C, et al. The Revolution in Migraine Genetics: From Aching Channels

Disorders to a Next-Generation Medicine. Front Cell Neurosci. 2016; 10: 156.

Riley BD, Culver JO, Skrzynia C, et al. Essential elements of genetic cancer risk assessment, counseling,

and testing: updated recommendations of the National Society of Genetic Counselors. J Genet Couns.

2012; 21(2): 151 – 161.

Simeoni I, Stephens JC, Hu F, et al. A high-throughput sequencing test for diagnosing inherited bleeding,

thrombotic, and platelet disorders. Blood. 2016;127(23):2791-2803.

Southern KW, Mérelle MME, Dankert-Roelse JE, Nagelkerke A. Newborn screening for cystic fibrosis.

Cochrane Database Syst Rev. 2009; Issue 1. Art. No.: CD001402. DOI:

10.1002/14651858.CD001402.pub2.

Walsh, J. M. E. and Goldberg, J. D. Fetal aneuploidy detection by maternal plasma DNA sequencing: a

technology assessment. Prenat Diagn. 2013; 33(6): 514 – 520. doi: 10.1002/pd.4109.

Walter JH, Jahnke N, Remmington T. Newborn screening for homocystinuria. Cochrane Database Syst

Rev. 2015; Issue 10. Art. No.: CD008840. DOI: 10.1002/14651858.CD008840.pub4.

Weissman SM, Burt R, Church J, et al. Identification of individuals at risk for Lynch syndrome using

targeted interventions and genetic testing: National Society of Genetic Counselors and the Collaborative

Group of the Americas on Inherited Colorectal Cancer joint practice guideline. J Genet Couns. 2012;

21(4): 484 – 493.

Clinical trials:

Searched clinicaltrials.gov on September 30, 2016 using terms items | Open Studies. 943 studies found,

3 relevant.

Cure CMD. Myotubular Myopathy Genetic Testing Study. ClinicalTrials.gov Web site.

http://clinicaltrials.gov/show/NCT01817946. Published March 19, 2013. Updated July 2016. Accessed

September 30, 2016.

15

University of Utah. Genetic Analysis of Congenital Diaphragmatic Disorders. ClinicalTrials.gov Web site.

http://clinicaltrials.gov/show/NCT01243229. Published November 16, 2010. Updated March 2016.

Accessed September 30, 2016.

Medical College of Wisconsin. Genetic Analysis of PHACE Syndrome (Hemangioma With Other

Congenital Anomalies) (PHACE). ClinicalTrials.gov Web site. http://clinicaltrials.gov/show/NCT01016756.

Published November 18, 2009. Updated March 2016. Accessed September 30, 2016.

CMS National Coverage Determinations (NCDs):

No NCDs identified as of the writing of this policy, with the following technology assessment:

Update on Mapping the Landscape of Genetic Tests for Non-Cancer Diseases/Conditions.

https://www.cms.gov/Medicare/Coverage/DeterminationProcess/Downloads/id86TA.pdf. Accessed

September 30, 2015.

Local Coverage Determinations (LCDs):

No LCDs identified as of the writing of this policy.

Commonly submitted codes

Below are the most commonly submitted codes for the service(s)/item(s) subject to this policy. This is

not an exhaustive list of codes. Providers are expected to consult the appropriate coding manuals and

bill accordingly.

CPT Code Description Comment

81161 DMD (dystrophin) (E.g., Duchenne/Becker muscular dystrophy) deletion analysis, and duplication analysis, if performed.

81256 HFE (hemochromatosis) (e.g., hereditary hemochromatosis) gene analysis, common variants (e.g., C282Y, H63D).

81243 FMR1 (Fragile X mental retardation 1) (eg, fragile X mental retardation) gene analysis; evaluation to detect abnorma (eg, expanded) alleles

81244 FMR1 (Fragile X mental retardation 1) (eg, fragile X mental retardation) gene analysis; characterization of alleles (eg, expanded size and methylation status)

81265 Comparative analysis using Short Tandem Repeat (STR) markers: patient and comparative specimen (e.g., pre-transplant recipient and donor germline testing, post transplant non-hematopoietic recipient germline and donor testing, twin zygosity testing or maternal cell contamination of fetal cells.

81401 HTT (huntingtin) (eg, Huntington disease), evaluation to detect abnormal (eg, expanded) alleles

81479 Unlisted molecular pathology procedure.

ICD-10 Code Description Comment

16

C18.0 Malignant neoplasm of cecum

C18.1 Malignant neoplasm of appendix

C18.2 Malignant neoplasm of ascending colon

C18.3 Malignant neoplasm of hepatic flexure

C18.4 Malignant neoplasm of transverse colon

C18.5 Malignant neoplasm of splenic flexure

C18.6 Malignant neoplasm of descending colon

C18.7 Malignant neoplasm of sigmoid colon

C18.8 Malignant neoplasm of overlapping sites of colon

C18.9 Malignant neoplasm of colon, unspecified

C19 Malignant neoplasm of rectosigmoid junction

C20 Malignant neoplasm of rectum

C21.0 Malignant neoplasm of anus, unspecified

C50.011 Malignant neoplasm of nipple and areola, right female breast

C50.012 Malignant neoplasm of nipple and areola, left female breast

C50.019 Malignant neoplasm of nipple and areola, unspecified female breast

C50.111 Malignant neoplasm of central portion of right female breast

C50.112 Malignant neoplasm of central portion of left female breast

C50.119 Malignant neoplasm of central portion of unspecified female breast

C50.211 Malignant neoplasm of upper-inner quadrant of right female breast

C50.212 Malignant neoplasm of upper-inner quadrant of left female breast

C50.219 Malignant neoplasm of upper-inner quadrant of unspecified female breast

C50.311 Malignant neoplasm of lower-inner quadrant of right female breast

C50.312 Malignant neoplasm of lower-inner quadrant of left female breast

C50.319 Malignant neoplasm of lower-inner quadrant of unspecified female breast

C50.411 Malignant neoplasm of upper-outer quadrant of right female breast

C50.412 Malignant neoplasm of upper-outer quadrant of left female breast

C50.419 Malignant neoplasm of upper-outer quadrant of unspecified female breast

C50.511 Malignant neoplasm of lower-outer quadrant of right female breast

C50.512 Malignant neoplasm of lower-outer quadrant of left female breast

C50.519 Malignant neoplasm of lower-outer quadrant of unspecified female breast

C50.611 Malignant neoplasm of axillary tail of right female breast

C50.612 Malignant neoplasm of axillary tail of left female breast

C50.619 Malignant neoplasm of axillary tail of unspecified female breast

C50.811 Malignant neoplasm of overlapping sites of right female breast

C50.812 Malignant neoplasm of overlapping sites of left female breast

C50.819 Malignant neoplasm of overlapping sites of unspecified female breast

C50.911 Malignant neoplasm of unspecified site of right female breast

C50.912 Malignant neoplasm of unspecified site of left female breast

C50.919 Malignant neoplasm of unspecified site of unspecified female breast

C56.1 Malignant neoplasm of right ovary

C56.2 Malignant neoplasm of left ovary

C56.9 Malignant neoplasm of unspecified ovary

D56.4 Hereditary persistence of fetal hemoglobin [HPFH]

D56.8 Other thalassemias

D57.00 Hb-SS disease with crisis, unspecified

D57.01 Hb-SS disease with acute chest syndrome

D57.02 Hb-SS disease with splenic sequestration

D57.1 Sickle-cell disease without crisis

D57.20 Sickle-cell/Hb-C disease without crisis

D57.211 Sickle-cell/Hb-C disease with acute chest syndrome

D57.212 Sickle-cell/Hb-C disease with splenic sequestration

D57.219 Sickle-cell/Hb-C disease with crisis, unspecified

D57.80 Other sickle-cell disorders without crisis

17

D57.811 Other sickle-cell disorders with acute chest syndrome

D57.812 Other sickle-cell disorders with splenic sequestration

D57.819 Other sickle-cell disorders with crisis, unspecified

D58.2 Other hemoglobinopathies

D66 Hereditary factor VIII deficiency

D67 Hereditary factor IX deficiency

D68.0 Von Willebrand's disease

D68.1 Hereditary factor XI deficiency

D68.2 Hereditary deficiency of other clotting factors

E83.110 Hereditary hemochromatosis

E88.40 Mitochondrial metabolism disorder, unspecified

E88.41 MELAS syndrome

E88.42 MERRF syndrome

E88.49 Other mitochondrial metabolism disorders

G10 Huntington's disease

G71.0 Muscular dystrophy

G71.13 Myotonic chondrodystrophy

G72.3 Periodic paralysis

H49.811 Kearns-Sayre syndrome, right eye

H49.812 Kearns-Sayre syndrome, left eye

H49.813 Kearns-Sayre syndrome, bilateral

H49.819 Kearns-Sayre syndrome, unspecified eye

I42.0 Dilated cardiomyopathy

I42.4 Endocardial fibroelastosis

I42.5 Other restrictive cardiomyopathy

I42.8 Other cardiomyopathies

I42.9 Cardiomyopathy, unspecified

Q77.0 Achondrogenesis

Q77.1 Thanatophoric short stature

Q77.4 Achondroplasia

Q77.5 Diastrophic dysplasia

Q77.7 Spondyloepiphyseal dysplasia

Q77.8 Other osteochondrodysplasia with defects of growth of tubular bones and spine

HCPCS Level II

Description Comment