There are more than 1300 inherited recessive disorders (autosomal or X-linked) that affect 30 out of every 10000 children.^1, 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."^2, 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 U. S. and Canada.^3, An example of pan-ethnic screening involves cystic fibrosis when the American College of Obstetricians and Gynecologists noted that ethnic intermarriage was increasing in the U.S.^4,5, and recommended pan-ethnic cystic fibrosis carrier screening in 2005.^6,

Expanded Carrier Screening

ECS involves screening individuals or couples for disorders in many genes (up to 100s) by next-generation sequencing. ECS 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 ECS include the potential to assess ethnicity, identify more potential conditions, efficiency, and cost. Uncertain are the possible downsides of screening individuals at low-risk, including potential for incorrect variant ascertainment and the consequences of screening for rare single-gene disorders in which the likely phenotype may be uncertain (eg, due to variable expressivity and uncertain penetrance). The conditions included in ECS 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 herein.

Regulatory Status

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed by Clinical Laboratory Improvement Amendments 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 expanded panels that test for numerous diseases.

Related Policies

• None

• 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.
  
(NOTE: First-degree relatives include a biological parent, brother, sister, or child; second-degree relatives include biologic grandparent, aunt, uncle, niece, nephew, grandchildren, and half-sibling.)


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 in the homozygous or compound heterozygous state.
• 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 (see Policy Guidelines 2 section).
• An association of the marker with the disorder has been established.

The American College of Medical Genetics and Genomics 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 American College of Obstetricians and Gynecologists (ACOG) Committee Opinion 690 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" (ACOG Committee Opinion No. 690, 2017).

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 policy updates starting in 2017 (see Table PG1). 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 PG2 shows the recommended standard terminology-"pathogenic," "likely pathogenic," "uncertain significance," "likely benign," and "benign"-to describe variants identified that cause Mendelian disorders.

Table PG1. 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 PG2. 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

ACMG: American College of Medical Genetics and Genomics; AMP: Association for Molecular Pathology.


Medicare Coverage:
Per National Coverage Determination (NCD) for Cytogenetic Studies 190.3, Medicare covers cytogenetic studies when they are reasonable and necessary for the diagnosis or treatment of Genetic disorders (e.g., mongolism) in a fetus. Novitas Solutions, Inc, the Local Medicare Carrier for jurisdiction JL, has determined that germline testing for Ashkenazi Jewish disorders (CPT code 81412) is covered when all the following criteria are met:

· The beneficiary must display clinical features of an associated disease: and
· The result of the test will directly impact the treatment being delivered to the beneficiary; and
· A definitive diagnosis remains uncertain after history, physical examination, pedigree analysis, genetic counseling, and completion of conventional diagnostic studies.

For members enrolled in Medicaid and NJ FamilyCare plans, Horizon BCBSNJ applies the above medical policy.

FIDE SNP:

For members enrolled in a Fully Integrated Dual Eligible Special Needs Plan (FIDE-SNP): (1) to the extent the service is covered under the Medicare portion of the member’s benefit package, the above Medicare Coverage statement applies; and (2) to the extent the service is not covered under the Medicare portion of the member’s benefit package, the above Medicaid Coverage statement applies.

[RATIONALE: This policy was originally created in 2014 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through July 10, 2020.

Evidence reviews assess whether a medical test is clinically useful. A useful test provides information to make a clinical management decision that improves the net health outcome. That is, the balance of benefits and harms is better when the test is used to manage the condition than when another test or no test is used to manage the condition.

The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.

Targeted Risk-based Carrier Screening

Clinical Context and Test Purpose

The purpose of targeted risk-based carrier screening is to identify asymptomatic individuals who are heterozygous for serious or lethal single-gene disorders with the purpose of determining the risk of conceiving an affected child and inform reproductive decisions.

The question addressed in this policy is: Does the use of targeted risk-based carrier screening improve the net health outcome of asymptomatic individuals at risk of having offspring with inherited gene disorders?

The following PICO was used to inform literature selection.

Patients

The relevant population of interest are individuals or couples at risk for having offspring with inherited genetic disorders due to family history, ethnicity, or race.

Interventions

The intervention of interest is targeted risk-based carrier screening with genes or focused gene panels specific to risk, for example, a Jewish Askenazi panel.

Comparators

The comparator of interest is no carrier screening.

Outcomes

The primary outcome of interest is reproductive decision making

A beneficial outcome of a true test result is an informed reproductive decision that is consistent with the prospective parent(s)' personal preferences and values. Informed reproductive decisions can include those concerning preimplantation genetic diagnosis, in vitro fertilization, not having a child, invasive prenatal testing, adoption, or pregnancy termination.

A harmful outcome is a reproductive decision based on an incorrect test or assessment of the genotype-phenotype relationship. A false-positive result or incorrect genotype-phenotype association could lead to avoiding or terminating a pregnancy unnecessarily. A false-negative test could lead to an affected offspring.

Study Selection Criteria

For the evaluation of the clinical utility of targeted risk-based carrier screening for genetic disorders, studies would need to use the test to inform reproductive decisions in asymptomatic individuals who are at risk of having an offspring with inherited recessive single-gene disorders. In addition, because the American College of Obstetricians and Gynecologists (ACOG) and the American College of Medical Genetics and Genomics (ACMG) consider risk-based carrier screening an established practice, guideline recommendations from these organizations will also be included in the evidence discussion.

Technically Reliable

Assessment of technical reliability focuses on specific tests and operators and requires a review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this policy, and alternative sources exist. This policy focuses on the clinical validity and clinical utility.

Clinically Valid

The clinical validity of a carrier screening test is evaluated by its ability to predict carrier status. Clinical validity is influenced by carrier prevalence, penetrance, expressivity, and environmental factors.^1, Different variants in the same gene can result in different phenotypes (allelic heterogeneity) in most genetic disorders and impact clinical validity. Depending on the assay method (eg, next-generation sequencing, microarray), clinical sensitivity and predictive values vary according to the proportion of known pathogenic variants evaluated. Clinical sensitivity will vary according to the number of known variants tested. Additionally, not all testing strategies rely solely on genetic testing-eg, biochemical testing (hexosaminidase A) may be the initial test to screen for Tay-Sachs carrier status and blood counts for hemoglobinopathies. Finally, following a negative carrier screening test, the estimated residual risk of being a carrier reflects both the pretest probability (eg, estimated carrier prevalence in the population) and clinical validity (test clinical sensitivity and specificity). Consequently, limitations in clinical validity are quantified in residual risk estimates.

Review of Evidence

Targeted Risk-Based Screening Recommendations

ACOG and ACMG have issued numerous guidelines on targeted risk-based screening (see Table 1).

Table 1. ACOG and ACMG Recommendations for Risk-Based Screening

Society	Recommendation	Year
Cystic fibrosisa
ACOG	"Cystic fibrosis carrier screening should be offered to all women considering pregnancy or are pregnant."7,	2017
ACMG	Current ACMG guidelines use a 23-variant panel and were developed after assessing the initial experiences on implementation of cystic fibrosis screening into clinical practice. Using the 23-variant panel, the detection rate is 94% in the Ashkenazi Jewish population and 88% in the non-Hispanic white general population.8,	2013
Spinal muscular atrophyb
ACOG	"Screening for spinal muscular atrophy should be offered to all women considering pregnancy or are pregnant. In patients with a family history of spinal muscular atrophy, molecular testing reports of the affected individual and carrier testing of the related parent should be reviewed, if possible, before testing. If the reports are not available, SMN1 deletion testing should be recommended for the low-risk partner."7,	2017
ACMG	Because spinal muscular atrophy is present in all populations, carrier testing should be offered to all couples regardless of race or ethnicity.9,	2013
Tay-Sachs disease
ACOG	"Screening for Tay-Sachs disease should be offered when considering pregnancy or during pregnancy, if either member of a couple is of Ashkenazi Jewish, French-Canadian, or Cajun descent. Those with a family history consistent with Tay-Sachs disease should also be screened"7,	2017
Fragile X syndrome
ACOG	"Fragile X premutation carrier screening is recommended for women with a family history of fragile X-related disorders or intellectual disability suggestive of fragile X syndrome and who are considering pregnancy or are currently pregnant. If a woman has unexplained ovarian insufficiency or failure or an elevated follicle-stimulating hormone level before age 40 years, fragile X carrier screening is recommended to determine whether she has an FMR1 premutation."7,	2017

ACMG: American College of Medical Genetics and Genomics; ACOG: American College of Obstetricians and Gynecologists.
a Carrier rates: Ashkenazi Jews 1/24, non-Hispanic white 1/25, Hispanic white 1/58, African American 1/61, Asian American 1/94.
b General population carrier rate: 1/40 to 1/60.

The ACOG^7, and the ACMG^10, provided recommendations specific to individuals of Ashkenazi Jewish descent due to high carrier rates for multiple conditions in this population (see Table 2). According to ACMG, if only one member of the couple is Jewish, ideally, that individual should be tested first. If the Jewish partner has a positive carrier test result, the other partner (regardless of ethnic background) should be screened for that particular disorder. One Jewish grandparent is sufficient to offer testing.

Table 2. ACMG (2008, 2013) and ACOG (2017) Carrier Screening Recommendations for Individuals of Ashkenazi Jewish Descent^7,10,

Condition	Incidence (Lifetime)	Carrier Rate	ACMG (2008, 2013)	ACOG (2017)
Tay-Sachs disease	1/3000	1/30	R	R
Canavan disease	1/6400	1/40	R	R
Cystic fibrosis	1/2500-3000	1/29	R	R
Familial dysautonomia	1/3600	1/32	R	R
Fanconi anemia (group C)	1/32,000	1/89	R	C
Niemann-Pick disease type A	1/32,000	1/90	R	C
Bloom syndrome	1/40,000	1/100	R	C
Mucolipidosis IV	1/62,500	1/127	R	C
Gaucher disease	1/900	1/15	R	C
Familial hyperinsulinism		1/52		C
Glycogen storage disease type I		1/71		C
Joubert syndrome		1/92		C
Maple syrup urine disease		1/81		C
Usher syndrome		≤ 1/40		C

ACMG: American College of Medical Genetics and Genomics; ACOG: American College of Obstetricians and Gynecologists; C: should be considered; R: recommended.

Clinical Utility

Review of Evidence

The clinical utility of carrier screening is defined by the extent to which reproductive decision making or choices are informed (ie, increases "reproductive autonomy and choice"^1,). Evidence to support the clinical utility of carrier screening for conditions with the highest carrier rates (eg, Tay-Sachs disease, cystic fibrosis [CF]) among specific ethnic groups is robust concerning the effect on reproductive decision making.^3,11,12,13, For example, early studies of Tay-Sachs carrier screening in Ashkenazi Jews demonstrated a marked impact on reproductive decisions^11,13, and, after some 4 decades of ethnicity-based carrier screening, most Tay-Sachs disease cases occur in non-Jewish individuals.^12, As another example, a 2014 systematic review of CF carrier screening found that while individual carrier status "did not affect reproductive intentions or behaviors," most couple carriers terminated affected fetuses.^14, For inherited single-gene disorders where carrier rates are of similar magnitude, recommendations to offer screening have a convincing rationale, even if partially based indirectly on results from other conditions. One caveat is that family history, ethnicity, and race are self-reported, and may not be completely accurate, particularly in multi-ethnic and multi-racial societies.^15,,

Section Summary: Risk-Based Carrier Screening

Risk-based carrier screening involves testing for a defined set of pathogenic variants for specified conditions. The clinical validity is sufficiently defined and reflected in the estimated residual risk. Numerous studies have shown that reproductive decisions were affected by results from targeted risk-based carrier screening. In addition, ACOG and ACMG consider risk-based carrier screening an established practice and have issued guidance on targeted risk-based screening. There is sufficient evidence to support the clinical utility of targeted risk-based screening.

Expanded Carrier Screening

Clinical Context and Test Purpose

The purpose of ECS is to identify asymptomatic individuals who are heterozygous for serious or lethal recessive single-gene disorders with the purpose of determining the risk of conceiving an affected child and inform reproductive decisions. ECS panels screen for carrier status in a prospective or expectant parent for multiple conditions for which that individual is not known to be at risk based on family history or ethnic background.

The question addressed in this policy is: Does the use of ECS improve the net health outcome of asymptomatic individuals at either an increased risk or population risk of having offspring with inherited recessive single-gene disorders?

The following PICO was used to inform literature selection.

Patients

The relevant population of interest are individuals or couples either at increased risk or population risk for having offspring with inherited gene disorders. Individuals at elevated risk for the purposes of ECS include:

• Individuals at increased risk due to race, ethnicity, or family history.
• Families that carry a single-gene variant indicative of impairment in DNA repair mechanism.
• Individuals with a history of pregnancy loss not explained by a physiologic condition.
• History of infertility (after standard work-ups to identify cause).

The intervention of interest is ECS.

Comparators

The comparator of interest is targeted carrier screening.

Outcomes

The primary outcome of interest is reproductive decision making.

A beneficial outcome of a true test result is an informed reproductive decision that is consistent with the prospective parent(s)' personal preferences and values. Informed reproductive decisions can include those concerning preimplantation genetic diagnosis, in vitro fertilization, not having a child, invasive prenatal testing, adoption, or pregnancy termination.

A harmful outcome is a reproductive decision based on an incorrect test or assessment of the genotype-phenotype relationship. A false-positive result or incorrect genotype-phenotype association could lead to avoiding or terminating a pregnancy unnecessarily. A false-negative test could lead to an affected offspring.

Study Selection Criteria

For the evaluation of the clinical utility ECS, studies would need to use the test to inform reproductive decisions in asymptomatic individuals who are at risk of having an offspring with inherited recessive single-gene disorders. In addition, because ACOG and ACMG consider risk-based carrier screening an established practice, guideline recommendations from these organizations will also be included in the evidence discussion.

Technically Reliable

Assessment of technical reliability focuses on specific tests and operators and requires a review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this policy, and alternative sources exist. This policy focuses on the clinical validity and clinical utility.

Clinically Valid

For conditions where pathogenic variants would be included in an ECS panel, clinical validity should be demonstrated. Outside those targeted variants, pathogenicity, penetrance, and expressivity together with disease severity require accurate definition. Subsumed in clinical validity is the effect of a condition's severity on quality of life, impairments, and the need for intervention.

• ACOG (2017) made the following recommendations on ECS^16,:

Based on consensus, ACOG recommended the following criteria:

• carrier frequency ≥1/100
• well-defined phenotype
• detrimental effect on the quality of life, cause cognitive or physical impairment, require surgical or medical intervention, or have an onset early in life
• not be primarily associated with a disease of adult-onset.

Review of Evidence

Many of the genes included in ECS panels from different laboratories do not meet the prevalence criterion in all ethnic groups.^17, However, self-reports of ethnicity may not be consistent with genetic ancestry in substantial proportion of individuals, particularly in countries with intermixed ethnicity such as the United States.^15,18,19, A study by Guo and Gregg (2019) found that screening for the 40 genes that met the criterion of at least 1% prevalence in any ethnic group identified nearly all of the 2.52% of couples who would have been identified as at-risk.^20,

Studies have been reported on larger ECS panels (approximately 200 disorders) in the reproductive setting and are described in Tables 3 and 4. Terhaar et al (2018) compared positivity rates from 3 multi-gene carrier screening panels.^21, Positivity rates increased with the number of genes tested, with 7.2% positivity for trio testing, 13.2% for a standard screen, and 35.8% for a global panel. Peyser et al reported that an ECS panel identified 1243 carriers out of 4232 infertility patients (29.4%), while an ethnicity based screen would have identified 359 (8.5%). The investigators calculated that out of the 1.2% of couples who carried the pathogenic variants for the same gene, 47% would have been missed with an ethnicity-based screen.^22, In another study of patients who received ECS at a fertility clinic, 1.7% of couples were at-risk for a recessive or X-linked disorder.^23,

Several reports have been published on a commercially available 176 gene panel. The ECS panel was designed for maximizing per-disease sensitivity for diseases categorized as severe or profound. Ben-Shachar et al (2019) considered all 176 conditions in a panel to meet ACOG criteria, except for the criterion of a carrier rate exceeding 1 in 100.^24, In another analysis, medical geneticists evaluated disease severity associated with the 176 genes in the panel.^25,After evaluation of published literature and mapping according to ACOG severity criteria, the investigators concluded that 65 of the genes (36.9%) were associated with profound symptoms (shortened lifespan in infancy/childhood/adolescence and intellectual disability), 65 genes (36.9%) were associated with severe symptoms (shortened lifespan in infancy/childhood/adolescence or intellectual disability; or at least one of the following: shortened lifespan in premature adulthood, impaired mobility, internal physical manifestation with 3 or more traits: shortened lifespan in premature adulthood, impaired mobility, internal physical manifestation, sensory impairment, immunodeficiency/cancer, mental illness, or dysmorphic features), and 42 genes were associated with moderate symptoms. Moderate severity was classified as shortened lifespan in premature adulthood, impaired mobility, or internal physical manifestation; or, at least one of the following: sensory impairment, immunodeficiency/cancer, mental illness, or dysmorphic features. It is unclear if these would meet the ACOG criteria of a well-defined phenotype, a detrimental effect on quality of life, cause cognitive or physical impairment, require surgical or medical intervention, or have an onset early in life.

Other modeling studies have also estimated the incremental number of potentially affected fetuses if ECS replaced a risk-based approach. Carrier rates with ECS ranged from 19% to 36% in individuals and from 0.2% to 1.2% of couples. Westmeyer et al calculated that approximately 1 in 175 pregnancies would be affected by a disorder in a 274-gene screening panel.^19, Generally, as the size of the panel increases (risk-based to different sizes of expanded panels), the percentage of patients who are identified as carriers for any recessive disease also increases. The downstream impact similarly increases with a need for partner testing and genetic counseling.

Table 3. Relevant Clinical Validity Studies, Study Characteristics

Study	Setting	Panel	Study Design	Study Population	No. Screened	No. of Couples Screened	Disorders Screened
Terhaar et al (2018)21,	Referred for testing in a reproductive setting		Database review	51,584 samples analyzed with a trio panel 19,550 samples analyzed with a standard panel 3,902 samples analyzed with a global panel	75,036	NR	Trio = 3 Standard = 23 Global = 218
Peyser et al. 22,	Infertility clinic		Case series	All female and male patients who did not opt out	4,232	1206	100
Hernandez-Nieto et al (2020)23,	Infertility clinics in Mexico and U.S.		Case series	Patients undergoing fertility treatments were offered genetic testing.	805	391	283

ECS: expanded carrier screening; NR: not reported.
^a By obstetricians, family practitioners, geneticists, genetics counselors, perinatologists, and reproductive endocrinologists.

Table 4. Relevant Clinical Validity Studies, Results

Study	Individual Carriers, n (%)a	Couple Carriers, n (%)	Incremental Findings Over Risk-Based Testing N (95% CI)	Incremental Findings Over ACOG Recommended Screen
Terhaar et al (2018)21,	(35.8%)	NA	35.8%vs 7.2% for trio	35.8% vs 13.2% for a 23 gene panel
Peyser et al.22,	1243 (29.4%)	15 (1.2%)	884	584
Hernandez-Nieto et al (2020)23,	352 (43.7%)	17 (4.34%) 1.7% for X-linked or recessive disorders	NR

ACOG: American College of Obstetricians and Gynecologists; CI: confidence interval; NA: not applicable; NR: not reported.
^a One or more disorders.

Section Summary: Clinical Validity

Studies have found that ECS identifies more carriers and potentially affected fetuses.. Many of the genes in ECS do not meet the ACOG consensus-driven criteria of at least 1% carrier rate for all ethnic groups. However, pan-ethnic testing has also been supported by ACOG, which may address the discrepancies between self-reported ethnicity and genetic ancestry, particularly in ethnically mixed populations such as the U.S. One study calculated that a pan-ethnic panel of 40 genes with at least a 1% prevalence in any ethnicity would address nearly all of the at-risk couples. As panels become larger, the likelihood of being identified as a carrier of a rare genetic disorder increases, resulting in an at-risk couple rate of nearly 2% for a recessive or X-linked disorder. Many, though not all, of these rare genetic disorders are associated with severe or profound symptoms including shortened lifespan and intellectual or physical disability.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care.

Review of Evidence

Direct Evidence

Although direct evidence of clinical utility is optimally provided by studies that compare health outcomes for patients managed with and without the test, this is not reasonably expected for carrier screening.

Chain of Evidence

A chain of evidence that ECS offers greater clinical utility than recommended risk-based approaches, relies on clinical validity-a well-defined predictable risk that the offspring will be affected by severe phenotype-to ECS and should correctly identify more carrier couples of severe phenotype conditions than recommended risk-based screening.

Several survey studies evaluated patients' perspectives and reproductive behaviors concerning ECS (see Table 5 and 6). For couples in which both partners carried genes for the same recessive disorder, actions following ECS were reported in 60% to 91% of couples; the exact percentage depended upon the severity of disease. Frequently reported actions are prenatal screening or in vitro fertilization with preimplantation genetic diagnosis.

Clinical utility is supported by studies noted in the section above on ethnicity-based carrier testing, for which there is strong evidence of the impact of carrier screening on reproductive decision making and its effect on the prevalence of severe recessive disorders.^3,11,12,13, For ECS, a modeling study of the 176 gene panel described above found that compared with testing just for cystic fibrosis and spinal muscular atrophy, there would be a clinical impact on lifetime costs and life-years lost for 290 out of 100,000 pregnancies.^26,

Table 5. Characteristics of Observational Studies for Clinical Utility

Author (Year)	Study Type	Country	Dates	Participants	Number	Outcomes
Ghiossi (2018)27,	Retrospective survey	United States	2014 to 2015	Couples in which both partners carry genes for the same recessive disease who had received ECS	537 eligible couples,64 (12%) completed survey	Action (defined as IVF with PGD or prenatal diagnosis) No action
Johansen Taber et al (2018)28,	Retrospective survey	United States	2015 to 2017	Women for which both partners carry genes for the same recessive disease who had received ECS; 54% were for IVF	1701 eligible couples who were at risk (78 conditions), 391 women completed the survey	Reproductive planning

ECS: expanded carrier screening; IVF: in vitro fertilization; NR: not reported; PGD: preimplantation genetic diagnosis.

Table 6. Results of Observational Studies for Clinical Utility

Study (Year)	Results
Ghiossi (2018)27,	60% reported taking action (IVF with PGD or prenatal diagnosis) following ECS results 40% reported taking no action following ECS results
Johansen Taber et al (2018)28,	77% of patients screened before becoming pregnant planned or pursued actions to avoid having affected offspring (91% for a profound condition, 77% for a severe condition, and 65% for a moderate condition) 37% of patients screened during pregnancy pursued prenatal diagnostic testing Reasons for declining prenatal testing were fear of miscarriage, belief that termination would not be pursued in the event of a positive diagnosis or perception that the risk of an affected pregnancy was low.

ECS: expanded carrier screening; IVF: in vitro fertilization; PGD: preimplantation genetic diagnosis.

Section Summary: Clinical Utility

Indirect evidence on clinical utility depends on the demonstration that the genes included in ECS are associated with severe genetic disorders, as described in the section above on clinical validity. The clinical utility of ECS is the ability to affect reproductive choices such as in vitro fertilization with preimplantation genetic diagnosis or prenatal genetic testing to avoid a severe genetic disorder in the offspring. Observational studies have shown that a majority of couples would consider intervention, with a percentage choosing intervention that depends on the severity of the condition. Modeling suggests that the clinical impact of avoiding severe genetic disorders, even if rare, is high.

Summary of Evidence

For individuals who are asymptomatic but at risk for having offspring with an inherited recessive genetic disorder who receive targeted risk-based carrier screening, the evidence includes studies supporting clinical validity and clinical utility. Relevant outcomes are test validity and changes in reproductive decision making. Results of carrier testing can be used to inform reproductive decisions such as preimplantation genetic diagnosis, in vitro fertilization, not having a child, invasive prenatal testing, adoption, or pregnancy termination. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who are either at increased risk or population risk for having offspring with an inherited recessive genetic disorder who receive ECS, the evidence includes studies supporting clinical validity and clinical utility. Relevant outcomes are test validity and changes in reproductive decision making. Studies have found that ECS identifies more carriers and more potentially affected fetuses. Many of the genes in ECS do not meet the ACOG consensus-driven criteria of at least 1% carrier rate for all ethnic groups. However, panethnic testing can address the discrepancies between self-reported ethnicity and genetic ancestry in an ethnically mixed population. As panels become larger the likelihood of being identified as a carrier of a rare genetic disorder increases, leading to an at-risk couple rate of nearly 2% for having an offspring with a recessive or X-linked disorder. Many, though notably not all, of these rare genetic disorders are associated with severe or profound symptoms including shortened lifespan and intellectual or physical disability. With adequate genetic counseling ECS can inform reproductive choices, and observational studies have shown that a majority of couples would consider intervention that depends on the severity of the condition. Panethnic carrier screening for severe recessive and X-linked genetic disorders can have a significant clinical impact. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

SUPPLEMENTAL INFORMATION

Practice Guidelines and Position Statements

American College of Obstetricians and Gynecologists

In 2017, the American College of Obstetricians and Gynecologists (ACOG) made the following recommendations on expanded carrier screening (ECS)^16,:

"Ethnic-specific, pan-ethnic, and expanded carrier screening are acceptable strategies for prepregnancy and prenatal carrier screening. Each obstetrician-gynecologist or other health care provider or practice should establish a standard approach that is consistently offered to and discussed with each patient, ideally before pregnancy. After counseling, a patient may decline any or all carrier screening."

"Expanded carrier screening does not replace previous risk-based screening recommendations."

Based on "consensus," characteristics of included disorders should meet the following criteria:

• carrier frequency ≥1/100
• well-defined phenotype
• detrimental effect on the quality of life, cause cognitive or physical impairment, require surgical or medical intervention, or have an onset early in life
• not be primarily associated with a disease of adult-onset.

In 2015, a joint statement on ECS was issued by ACOG, the American College of Medical Genetics and Genomics, the National Society of Genetic Counselors, the Perinatal Quality Foundation, and the Society for Maternal-Fetal Medicine.^2, The statement was not intended to replace current screening guidelines but to demonstrate an approach for health care providers and laboratories seeking to or currently offering ECS panels. Some points considered included the following.

"Expanded carrier screening panels include most of the conditions recommended in current guidelines. However, molecular methods used in expanded carrier screening are not as accurate as methods recommended in current guidelines for the following conditions:

• Screening for hemoglobinopathies requires use of mean corpuscular volume and hemoglobin electrophoresis.
• Tay-Sachs disease carrier testing has a low detection rate in non-Ashkenazi populations using molecular testing for the 3 common Ashkenazi mutations. Currently, hexosaminidase A enzyme analysis on blood is the best method to identify carriers in all ethnicities."

The statement also included a set of recommendations for screened conditions:

• "The condition being screened for should be a health problem that encompasses one or more of the following:
  • Cognitive disability.
  • Need for surgical or medical intervention.
  • Effect on quality of life.
  • Conditions for which a prenatal diagnosis may result in:
    • Prenatal intervention to improve perinatal outcome and immediate care of the neonate.
    • Delivery management to optimize newborn and infant outcomes such as immediate, specialized neonatal care.
    • Prenatal education of parents regarding special needs care after birth; this often may be accomplished most effectively before birth."

In 2013, the American College of Medical Genetics and Genomics issued a position statement on prenatal/preconception expanded carrier testing.^29, For a particular disorder to be included in carrier screening, the following criteria should be met:

"1. Disorders should be of a nature that most at-risk patients and their partners identified in the screening program would consider having a prenatal diagnosis to facilitate making decisions surrounding reproduction.
• The inclusion of disorders characterized by variable expressivity or incomplete penetrance and those known to be associated with a mild phenotype should be optional and made transparent when using these technologies for screening. This recommendation is guided by the ethical principle of nonmaleficence.
2. When adult-onset disorders (disorders that could affect offspring of the individual undergoing carrier screening once offspring reach adult life) are included in screening panels, patients must provide consent to screening for these conditions, especially when there may be implications for the health of the individual being screened or for other family members.
• This recommendation follows the ethical principles of autonomy and nonmaleficence.
3. For each disorder, the causative gene(s), mutations, and mutation frequencies should be known in the population being tested, so that meaningful residual risk in individuals who test negative can be assessed.
• Laboratories should specify in their marketing literature and test results how residual risk was calculated using pan-ethnic population data or a specific race/ethnic group.
• The calculation of residual risk requires knowledge of 2 factors: one is the carrier frequency within a population, the other is the proportion of disease-causing alleles detected using the specific testing platform. Laboratories using multiplex platforms often have limited knowledge of one or both factors. Laboratories offering expanded carrier screening should keep data prospectively and regularly report findings that allow computation of residual risk estimates for all disorders being offered. When data are inadequate, patient materials must stress that negative results should not be overinterpreted.
4. There must be validated clinical association between the mutation(s) detected and the severity of the disorder.
• Patient and provider materials must include specific citations that support inclusion of the mutations for which screening is being performed.
5. Compliance with the American College of Medical Genetics and Genomics Standards and Guidelines for Clinical Genetics Laboratories, including quality control and proficiency testing.
• Quality control should include the entire test process, including preanalytical, analytical, and postanalytical phases. Test performance characteristics should be available to patients and providers accessing testing.

U.S. Preventive Services Task Force Recommendations

The U.S. Preventive Services Task Force makes recommendations for carrier testing for BRCA-associated genetic diseases and for hereditary hemochromatosis, topics that are not included herein but are in evidence reviews for each condition.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this review are listed in Table 7.

Table 7. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
NCT04157595	Mackenzie's Mission: The Australian Reproductive Carrier Screening Project	20,000	Dec 2022
Unpublished
NCT02742116	Evaluation of the Implementation of Expanded Carrier Screening Before Pregnancy in Hong Kong	100	Oct 2016
NCT01902901	Clinical Implementation of Carrier Status Using Next Generation Sequencing	384	May 2018

NCT: national clinical trial.]
________________________________________________________________________________________

Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

___________________________________________________________________________________________________________________________

Index:
Carrier Screening for Genetic Diseases
Carrier Testing for Genetic Diseases
Genetic Carrier Status Testing
Counsyl™
GoodStart Select™
Inherigen™
Inheritest™
Natera One™ Disease Panel

References:
1. Henneman L, Borry P, Chokoshvili D, et al. Responsible implementation of expanded carrier screening. Eur J Hum Genet. Jun 2016; 24(6): e1-e12. PMID 26980105

2. 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. Mar 2015; 125(3): 653-62. PMID 25730230

3. Kaback MM. Population-based genetic screening for reproductive counseling: the Tay-Sachs disease model. Eur J Pediatr. Dec 2000; 159 Suppl 3: S192-5. PMID 11216898

4. Banda Y, Kvale MN, Hoffmann TJ, et al. Characterizing Race/Ethnicity and Genetic Ancestry for 100,000 Subjects in the Genetic Epidemiology Research on Adult Health and Aging (GERA) Cohort. Genetics. Aug 2015; 200(4): 1285-95. PMID 26092716

5. Grant MD, Lauderdale DS. Cohort effects in a genetically determined trait: eye colour among US whites. Ann Hum Biol. Nov-Dec 2002; 29(6): 657-66. PMID 12573082

6. Committee on Genetics, American College of Obstetricians and Gynecologists. ACOG Committee Opinion. Number 325, December 2005. Update on carrier screening for cystic fibrosis. Obstet Gynecol. Dec 2005; 106(6): 1465-8. PMID 16319281

7. Rink B, Romero S, Biggio JR, et al. Committee Opinion No. 691: Carrier Screening for Genetic Conditions. Obstet Gynecol. Mar 2017; 129(3): e41-e55. PMID 28225426

8. 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. Sep-Oct 2004; 6(5): 387-91. PMID 15371902

9. Prior TW. Carrier screening for spinal muscular atrophy. Genet Med. Nov 2008; 10(11): 840-2. PMID 18941424

10. Gross SJ, Pletcher BA, Monaghan KG. Carrier screening in individuals of Ashkenazi Jewish descent. Genet Med. Jan 2008; 10(1): 54-6. PMID 18197057

11. Burke W, Tarini B, Press NA, et al. Genetic screening. Epidemiol Rev. 2011; 33: 148-64. PMID 21709145

12. Bajaj K, Gross SJ. Carrier screening: past, present, and future. J Clin Med. Sept 2015 2014;3(3):1033-1042. PMC4449659

13. Kaback M, Lim-Steele J, Dabholkar D, et al. Tay-Sachs disease--carrier screening, prenatal diagnosis, and the molecular era. An international perspective, 1970 to 1993. The International TSD Data Collection Network. JAMA. Nov 17 1993; 270(19): 2307-15. PMID 8230592

14. Ioannou L, McClaren BJ, Massie J, et al. Population-based carrier screening for cystic fibrosis: a systematic review of 23 years of research. Genet Med. Mar 2014; 16(3): 207-16. PMID 24030436

15. Shraga R, Yarnall S, Elango S, et al. Evaluating genetic ancestry and self-reported ethnicity in the context of carrier screening. BMC Genet. Nov 28 2017; 18(1): 99. PMID 29179688

16. Romero S, Rink B, Biggio JR, et al. Committee Opinion No. 690: Carrier Screening in the Age of Genomic Medicine. Obstet Gynecol. Mar 2017; 129(3): e35-e40. PMID 28225425

17. Stevens B, Krstic N, Jones M, et al. Finding Middle Ground in Constructing a Clinically Useful Expanded Carrier Screening Panel. Obstet Gynecol. Aug 2017; 130(2): 279-284. PMID 28697118

18. Kaseniit KE, Haque IS, Goldberg JD, et al. Genetic ancestry analysis on 93,000 individuals undergoing expanded carrier screening reveals limitations of ethnicity-based medical guidelines. Genet Med. Jun 29 2020. PMID 32595206

19. Westemeyer M, Saucier J, Wallace J, et al. Clinical experience with carrier screening in a general population: support for a comprehensive pan-ethnic approach. Genet Med. Aug 2020; 22(8): 1320-1328. PMID 32366966

20. Guo MH, Gregg AR. Estimating yields of prenatal carrier screening and implications for design of expanded carrier screening panels. Genet Med. Sep 2019; 21(9): 1940-1947. PMID 30846881

21. Terhaar C, Teed N, Allen R, et al. Clinical experience with multigene carrier panels in the reproductive setting. Prenat Diagn. Apr 23 2018. PMID 29683194

22. Peyser A, Singer T, Mullin C, et al. Comparing ethnicity-based and expanded carrier screening methods at a single fertility center reveals significant differences in carrier rates and carrier couple rates. Genet Med. Jun 2019; 21(6): 1400-1406. PMID 30327537

23. Hernandez-Nieto C, Alkon-Meadows T, Lee J, et al. Expanded carrier screening for preconception reproductive risk assessment: Prevalence of carrier status in a Mexican population. Prenat Diagn. Apr 2020; 40(5): 635-643. PMID 32003480

24. Ben-Shachar R, Svenson A, Goldberg JD, et al. A data-driven evaluation of the size and content of expanded carrier screening panels. Genet Med. Sep 2019; 21(9): 1931-1939. PMID 30816298

25. Arjunan A, Bellerose H, Torres R, et al. Evaluation and classification of severity for 176 genes on an expanded carrier screening panel. Prenat Diagn. May 31 2020. PMID 32474937

26. Beauchamp KA, Johansen Taber KA, Muzzey D. Clinical impact and cost-effectiveness of a 176-condition expanded carrier screen. Genet Med. Sep 2019; 21(9): 1948-1957. PMID 30760891

27. Ghiossi CE, Goldberg JD, Haque IS, et al. Clinical Utility of Expanded Carrier Screening: Reproductive Behaviors of At-Risk Couples. J Genet Couns. Jun 2018; 27(3): 616-625. PMID 28956228

28. Johansen Taber KA, Beauchamp KA, Lazarin GA, et al. Clinical utility of expanded carrier screening: results-guided actionability and outcomes. Genet Med. May 2019; 21(5): 1041-1048. PMID 30310157

29. Grody WW, Thompson BH, Gregg AR, et al. ACMG position statement on prenatal/preconception expanded carrier screening. Genet Med. Jun 2013; 15(6): 482-3. PMID 23619275

Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*

81412
81443
81479