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A.2.04.107
Carrier screening is performed to identify individuals at risk of having offspring with inherited recessive single-gene disorders. Carriers are usually not at risk of developing the disease, but can pass pathogenic variants to their offspring. Carrier testing may be performed in the prenatal or preconception periods.
Inherited Recessive Disorders
There are more than 1,300 inherited recessive disorders (autosomal or X-linked) that affect 30 out of every 10,000 children. Some diseases have limited impact on either length or quality of life, while others are uniformly fatal in childhood.
Targeted Carrier Screening
Carrier screening tests asymptomatic individuals in order to identify those who are heterozygous for serious or lethal single-gene disorders. The purpose of screening is to determine the risk of conceiving an affected child and “to optimize pregnancy outcomes based on … personal preferences and values.” Risk-based carrier screening is performed in individuals having an increased risk based on population carrier prevalence, or personal or family history. Conditions selected for screening can be based on ethnicities at high risk or may be pan-ethnic. An example of effective ethnicity-based screening involves Tay-Sachs disease, with a 90% reduction in the disease following the introduction of carrier screening in the 1970s in the United States and Canada. An example of pan-ethnic screening involves cystic fibrosis when the American College of Obstetricians and Gynecologists (ACOG) noted that ethnic intermarriage was increasing in the U.S and recommended pan-ethnic cystic fibrosis carrier screening in 2005.
Non-targeted Carrier Screening
Non-targeted carrier screening involves screening individuals or couples for disorders in many genes (up to 100s) by next-generation sequencing. Non-targeted carrier screening panels may screen for diseases that are present with increased frequency in specific populations, but also include a wide range of diseases for which the patient is not at increased risk of being a carrier. Arguments for non-targeted carrier screening include the potential to assess ethnicity, identify more potential conditions, efficiency, and cost. The conditions included in non-targeted carrier screening panels are not standardized and the panels may include many conditions not routinely evaluated and for which there are no existing professional guidelines.
This policy applies only if there is no separate policy that outlines specific criteria for carrier screening. If a separate policy exists, then criteria for medical necessity in that policy supersede the guidelines in this policy. Refer to the Genetic Testing medical policy.
Carrier screening for mitochondrial disorders associated with autosomal recessive inheritance of nuclear DNA variants is addressed in this policy. Diagnostic genetic testing for mitochondrial disorders and carrier testing of known familial variants associated with mitochondrial disorders are addressed in the Genetic Testing for Mitochondrial Disorders medical policy.
Carrier screening with the UNITY non-invasive prenatal screen to determine if the mother is a carrier for five autosomal recessive single-gene disorders (cystic fibrosis, spinal muscular atrophy, sickle cell disease, alpha thalassemia, beta thalassemia) is covered in the Noninvasive Prenatal Screening for Fetal Aneuploidies, Microdeletions, Single-Gene Disorders, and Twin Zygosity Using Cell-Free Fetal DNA medical policy. This is due to the reflex single-gene non-invasive prenatal testing of the fetus which is provided if the mother is identified as a carrier.
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Laboratories that offer LDTs must be licensed by the CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.
A number of commercially available genetic tests exist for carrier screening. They range from testing for individual diseases, to small panels designed to address testing based on ethnicity as recommended by practice guidelines (American College of Obstetricians and Gynecologists, American College of Medical Genetics and Genomics), to large non-targeted panels that test for numerous diseases.
Targeted Risk-Based Carrier Screening
Targeted carrier screening for X-linked and autosomal recessive genetic diseases is considered medically necessary for individuals who are pregnant or are considering pregnancy and are at increased risk of having offspring with an X-linked or autosomal recessive disease when ONE of the following criteria is met:
One or both individuals have a first- or second-degree relative* who is affected; OR
One individual is known to be a carrier; OR
One or both individuals are members of a population known to have a carrier rate that exceeds a threshold considered appropriate for testing for a particular condition.
AND all of the following criteria are met:
The natural history of the disease is well understood and there is a reasonable likelihood that the disease is one with high morbidity or early mortality in the homozygous or compound heterozygous state (see Policy Guidelines);
Alternative biochemical or other clinical tests to definitively diagnose carrier status are not available, or, if available, provide an indeterminate result or are individually less efficacious than genetic testing;
The genetic test has adequate clinical validity to guide decision-making and residual risk is understood;
An association of the marker with the disorder has been established;
If targeted testing is performed by a panel, the panel meets the minimum number of recommended gene variants, but does not exceed the maximum, as determined by professional clinical guidelines (see Policy Guidelines). Non-targeted panels can be used instead of targeted testing when the criteria for non-targeted carrier screening are met (see below);
Previous carrier screening or individual targeted gene testing for the gene variant(s) of interest has not been performed (see Policy Guidelines).
All targeted carrier screening not meeting any of the above criteria is considered investigational.
*First-degree relatives include a biological parent, brother, sister, or child; second-degree relatives include a biologic grandparent, aunt, uncle, niece, nephew, grandchildren, and half-sibling.
Non-Targeted Carrier Screening
Non-targeted carrier screening panels for autosomal recessive and X-linked genetic disorders may be considered medically necessary as an alternative to testing of individual genes (eg, SMN1 gene and CFTR gene) for individuals who are pregnant or are considering pregnancy at any risk level including high risk and average risk when all of the following criteria are met:
The natural history of each disease is well understood and there is reasonable likelihood that the disease is one with high morbidity or early mortality in the homozygous or compound homozygous state (see Policy Guidelines);
Alternative biochemical or other clinical tests to definitively diagnose carrier status are not available, or, if available, provide an indeterminate result or are individually less efficacious than genetic testing;
The genetic test has adequate clinical validity to guide clinical decision-making and residual risk is understood;
An association of the markers with the disorders has been established;
If testing is performed by a panel, the panel meets the minimum number of recommended gene variants but does not exceed the maximum, as determined by professional clinical guidelines (see Policy Guidelines);
Previous carrier screening has not been performed (see Policy Guidelines).
Non-targeted carrier screening panels are considered investigational in all other situations when above criteria are not met (see Policy Guidelines).
None
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
Carrier screening (targeted or non-targeted) is only medically necessary once per lifetime. Exceptions may be considered if advances in technology support medical necessity for retesting.
Targeted carrier screening for autosomal recessive or X-linked conditions is also called risk-based test or ethnic-based testing. If targeted testing is performed by a panel, the most appropriate panel code available should be used. The panel and the panel billing code should include CFTR and SMN1. If the carrier screening test is a panel less than 15 genes and does not include CFTR or SMN1, but would be 15 or more genes if including CFTR or SMN1, then it should be coded with 81443. Panels closely resembling 81443 should be billed using 81443 rather than billing individually (ie, unbundling).
Non-targeted carrier screening applies to persons of any risk including average risk. Any panel using 81443 for non-targeted carrier screening must include the CFTR and SMN1 genes. Non-targeted carrier screening panels should include the minimum number of genes but not exceed the maximum number of genes recommended by professional guidelines from the American College of Obstetricians and Gynecologists (ACOG; 2-22 conditions) or the American College of Medical Genetics and Genomics (ACMG; 113 genes).
The ACOG Committee Opinion 690 (reaffirmed in 2023) states that "Ethnic-specific, panethnic, and expanded carrier screening are acceptable strategies for prepregnancy and prenatal carrier screening" and offered the following summary pertaining to expanded carrier screening: "Given the multitude of conditions that can be included in expanded carrier screening panels, the disorders selected for inclusion should meet several of the following consensus-determined criteria: have a carrier frequency of 1 in 100 or greater, have a well-defined phenotype, have a detrimental effect on quality of life, cause cognitive or physical impairment, require surgical or medical intervention, or have an onset early in life. Additionally, screened conditions should be able to be diagnosed prenatally and may afford opportunities for antenatal intervention to improve perinatal outcomes, changes to delivery management to optimize newborn and infant outcomes, and education of the parents about special care needs after birth. Carrier screening panels should not include conditions primarily associated with a disease of adult onset."
The ACOG guideline includes a list of 22 conditions deemed reasonable to include in a carrier screening panel. While there is no agreed upon definition of severity across professional societies, these 22 conditions have severity that would be deemed profound or severe per publication based on previous work by ACMG and cited by the most recent ACMG guidelines. All but one condition deemed reasonable by ACOG (alpha-thalassemia) would be classified as profound or severe based on collaborative clinical expert application of a trait-based algorithm; however, in this work it is not clear if the alpha-thalassemia genes HBA1/HBA2 were classified based on hemoglobin Bart hydrops fetalis syndrome or hemoglobin H disease. Carrier testing of autosomal recessive genes associated with severe disease with carrier frequency of greater than 1/100 is estimated to identify 82% of at-risk couples.
In 2021, the ACMG recommended that the phrase "expanded carrier screening" be replaced by "carrier screening" as expanded carrier screening is not well or precisely defined by professional organizations. Previously, ACMG has defined expanded panels as those that use next-generation sequencing to screen for variants in many genes, as opposed to gene-by-gene screening (eg, ethnic-specific screening or panethnic testing for cystic fibrosis).
The updated ACMG guideline now recommends a multi-tier approach to carrier screening for autosomal recessive and X-linked conditions, incorporating recommendations from the ACOG Committee Opinion 691 (2017; reaffirmed in 2023), [ACOG Committee Opinion No. 691; PMID: 28225426] to enhance communication and precision while advancing equity in carrier screening (see Table 1). The consensus group recognized no accepted standard in defining the severity of various conditions; and, based on previously published work, use the following definitions: (1) profound: shortened lifespan during infancy or childhood, intellectual disability; (2) severe: death in early adulthood, impaired mobility or a [disabling] malformation involving an internal organ; (3) moderate: neurosensory impairment, immune deficiency or cancer, mental illness, dysmorphic features; and (4) mild: not meeting one of those described.
The ACMG consensus group recommends offering Tier 3 carrier screening (≥1/200 carrier frequency + Tier 2; see Table 1) to all pregnant patients and those planning a pregnancy. Carrier testing of autosomal recessive genes associated with severe disease with carrier frequency greater than 1/100 is estimated to identify 82% of at-risk couples, and identify 93% of at-risk couples when testing for genes with greater than 1/200 carrier frequency. The ACMG Tier 3 recommendations were based on estimates that moving from Tier 2 (≥1/100 carrier frequency) to Tier 3 (1/200 carrier frequency) provided additional identification of 4-9/10,000 at-risk couples depending on the endogamous population examined. When the population evaluated was weighted by U.S. census data, at-risk couples identified increased by 6 per 10,000 couples when moving from the Tier 2 (≥1/100) carrier frequency to that of Tier 3 (≥1/200). Assuming ~4 million births per year, this translates to an annual increase of identifying 2,400 additional U.S. couples.
The ACMG consensus group specified gene recommendations which include testing for 97 autosomal recessive genes and 16 X-linked genes, all of which associate with disorders of moderate, severe, or profound severity and are of 1/200 or greater carrier frequency. Non-targeted carrier screening panels that test for genes beyond this provide diminishingly small results, and pleiotropy, locus heterogeneity, variant interpretation, and poor genotype-phenotype correlation may disproportionately impact the ability to provide accurate prognostic information.
Additionally, the recommendations include that male partners of pregnant women and those planning a pregnancy may be offered Tier 3 carrier screening for autosomal recessive conditions when carrier screening is performed simultaneously with their female partner. Tier 4 screening may be offered when a pregnancy stems from a known or possible consanguineous relationship (second cousins or closer) or when family or personal medical history warrants. The ACMG does not recommend offering Tier 1 and/or Tier 2 screening, because these do not provide equitable evaluation of all racial/ethnic groups, or the routine offering of Tier 4 panels.
Testing Strategy
After testing the proband, targeted testing on the reproductive partner is preferred. Testing only applies to genes meeting criteria outlined above. If a lab does a more extensive test, then testing for other findings in the reproductive partner would not meet criteria. In general, carrier screening can be done once per lifetime. However, if only targeted or limited testing was done previously, then a more general non-targeted panel could be performed, particularly in cases where there is a new reproductive partner. In this case it is likely that genes could be re-tested.
Table 1. American College of Medical Genetics and Genomics Tiered Approach to Carrier Screening
Tier | Screening Recommendations |
1 | Cystic fibrosis + spinal muscular atrophy + risk-based screening |
2 | ≥1/100 carrier frequency + Tier 1 |
3 | ≥1/200 carrier frequency + Tier 2 (includes X-linked conditions) |
4 | <1/200 carrier frequency + Tier 3 (genes and conditions will vary by laboratory |
ACMG: American College of Medical Genetics and Genomics
X-linked genes considered appropriate for carrier screening in Tier 3 include: ABCD1, AFF2, ARX, DMD, F8, F9, FMR1, GLA, L1CAM, MID1, NR0B1, OTC, PLP1, RPGR, RS1, and SLC6A8. Refer to Tables 1 through 5 in the ACMG position statement for additional details regarding appropriate autosomal recessive conditions and their associated carrier frequencies.
Carrier screening should only be performed in adults.
Genetic Counseling
Genetic counseling is primarily aimed at patients who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex. Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, including the possible impact of the information on the individual’s family. Genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods. Carrier screening with appropriate genetic counseling is performed in adults.
Genetics Nomenclature Update
Human Genome Variation Society (HGVS) nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics. It is being implemented for genetic testing medical evidence review updates starting in 2017 (see Table 2). HGVS nomenclature is recommended by HGVS, the Human Variome Project, and the HUman Genome Organization (HUGO).
The American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP) standards and guidelines for interpretation of sequence variants represent expert opinion from ACMG, AMP, and the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table 3 shows the recommended standard terminology—“pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign”—to describe variants identified that cause Mendelian disorders.
Table 2. Nomenclature to Report on Variants Found in DNA
Previous | Updated | Definition |
Mutation | Disease-associated variant | Disease-associated change in the DNA sequence |
Variant | Change in the DNA sequence | |
Familial variant | Disease-associated variant identified in a proband for use in subsequent targeted genetic testing in first-degree relatives |
Table 3. ACMG-AMP Standards and Guidelines for Variant Classification
Variant Classification | Definition |
Pathogenic | Disease-causing change in the DNA sequence |
Likely pathogenic | Likely disease-causing change in the DNA sequence |
Variant of uncertain significance | Change in DNA sequence with uncertain effects on disease |
Likely benign | Likely benign change in the DNA sequence |
Benign | Benign change in the DNA sequence |
Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Mental Health Disorders, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:
A. consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and
B. appropriate with regard to standards of good medical practice; and
C. not solely for the convenience of the Member, his or her Provider; and
D. the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.
For the definition of medical necessity, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.
Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.
04/01/2014: Approved by Medical Policy Advisory Committee.
11/18/2014: Policy reviewed; description updated regarding laboratory testing. Policy statement unchanged. Policy guidelines updated regarding spinal muscular atrophy.
12/16/2015: Policy description updated regarding laboratory-developed tests. Policy statements unchanged. Policy guidelines updated to add medically necessary and investigative definitions.
06/07/2016: Policy number A.2.04.107 added.
06/12/2017: Policy title updated to change "Testing" to "Screening." Policy description updated with information on carrier screening. Medically necessary criteria updated for clarity. Removed the following statements: 1) The individuals have a previously affected child with the genetic disease. 2) One or both individuals have a first-degree relative with an affected offspring. Added statement to define first- and second-degree relatives. Added statement that all targeted screening not meeting any of the above criteria is considered not medically necessary. Policy statement on expanded carrier screening panels changed from not medically necessary to investigational. Policy Guidelines updated regarding the ACOG Committee Opinions, standard terminology for variant classification, and genetic counseling information.
01/18/2019: Policy description updated regarding targeted and expanded carrier screening. Policy statements unchanged.
09/04/2019: Policy description updated to remove table regarding expanded carrier screening tests. Policy statements unchanged. Table in Policy Guidelines updated.
04/13/2022: Policy description updated regarding non-targeted carrier screening. Policy section updated regarding targeted risk-based carrier screening and non-targeted carrier screening. Policy Guidelines extensively revised to add information regarding appropriate use and extent of panel testing.
11/16/2022: Policy reviewed. Medically necessary criteria for targeted risk-based carrier screening updated to add "early mortality" as an indication.
07/01/2023: Code Reference section updated to add new CPT code 0400U as investigational.
10/10/2023: Policy reviewed. Policy section updated to change "patients" to "individuals" and "not medically necessary" to "investigational." Policy Guidelines updated.
02/15/2024: Code Reference section updated to add CPT codes 0136U, 81412, 81442, and 81443.
03/27/2024: Code Reference section updated to add new CPT code 0449U, effective 04/01/2024.
10/23/2024: Policy description updated regarding the UNITY non-invasive prenatal screen. Policy statements unchanged. Policy Guidelines updated.
04/28/2025: Added link to the Genetic Testing medical policy.
Blue Cross and Blue Shield Association Policy # 2.04.107
This may not be a comprehensive list of procedure codes applicable to this policy.
Investigational Codes
Code Number | Description |
CPT-4 | |
Refer to the Genetic Testing medical policy for coverage criteria of specific procedures. | |
0136U | ATM (ataxia telangiectasia mutated) (eg, ataxia telangiectasia) mRNA sequence analysis (List separately in addition to code for primary procedure) |
0400U | Obstetrics (expanded carrier screening), 145 genes by next-generation sequencing, fragment analysis and multiplex ligation-dependent probe amplification, DNA, reported as carrier positive or negative |
0449U | Carrier screening for severe inherited conditions (eg, cystic fibrosis, spinal muscular atrophy, beta hemoglobinopathies [including sickle cell disease], alpha thalassemia), regardless of race or self-identified ancestry, genomic sequence analysis panel, must include analysis of 5 genes (CFTR, SMN1, HBB, HBA1, HBA2) (New 04/01/2024) |
81412 | Ashkenazi Jewish associated disorders (eg, Bloom syndrome, Canavan disease, cystic fibrosis, familial dysautonomia, Fanconi anemia group C, Gaucher disease, Tay-Sachs disease), genomic sequence analysis panel, must include sequencing of at least 9 genes, including ASPA, BLM, CFTR, FANCC, GBA, HEXA, IKBKAP, MCOLN1, and SMPD1 |
81442 | Noonan spectrum disorders (eg, Noonan syndrome, cardio-facio-cutaneous syndrome, Costello syndrome, LEOPARD syndrome, Noonan-like syndrome), genomic sequence analysis panel, must include sequencing of at least 12 genes, including BRAF, CBL, HRAS, KRAS, MAP2K1, MAP2K2, NRAS, PTPN11, RAF1, RIT1, SHOC2, and SOS1 |
81443 | Genetic testing for severe inherited conditions (eg, cystic fibrosis, Ashkenazi Jewish-associated disorders [eg, Bloom syndrome, Canavan disease, Fanconi anemia type C, mucolipidosis type VI, Gaucher disease, Tay-Sachs disease], beta hemoglobinopathies, phenylketonuria, galactosemia), genomic sequence analysis panel, must include sequencing of at least 15 genes (eg, ACADM, ARSA, ASPA, ATP7B, BCKDHA, BCKDHB, BLM, CFTR, DHCR7, FANCC, G6PC, GAA, GALT, GBA, GBE1, HBB, HEXA, IKBKAP, MCOLN1, PAH) |
HCPCS | |
ICD-10 Procedure | |
ICD-10 Diagnosis |
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