Clinical UM Guideline

This document addresses testing for certain diseases with an established genetic basis. It includes testing of individual genes for individuals at risk and preconception or prenatal genetic testing of a prospective parent or parent to determine carrier status for an autosomal recessive disorder, an x-linked disorder, or a disorder with variable penetrance.

Notes:

• Genetic counseling should be a component of a decision to perform genetic testing.
• This document only addresses molecular genetic testing and does not provide criteria for karyotype analysis or biochemical testing.
• This document does not address whole exome or whole genome testing or testing of 5 or more genes as a panel.
• This document does not address panel testing. Please refer to:
  • GENE.00049 Circulating Tumor DNA Panel Testing for Cancer (Liquid Biopsy)
  • GENE.00052 Whole Genome Sequencing, Whole Exome Sequencing, Gene Panels, and Molecular Profiling
• When another document exists that addresses a specific condition or genetic test, that document supersedes this one.
• Other related documents include:
  • CG-GENE-08 Genetic Testing for PTEN Hamartoma Tumor Syndrome
  • CG-GENE-21 Cell-Free Fetal DNA-Based Prenatal Testing
  • CG-MED-88 Preimplantation Genetic Diagnosis Testing

Medically Necessary:

Testing of individual genes for inherited diseases is considered medically necessary when all the criteria for the individual to be tested and for the genetic disorder being tested for (both Criteria A and B) are met:

1. Requirements for the individual:
   The individual to be tested:
   1. Is either at significant risk for a genetic disease (for example, based on family history) or suspected to have a known genetic disease; and
   2. Has received genetic counseling encompassing all of the following components:
      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.
         and
2. Requirements for the genetic disorder(s) being tested for:
   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. A positive or negative result of the genetic test 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 improvement in net health outcomes; that is, the expected health benefits of the interventions outweigh any harmful effects (medical or psychological) of the intervention.

   *Note:  See the Definitions section for information about predictive, diagnostic, prognostic and therapeutic genetic testing.

   Preconception or prenatal genetic screening of a parent or prospective parent to determine carrier status of inherited disorders is considered medically necessary when criteria for family history and for the specific genetic test (both Criteria C and D) are met:
    
3. Criteria based on family history:
   Genetic screening of the parent or prospective parent is considered medically necessary when one of the following criteria is met:
   1. An affected child is identified with either an autosomal recessive disorder, an x-linked disorder, or an inherited disorder with variable penetrance and genetic testing is performed to determine the pattern of inheritance and to guide subsequent reproductive decisions; or
   2. One or both parents or prospective parent(s) have a first or a second degree relative who is affected with either an autosomal recessive disorder, an x-linked disorder, or an inherited disorder with variable penetrance and genetic testing is performed to determine the pattern of inheritance and to guide subsequent reproductive decisions; or
   3. The parent or prospective parent is at high risk for a genetic disorder with a late onset presentation, and genetic testing is performed to determine carrier status and to guide subsequent reproductive decisions; or
   4. The parent or prospective parent is a member of an ethnic group with a high risk of a specific genetic disorder with an autosomal recessive pattern of inheritance and genetic testing is performed to determine carrier status and to guide subsequent reproductive decisions, including but not limited to Tay-Sach’s disease, Canavan disease, familial dysautonomia, mucolipidosis IV, Niemann Pick Disease Type A, Fanconi anemia group C, Bloom syndrome or Gaucher disease.
      and
4. Criteria for Specific Genetic Test:
   In the parent or prospective parent who meets one of the applicable criteria above, specific genetic testing is considered medically necessary when all of the following criteria are met:
   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 severe disability or has a lethal natural history; and
   4. 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.

Preconception or prenatal genetic screening of a parent or prospective parent to determine carrier status for the following conditions is considered medically necessary:

1. Cystic fibrosis, common variants (the current standard includes 23 of the more common gene mutations);
2. Spinal muscular atrophy.

Not Medically Necessary:

Genetic testing of individual genes for inherited diseases in individuals not meeting the above criteria is considered 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.

Preconception or prenatal genetic testing of a parent or prospective parent for inherited medical disorders that do not meet the above criteria, including but not limited, to amyotrophic lateral sclerosis (ALS, Lou Gehrig’s disease) is considered not medically necessary.  

Preconception or prenatal genetic screening of a parent or prospective parent to determine carrier status for cystic fibrosis, using any of the following is considered not medically necessary:

1. Complete DNA sequencing of the cystic fibrosis transmembrane conductance regulator (CFTR) gene;
2. Gene analysis of known CFTR familial variants;
3. Gene analysis of CFTR duplication/deletion variants.

The following codes for treatments and procedures applicable to this guideline 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.

Cystic fibrosis and spinal muscular atrophy testing

When services are Medically Necessary for carrier testing:

When services are Not Medically Necessary for carrier testing:

When services are Medically Necessary for other than carrier testing:

When services may be Medically Necessary when criteria are met for other than carrier testing:
For the procedure codes listed above, for all other diagnoses

Other gene testing for inherited diseases for all indications:
When services may be Medically Necessary when criteria are met:

When services are Not Medically Necessary:
For the procedure codes listed above when criteria are not met.

Other gene testing for preconception/prenatal testing
When services may be Medically Necessary when criteria are met:

When services are Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met or for all other diagnoses not listed.

Other gene testing of individuals:
When services may be Medically Necessary when criteria are met:

When services are Not Medically Necessary:
For the procedure codes listed above for the following diagnoses

Other testing
When services are Not Medically Necessary:

The phrase genetic testing can refer to 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 germline (inherited) or somatic (non-inherited) genetic variations associated with health or disease. This document is only concerned with the testing of individual genes at the molecular level for individuals at risk or for preconception or prenatal testing.

The use of genetic testing information is being explored as a means to:

• Guide predictive considerations and prognosis in asymptomatic individuals;
• Guide diagnosis, prognosis and treatment options, including response to therapies, in symptomatic individuals;
• Identify individuals at risk for the development of disorders in the future, (for example, susceptibility testing or population risk assessment).

Genetic tests are done for many reasons:

• Pregnancy-related genetic testing (preconception, prenatal, pre-implantation, in vitro fertilization) may be done prior to or during pregnancy to guide reproductive decisions, as part of assistive reproductive procedures, and for other reasons. This includes carrier testing to identify individuals who possess one copy of a gene variant that, when present in two copies, results in a specific genetic disorder. Having only one copy of the gene variant 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 addressed in this document and in the following document: CG-GENE-06 Preimplantation Genetic Diagnosis Testing.
• Somatic cell genetic testing involves the testing of tissue, (most often cancerous tissue), for variants 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 variants is addressed more specifically in other documents.
• Predictive, diagnostic, prognostic or therapeutic (see definition section) testing is also performed. Each gene to be tested is evaluated to determine whether or not identified genetic variants reliably identify a genetic disorder and that results of the genetic test will impact the management of the individual’s condition with a likelihood of improved clinical outcomes. Examples of ways a test may impact these objectives include guiding treatment decisions, formulating surveillance recommendations or guiding preventive strategies. The results of genetic testing are also expected to improve net health outcomes, which requires that the test results are actionable and that any actions taken are not outweighed by harmful effects from the intervention.

Genetic Counseling
Due to the potential impact of positive genetic test results, it is generally recommended that genetic testing only be provided in conjunction with genetic counseling. Genetic counseling should include a discussion of the potential risks for a particular genetic disorder and how identification of a genetic variant will impact treatment management. 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).

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, determining carrier status, or guiding reproductive decisions. Tests listed in the table with a check in the column for, “Individual genome testing may impact clinical management” have been shown to be useful in guiding clinical management and, in the right circumstances, findings from genetic testing may result in improved net clinical outcomes. There are many reasons why some of the tests below do not have a check mark. This may be because knowledge of the genetic status does not change the management of the condition, has not been shown to facilitate decision making around reproduction, or may be associated with genes that exhibit problematic interpretation in the context of preconception or prenatal genetic testing (for example, conditions primarily associated with late age of onset, mild phenotype, and/or incomplete penetrance).

In addition to showing that a test may be useful for guiding clinical management, determining carrier status, or guiding reproductive decisions, requests for test coverage must also document that improvements in net health outcomes are expected as a result of the testing.

*American College of Obstetricians and Gynecologists Committee on Genetics. ACOG Committee Opinion No. 690: Carrier screening in the age of genomic medicine. Obstet Gynecol. 2017(a); 129(3):e35-e40. Reaffirmed 2019.

Preconception or Prenatal Testing

Carrier testing for inherited genetic conditions is a key component of preconception and prenatal care. Carrier testing is conducted to identify an individual or a couple at risk (parent or prospective parent) for passing on genetic conditions to their offspring. Carriers are asymptomatic individuals who are typically not at risk for developing the disease, but who possess the potential to pass the gene variant to their offspring. Carrier testing is frequently performed on the parent or prospective parent before conception or during a pregnancy.

Carrier screening may be conducted for conditions that are found in the general population (panethnic), for diseases that are more common in a particular population, or based on family history. Panethnic screening (population screening) for carrier status is done for single-gene disorders that are common in the population.

Preconception or prenatal genetic testing of a parent or prospective parent is a common practice to determine carrier status. For example, the American College of Obstetrics and Gynecology (ACOG) and the American College of Medical Genetics (ACMG) recommend carrier screening for: Tay-Sach’s disease, Canavan disease, mucolipidosis IV, Niemann Pick Disease Type A, Fanconi anemia group C, Bloom syndrome, Gaucher’s disease and familial dysautonomia among individuals of Ashkenazi Jewish descent (ACOG, 2009; Gross, 2008). With regard to Fragile X syndrome, the ACMG has provided guidance on prenatal and preconception testing, and ACOG has published a Committee Opinion for carrier screening (Sherman, 2005; ACOG, 2009; ACOG, 2010; ACOG, 2017[b]).

Amyotrophic Lateral Sclerosis and Other Adult-onset Diseases
There has also been a growing interest in the use of genetic testing for amyotrophic lateral sclerosis (ALS, Lou Gehrig’s disease). ALS is an adult-onset, progressive neurodegenerative disorder that affects nerve cells in the spinal cord and brain that eventually results in paralysis and death. The mean age of onset for ALS is 56 years in individuals without a positive family history and 46 years in individuals with more than one affected family member (familial ALS). Disease duration can vary significantly, but has been estimated to average approximately 3 years. Death usually results from respiratory failure. Alterations in several genes, including superoxide dismutase 1 (SOD1), angiogenin (ANG), TAR DNA binding protein (TARDP), and optineurin (OPTN), have been associated with the development of ALS. Familial ALS can be inherited in an autosomal recessive, autosomal dominant, or X-linked fashion. Penetrance of familial ALS is age and variant dependent; approximately 50% of individuals with an SOD1 pathogenic variant are symptomatic by 46 years of age and 90% are symptomatic by 70 years of age. However, these percentages may be inflated due to ascertainment bias in families with high penetrance (Gene Reviews, 2015).

Neither ACOG nor ACMG recommend prenatal genetic testing for ALS. With regard to predictive genetic testing and the screening of children for adult-onset conditions, the ACMG has indicated that, “If clinical benefits will not accrue for years to decades, testing should be deferred until adulthood or should require parent or guardian permission, as well as adolescent assent.” ACMG also notes that most predictive genetic testing for adult-onset conditions is predispositional, that is, testing for genes that are incompletely penetrant and may never become manifest (Ross, 2013). The ACOG Committee Opinion number 690 states, “Carrier screening panels should not include conditions primarily associated with a disease of adult onset” (ACOG, 2017[a]). The National Society of Genetic Counselors (NSGC) does not support the use of prenatal genetic testing for known adult-onset conditions if pregnancy or childhood management will not be affected (Hercher, 2016). Alpha 1 antitrypsin deficiency (incompletely associated with mutations in the SERPINA1 gene) provides another example of a condition with an adult-onset phenotype where molecular testing cannot distinguish between childhood or adult onset. Likewise, preconception or prenatal genetic testing may not be appropriate for conditions, such as spinocerebellar ataxias (SCA) type 5 and familial malignant melanoma. Mutations in the beta III spectrin gene (SPTBN2 gene) have been associated with spinocerebellar ataxias (SCA) type 5. This is a relatively mild disorder that typically begins between the ages of 20 and 30 and progresses slowly. CDKN2A, the most commonly identified gene variant in familial forms of melanoma (adulthood age of onset), exhibits incomplete penetrance.

Cystic Fibrosis
Cystic fibrosis (CF) is a hereditary disease that affects many organs throughout the body and most of the exocrine glands. As a result of the abnormal production of secretions, CF leads to organ and tissue damage, especially in the airways, liver, pancreas, intestines, sweat glands, and, in males, the vas deferens. While several organs and tissues are affected by CF, pulmonary disease remains the predominant cause of morbidity and mortality in individuals with CF. It has been estimated approximately 1 in every 31 Americans is an asymptomatic carrier of the defective CF gene. 

CF results when an individual inherits a gene variant in both alleles of the CF transmembrane conductance regulator (CFTR) gene, located on chromosome 7q31. The CFTR gene produces a protein that functions as a chloride channel and regulates bicarbonate and chloride transport, as well as other transport pathways. More than 1900 different mutations in the CF gene have been identified. The prevalence of carrier frequencies and mutation types varies among populations. Non-Hispanic whites of Northern European descent have a carrier rate of 1 in 25 with the ΔF508 mutation being the most common. It has been estimated that amongst individuals of Ashkenazi Jewish descent, CFTR mutation carrier frequency is 1 in 24. When considered all together, the most common variants in this population (W1282X, ΔF508, G542X, 3849+10kb C>T, and N1303K) account for at least 94% of the CF cases.

The clinical severity of CF symptoms is largely determined by the specific variants that an individual carries. Any individual who screens positive for CF should receive genetic counseling. Negative screening results reduce, but do not totally eliminate, the possibility that the individual is a CF carrier. A negative screening test only indicates that the individual does not carry any of the CF variants specifically tested for during the screening. 

Due to the high prevalence of carriers of CF, ACOG and ACMG recommend that DNA screening for CF be made available to all individuals seeking preconception or prenatal care regardless of personal or family history for the disease or carrier status (ACOG, 2017[a], 2017[b]). The National Society of Genetic Counselors (NSGC) recommends that carrier testing for CF be provided to women of reproductive age, regardless of ancestry. The NSGC also recommends that prior to conception, “CF carrier testing should also be offered to any individual with a family history of CF and to partners of mutation carriers and people with CF” (Langfelder-Schwind, 2014).

Because so many different mutations in the CF gene have been identified, it is impractical to test for every known variant. In 2001, the ACMG Accreditation of Genetic Services Committee compiled a standard screening panel of 25 CF variants to screen for CF in the U.S. population (Grody et al, 2001). This 25-mutation test incorporated all CF-causing variants with an allele frequency of greater than or equal to 0.1 % in the general U.S. population. The test also included variant subsets shown to be sufficiently predominant in certain ethnic groups, such as African Americans and Ashkenazi Jews. The ACMG recommended that this standard panel of mutations be used to provide the greatest panethnic detectability that can be performed practically. In the 2004 guidelines on CF Population Carrier Screening, the ACMG recommended using a panel that contains, at a minimum, 23 of the most common CF mutations (Watson, 2004).

According to the NSGC, carrier testing panels should include the mutations recommended by ACOG and ACMG. For individuals of non-Northern European descent, panethnic panels that include additional mutations more commonly identified in minority populations are appropriate to consider. NSGC also recommends that general population screening practices focus on, “Identifying carriers of established disease-causing CFTR mutations” (Langfelder-Schwind, 2014). 

In a recent Consensus Opinion, ACOG stipulated that:

Complete analysis of the CFTR gene by DNA sequencing is not appropriate for routine carrier screening. This type of testing generally is reserved for patients with cystic fibrosis, patients with negative carrier screening result but a family history of cystic fibrosis (especially if family test results are not available), males with congenital bilateral absence of the vas deferens, or newborns with a positive newborn screening result when mutation testing (using the standard 23-mutation panel) has a negative result. Because carrier screening detects most mutations, sequence analysis should be considered only after discussion with a genetics professional to determine if it will add value to the standard screening that was performed previously (ACOG, 2017[b]).

Spinal Muscular Atrophy
Spinal muscular atrophy (SMA) is a disease characterized by muscle atrophy and weakness caused by the progressive degeneration and loss of the brain stem nuclei and the anterior horn cells in the spinal cord, (that is, the lower motor neurons). The onset of muscle weakness ranges from before birth to adolescence or young adulthood. The weakness is symmetrical and progresses from proximal to distal. Growth failure and poor weight gain, restrictive lung disease, scoliosis, joint contractures, and sleep difficulties are common complications (Prior, 2016). The age of onset of symptoms roughly correlates with the extent to which motor function is affected with the earlier the age of onset, the more profound the impact on motor function. Children who are symptomatic at birth or in infancy typically have the lowest level of function. 

SMA is caused by a mutation in the survival motor neuron gene (SMN1). Due to the severity of the disease and the relatively high carrier frequency, there has been interest in carrier screening for SMA in the general prenatal population. Because the genetics of SMA are complex and due to, “Limitations in the molecular diagnostic assays available, precise prediction of the phenotype in affected fetuses may not be possible” (ACOG, 2017[b]).

ACOG Committee Opinion No. 690 Carrier Screening in the Age of Genomic Medicine and No. 691 Carrier Screening for Genetic Conditions indicate that all individuals who are considering pregnancy or are already pregnant, regardless of screening strategy and ethnicity, should be offered carrier screening for SMA (ACOG 2017[a], ACOG 2017[b]). The ACMG position statement on Carrier Screening for Spinal Muscular Atrophy also recommends panethnic screening for SMA (Prior, 2008).

Rett Syndrome
Rett syndrome is a disorder of the nervous system that leads to regression in development, especially in the areas of expressive language and hand use. In most cases, it is caused by a genetic variant on the X chromosome in the gene that contains instructions for creating methyl-CpG-binding protein 2 (MeCP2). Rett syndrome occurs almost exclusively in girls and may be misdiagnosed as autism or cerebral palsy. A child affected with Rett syndrome normally follows a standard developmental path for the first 5 months of life. After that time, development in communication skills and motor movement in the hands seems to stagnate or regress. After a short period, stereotyped hand movements, gait disturbances, and slowing of the rate of head growth become apparent. Other problems may also be associated with Rett syndrome, including seizures, disorganized breathing patterns while awake and apraxia/dyspraxia (the inability to program the body to perform motor movements). Apraxia/dyspraxia is a key symptom of Rett syndrome, and it results in significant functional impairment, interfering with body movement, including eye gaze and speech.

Duchenne muscular dystrophy or Becker muscular dystrophy
Muscular dystrophy (MD) refers to a diverse group of genetic diseases (disorders) characterized by a decrease in muscle mass over time, including progressive damage and weakness of facial, limb, breathing, and heart muscles. Some disorders within this group, referred to as dystrophinopathies, are categorized based on clinical features, (such as the age when signs are first seen), genetic (inheritance) pattern, the muscles affected, and muscle biopsy features. A major type of MD is Duchenne muscular dystrophy (DMD) which is the most common form affecting children. DMD is an x-linked genetic disorder characterized by progressive muscle atrophy. This form of muscular dystrophy primarily affects the skeletal and cardiac muscles and occurs almost exclusively in males. In this condition, muscle weakness tends to appear in early childhood and worsen rapidly. Affected children may demonstrate delayed motor skills, such as sitting, standing, walking, and are usually wheelchair-dependent by adolescence. The onset of cardiomyopathy typically begins in adolescence (Genetics Home Reference, Duchenne and Becker muscular dystrophy, 2019).

DMD is X-linked and penetrance is complete in males and can manifest in female carriers as weakness or cardiomyopathy. The gene that codes for dystrophin is the largest known human gene. A molecular confirmation of DMD is achieved by confirming the presence of a pathogenic variant in this gene by a number of available assays. A dystrophin gene alteration is implicated in a spectrum of X-linked muscle disease, with overlapping clinical specifics and severity, resulting in a complex spectrum of dystrophinopathies. The clinical conditions within the spectrum include DMD, Becker muscular dystrophy (BMD), and DMD-associated cardiomyopathy. On December 12, 2019, the FDA cleared for marketing the first biochemical screening test to aid in newborn screening for DMD. The GSP Neonatal Creating Kinase-MM kit works by measuring the concentration of a type of protein called CK-MM, which is part of a group of proteins called creatine kinase. Results showing elevated CK-MM should be confirmed using other testing methods, such as other laboratory tests, muscle biopsy, or genetic testing.

In 2020, the U.S. Food and Drug Administration (FDA) approved the Genomic Unity^® Muscular Dystrophy Analysis by Variantyx Inc. (Framingham, MA), a test used for individuals who have been diagnosed with Duchenne or Becker muscular dystrophy or who exhibit symptoms of these disorders. High quality genomic DNA is isolated from whole blood and is subjected to next generation sequencing of the DMD gene.

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. 

Analytical validity: The accuracy with which a test identifies the presence or absence of a particular gene or genetic change (mutation).

Ashkenazi Jewish:  Persons related to Jewish settlers of the Rhine Valley in Germany and France in the middle ages.

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

Carrier: An individual who is asymptomatic (or has only mild symptoms) of a disorder but has the potential to pass on the gene for that disorder to his or her offspring.

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

Clinical validity: The extent to which a test identifies or predicts an individual's clinical status.

Cystic fibrosis (CF): An inherited disease that affects the mucus and sweat glands of the body; thick mucus is formed in the breathing passages of the lungs that predisposes the person to chronic lung infections.

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

Ethnicity: Coming from a large group that shares racial, national, language or cultural characteristics.

Exome: All the exons in a genome.

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

Genetic molecular testing: A type of test that is used to determine the presence or absence of a specific gene or set of genes to help diagnose a disease, screen for specific health conditions, and for other purposes.

Genetic testing is done for predictive, diagnostic, prognostic or therapeutic indications as follows:

• Predictive genetic testing involves use of a genetic test in an asymptomatic person to predict future risk of developing a certain disease. One of the limitations of predictive genetic testing is the challenge in interpreting positive test results, because some individuals who test positive for a disease-associated mutation may never develop the disease. Predictive testing can identify mutations that increase a person's risk of developing disorders with a genetic basis, such as certain types of cancer. Targeted pre-symptomatic genetic testing can determine whether a person will develop a genetic disorder, such as hereditary hemochromatosis (an iron overload disorder), before any signs or symptoms appear. 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 routine medical care without results of genetic testing.
• Diagnostic genetic testing is used to identify or rule out a specific genetic or chromosomal condition. In many cases, genetic testing is used to confirm a diagnosis when a particular condition is suspected based on physical signs and symptoms. Diagnostic testing can be performed before birth or at any time during a person's life, but is not available for all genes or all genetic conditions. The results of a diagnostic genetic test can influence a person's choices about health care and the management of the disorder.
• 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). For example, prognostic genetic testing, when performed in persons with confirmed chronic lymphocytic leukemia (CLL), helps to inform optimal disease management and also predicts survival and disease progression.
• 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 test results are used to inform treatment decisions with regards to how an individual is expected to respond to a particular drug therapy.

Genome: An organism's entire set of DNA.

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

Mutation:  A permanent change in the DNA code.

Next-generation sequencing: Any of the technologies that allow rapid sequencing of large numbers of segments of DNA, up to and including entire genomes.

Panel testing: Involves the analysis of multiple genes for multiple mutations simultaneously.

Panethnic screening: A screening approach that is done for single-gene disorders based on ethnicity, race, or both.

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.

Rett syndrome: A developmental disorder that affects the parts of the brain that control social interaction, communications, and motor function.

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

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21. Lyssenko V, Jonsson A, Almgren P, et al. Clinical risk factors, DNA variants, and the development of type 2 diabetes. N Engl J Med. 2008; 359(21):2220-2232. 
22. Lyssenko V, Lupi R, Marchetti P, et al. Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes. J Clin Invest. 2007; 117(8):2155-2163.
23. Mailman MD, Heinz JW, Papp AC, et al. Molecular analysis of spinal muscular atrophy and modification of the phenotype by SMN2. Genet Med. 2002; 4(1):20-26.
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25. Meigs JB, Shrader P, Sullivan LM, et al. Genotype score in addition to common risk factors for prediction of type 2 diabetes. N Engl J Med. 2008; 359(21):2208-2219.
26. Miyake K, Horikawa Y, Hara K, et al. Association of TCF7L2 polymorphisms with susceptibility to type 2 diabetes in 4,087 Japanese subjects. J Hum Genet. 2008; 53(2):174-180.
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28. Owen KR, McCarthy MI. Genetics of type 2 diabetes. Curr Opin Genet Dev. 2007; 17(3):239-244.
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33. Paynter NP, Chasman DI, Buring JE, et al. Cardiovascular disease risk prediction with and without knowledge of genetic variation at chromosome 9p21.3. Ann Intern Med. 2009; 150(2):65-72.
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35. Prior TW, Snyder PJ, Rink BD, et al. Newborn and carrier screening for spinal muscular atrophy. Am J Med Genet A. 2010; 152A (7):1608-1616.
36. Ramprasad VL, George R, Soumittra N, et al. Association of non-synonymous single nucleotide polymorphisms in the LOXL1 gene with pseudoexfoliation syndrome in India. Mol Vis. 2008; 9(14):318-322.
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39. Russell S, Bennett J, Wellman JA, et al. Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomized, controlled, open-label, phase 3 trial. Lancet. 2017; 390(10097):849-860.
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52. Weinstein LB. Selected genetic disorders affecting Ashkenazi Jewish families. Fam Community Health. 2007 30(1):50-62.
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Government Agency, Medical Society, and Other Authoritative Publications:

1. American Academy of Pediatrics Section on Cardiology and Cardiac Surgery. Clinical Report: cardiovascular health supervision for individuals affected by Duchenne or Becker muscular dystrophy. Pediatrics. 2005; 116(6):1569-1573.
2. ACMG Board of Directors. Points to consider in the clinical application of genomic sequencing. Genet Med. 2012; 14(8):759-761.
3. American College of Obstetricians and Gynecologists Committee on Genetics. ACOG Committee Opinion No. 442: Preconception and prenatal carrier screening for genetic diseases in individuals of Eastern European Jewish descent. Obstet Gynecol. 2009; 114(4):950-953. Reaffirmed 2014.
4. American College of Obstetricians and Gynecologists Committee on Genetics. ACOG Committee Opinion No. 469: Carrier screening for fragile X syndrome. Obstet Gynecol. 2010; 116(4):1008-1010.
5. American College of Obstetricians and Gynecologists Committee on Genetics. ACOG Committee Opinion No. 486: Update on carrier screening for cystic fibrosis. Obstet Gynecol. 2011; 117(4):1028-1031. Reaffirmed 2014.
6. American College of Obstetricians and Gynecologists Committee on Genetics. ACOG Committee Opinion No. 690: Carrier screening in the age of genomic medicine. Obstet Gynecol. 2017(a); 129(3):e35-e40. Reaffirmed 2019.
7. American College of Obstetricians and Gynecologists Committee on Genetics. ACOG Committee Opinion No. 691. Carrier screening for genetic conditions. Obstet Gynecol. 2017(b); 129(3):e41-e45.
8. Andersen PM, Abrahams S, Borasio GD, et al. EFNS guidelines on the clinical management of amyotrophic lateral sclerosis (MALS)-revised report of an EFNS task force. Eur J Neurol. 2012; 19(3):360-375.
9. Arnett DK, Baird AE, Barkley RA, et al. American Heart Association Council on Epidemiology and Prevention; American Heart Association Stroke Council; Functional Genomics and Translational Biology Interdisciplinary Working Group. Relevance of genetics and genomics for prevention and treatment of cardiovascular disease: a scientific statement from the American Heart Association Council on Epidemiology and Prevention, the Stroke Council, and the Functional Genomics and Translational Biology Interdisciplinary Working Group. Circulation. 2007; 115(22):2878-2901.
10. Blue Cross and Blue Shield Association. Sequencing for Clinical Diagnosis of Patients with Suspected Genetic Disorders. TEC Assessment, 2013; 28(3).
11. Brooks BR, Miller RG, Swash M, Munsat TL. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord. 2000; 1:293-299.
12. Burgunder JM, Schols L, Baets J, et al. EFNS guidelines for the molecular diagnosis of neurogenetic disorders: motoneuron, peripheral nerve and muscle disorders. Eur J Neurol. 2011; 18(2):207-217.
13. Committee on Genetics and the Society for Maternal-Fetal Medicine. Microarrays and Next-Generation Sequencing Technology: The Use of Advanced Genetic Diagnostic Tools in Obstetrics and Gynecology. Obstet Gynecol. 2016; 128(6):e262-e268.
14. Edwards JG, Feldman G, Goldberg J, et al. Expanded carrier screening in reproductive medicine-points to consider: a joint statement of the American College of Medical Genetics and Genomics, American College of Obstetricians and Gynecologists, National Society of Genetic Counselors, Perinatal Quality Foundation, and Society for Maternal-Fetal Medicine. Obstet Gynecol. 2015; 125(3):653-662.
15. European Society of Human Genetics. Genetic testing in asymptomatic minors: Recommendations of the European Society of Human Genetics. Eur J Hum Genet. 2009; 17(6):720-721.
16. Genetic and Rare Diseases Information Center. Alpha-1 antitrypsin deficiency. Last updated September 26, 2018. Available at: https://rarediseases.info.nih.gov/diseases/5784/alpha-1-antitrypsin-deficiency. Accessed on January 19, 2021. 
17. Green RC, Berg JS, Grody WW, et al. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med. 2013; 15(7):565-574.
18. Gross SJ, Pletcher BA, Monaghan KG; et al. Carrier screening in individuals of Ashkenazi Jewish descent. Genet Med. 2008; 10(1):54-56.
19. Grody WW, Cutting GR, Klinger KW, et al. Laboratory standards and guidelines for population-based cystic fibrosis carrier screening. Genet Med. 2001; 3(2):149-154.
20. Grody WW, Griffin JH, Taylor AK, et al. American College of Medical Genetics consensus statement on factor V Leiden mutation testing. Genet Med. 2001; 3(2):139-148.
21. Grody WW, Thompson BH, Gregg AR, et al. ACMG position statement on prenatal/preconception expanded carrier screening. Genet Med. 2013; 15(6):482-483.
22. Hercher L, Uhlmann WR, Hoffman EP, et al. Prenatal Testing for Adult-Onset Conditions: the Position of the National Society of Genetic Counselors. J Genet Couns. 2016; 25(6):1139-1145.
23. Holtzman NA, Watson MS. Promoting safe and effective genetic tests in the United States: work of the Task Force on Genetic Testing. Clin Chem. 1999; 45(5):732-738.
24. Kalia SS, Adelman K, Bale SJ, et al. Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics. Genet Med. 2017; 19(2):249-255.
25. Klintworth GK. Corneal dystrophies. Orphanet J Rare Dis. 2009; 4:7.
26. Kohne E. Hemoglobinopathies: Clinical Manifestations, Diagnosis, and Treatment. Dtsch Arztebl Int. 2011; 108(31-32): 532–540. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3163784/. Accessed on January 19, 2021.
27. Langfelder-Schwind E, Karczeski B, Strecker MN, et al. Molecular testing for cystic fibrosis carrier status practice guidelines: recommendations of the National Society of Genetic Counselors. J Genet Couns. 2014; 23(1):5-15.
28. Monaghan KG, Lyon E, Spector EB; American College of Medical Genetics and Genomics. ACMG Standards and Guidelines for fragile X testing: a revision to the disease-specific supplements to the Standards and Guidelines for Clinical Genetics Laboratories of the American College of Medical Genetics and Genomics. Genet Med. 2013; 15(7):575-586.
29. Moxley RT III, Ashwal S, Pandya S, et al. Practice parameter: corticosteroid treatment of Duchenne dystrophy: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology. 2005; 64(1):13-20.
30. National Center for Biotechnology Information (NCBI). GeneReviews: Available at: https://www.ncbi.nlm.nih.gov/books/NBK1116/. Accessed on January 19, 2021.
    • 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, 2017.
    • Dihydrolipoamide Dehydrogenase Deficiency (DLD Deficiency). Initial posting July 17, 2014.
    • DRPLA. Updated June 9, 2016.
    • Dystrophinopathies. April 26, 2018.
    • 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.
31. 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 19, 2021.
    • 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 19, 2021.
    • HBB gene. Hemoglobin subunit beta. Reviewed July 2015. Published January 29, 2019. Available at: https://ghr.nlm.nih.gov/gene/HBB. Accessed on January 19, 2021.
    • 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 19, 2021.
    • 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 19, 2021.
32. National Organization of Rare Disorders (NORD).
    • Beta thalassemia. Published 2018. Available at: https://rarediseases.org/rare-diseases/thalassemia-major/. Accessed on January 19, 2021.
    • Corneal dystrophies. Published 2010. Available at: https://rarediseases.org/rare-diseases/corneal-dystrophies/. Accessed on January 19, 2021.
    • Maple Syrup Urine Disease. Published 2017. Available at: https://rarediseases.org/rare-diseases/maple-syrup-urine-disease/. Accessed on January 19, 2021.
    • Mucolipidosis IV. Published 2014. Available at: https://rarediseases.org/rare-diseases/mucolipidosis-iv/. Accessed on January 19, 2021.
33. National Society of Genetic Counselors. Genetic Counselor Scope of Practice. Available at: https://www.nsgc.org/p/cm/ld/fid=18#scope. Accessed on January 19, 2021.
34. National Society of Genetic Counselors' Definition Task Force, Resta R, Biesecker BB, et al. A new definition of Genetic Counseling: National Society of Genetic Counselors' Task Force report. J Genet Couns. 2006; 5(2):77-83.
35. Prior TW; Professional Practice and Guidelines Committee. Carrier screening for spinal muscular atrophy. Genet Med. 2008; 10(11):840-842.
36. Ross LF, Saal HM, David KL, et al. Technical report: Ethical and policy issues in genetic testing and screening of children. Genet Med. 2013; 15(3):234-245.
37. Shen T, Dies KA, Holm IA, et al.; Autism Consortium Clinical Genetics/DNA Diagnostics Collaboration. Clinical genetic testing for patients with autism spectrum disorders. Pediatrics. 2010; 125(4):e727-e735.
38. Sherman S, Pletcher BA, Driscoll DA. Fragile X syndrome: diagnostic and carrier testing. Genet Med. 2005; 7(8):584-587.
39. 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.
40. 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.
41. U. S. Food and Drug Administration (FDA). FDA Advisory Committee Briefing Document: Spark Therapeutics, Inc. LUXTURNA^TM (voretigene neparvovec). October 27, 2017. Available at: https://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/bloodvaccinesandotherbiologics/cellulartissueandgenetherapiesadvisorycommittee/ucm579300.pdf. Accessed on January 19, 2021.
42. U.S. Food and Drug Administration (FDA). FDA News Release: FDA approves targeted treatment for rare Duchenne muscular dystrophy mutation. Updated August 12, 2020. Available at: https://www.fda.gov/news-events/press-announcements/fda-approves-targeted-treatment-rare-duchenne-muscular-dystrophy-mutation. Accessed January 19, 2021.
43. U.S. Preventive Services Task Force. Screening for hemochromatosis: recommendation statement. Ann Intern Med. 2006; 145(3):204-208.
44. Watson MS, Cutting GR, Desnick RJ, et al. Cystic fibrosis population carrier screening: 2004 revision of American College of Medical Genetics mutation panel. Genet Med. 2004; 6(5):3873-91.
45. 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 19, 2021.
46. 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.

1. American Board of Genetic Counselors. About genetic counseling. Available at: https://www.abgc.net/about-genetic-counseling/. Accessed on January 19, 2021.
2. American College of Obstetricians and Gynecologists. Frequently asked questions. FAQ179. Pregnancy. Preconception Carrier Screening (2017). Available at: https://www.acog.org/~/media/For%20Patients/faq179.pdf. Accessed on January 19, 2021.
3. National Library of Medicine (NLM). Genetics Home Reference. What are the types of genetic tests? Published March 12, 2019. Available at: https://ghr.nlm.nih.gov/primer/testing/uses. Accessed on January 19, 2021.
4. 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 19, 2021.

Becker muscular dystrophy
Bloom Syndrome
Canavan Disease
Counsyl Family Prep Screen
Cystic Fibrosis
Diagnostic genetic test
Duchenne muscular dystrophy (DMD)
Fanconi Anemia Group C
Fragile X syndrome
Gaucher's Disease
Genetic Testing, Preconception or Prenatal
GoodStart GeneVu
Inherigen
Inheritest Carrier Screen
Mucolipidosis IV
Muscular dystrophy
Niemann Pick Disease Type A
Pharmacotherapeutic genetic test
Predictive genetic test
Prognostic genetic test
Rett syndrome
Tay-Sach's Disease
Therapeutic genetic test

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.