Preconception and prenatal panethnic expanded carrier screening

INTRODUCTION — Individuals/couples may undergo carrier screening for genetic conditions before or during pregnancy. The purpose is to:

●Identify individuals/couples who carry variants associated with genetic diseases and thus at risk of transmitting a heritable disorder to their offspring.

●Provide appropriate reproductive counseling.

●Enhance reproductive autonomy.

●In ongoing pregnancies with an affected fetus, provide appropriate prenatal care and newborn management.

There are a variety of strategies for carrier screening (see 'Terminology' below). This topic will discuss issues related to panethnic expanded carrier screening for individuals/couples planning pregnancy or who are pregnant. However, carrier screening may be performed at any stage of life: newborn, childhood, premaritally, or opportunistically when the individual is undergoing laboratory testing for another reason.

Genetic screening in high-risk populations (eg, individuals with a personal or family history of a specific genetic condition) and selective screening for specific genetic conditions are reviewed separately. For example:

●(See "Genetic counseling: Family history interpretation and risk assessment".)

●(See "Preconception and prenatal carrier screening for genetic disorders more common in people of Ashkenazi Jewish descent and others with a family history of these disorders".)

●(See "Down syndrome: Overview of prenatal screening".)

●(See "Fragile X syndrome: Prenatal screening and diagnosis".)

●(See "Cystic fibrosis: Carrier screening".)

●(See "Spinal muscular atrophy".)

TERMINOLOGY

●Genetic carrier screening refers to screening asymptomatic individuals/couples to identify those who are heterozygous carriers of specific autosomal recessive or sex-linked conditions.

Historically, the approach to preconception and prenatal genetic carrier screening has been selective (ie, condition-directed or targeted) and based primarily on race/ethnicity or family history. However, a panethnic approach (ie, without regard to race or ethnicity; also called universal approach) is increasingly being utilized. (See 'Benefits and limitations' below.)

●Expanded genetic carrier screening refers to the practice of simultaneously screening for a large number of genetic conditions without consideration of reported race/ethnicity [1]. Numerous laboratories offer panels ranging from several to hundreds of disorders. Increased use of expanded carrier screening has been enabled by decreasing costs and rapid advancements in genetic testing technologies, such as next-generation sequencing (NGS). NGS uses parallel sequencing of multiple small DNA fragments to determine sequence. It can test for genetic variants across multiple genes simultaneously, accurately, and cost-effectively. (See "Next-generation DNA sequencing (NGS): Principles and clinical applications".)

Historically, expanded panel testing was only utilized for the genetic conditions observed at an increased frequency within a specific high-risk group (individuals of Ashkenazi Jewish descent). However, a panethnic approach is increasingly being utilized. (See 'Benefits and limitations' below.)

BENEFITS AND LIMITATIONS

Benefits — Benefits of a panethnic expanded carrier screening strategy compared with traditional carrier screening are discussed below.

Increased reproductive autonomy — Preconception identification of carriers of genetic disorders provides an opportunity for parental education regarding their risk of having an affected offspring, its prognosis, and their reproductive options. (See 'Patient counseling' below.)

Prenatal identification of carriers provides an opportunity for parental education regarding their risk of having an affected offspring and its prognosis, fetal diagnosis (when desired and indicated), reproductive options, and modification of pregnancy management with affected fetus, including planning for birth at a tertiary care facility if indicated. This could lead to reduction in diagnostic cost and time, earlier treatment, avoidance of unnecessary treatments, and potentially in utero treatment [2-4].

Identification of carriers regardless of race/ethnicity — Carriers may not be identified with traditional screening strategies because many individuals:

●Have a multiracial/multiethnic background, thus they may not be identified as belonging to a high-risk racial/ethnic group.

●Are unaware of their full ancestry or true race/ethnicity (increasing population intermixing confounds what many people believe to be their race/ethnicity). In a 2020 review including >90,000 individuals undergoing expanded carrier screening, 9 percent had >50 percent genetic ancestry from an ethnicity inconsistent with their self-reported ethnicity [5].

Furthermore, genetic conditions do not occur exclusively in specific racial/ethnic groups. It is increasingly difficult to assign a single race/ethnicity to individuals in the modern global society. For example:

●Up to 12 percent of infants born with a hemoglobinopathy identified via newborn testing in California in the 1990s did not belong to one of the groups targeted by the then-contemporary American College of Obstetricians and Gynecologists (ACOG) ethnic-based carrier screening guideline [6].

●In the largest observational study of routine recessive disease carrier screening (a multiethnic population of >23,000 individuals), 76.7 percent of carriers would have been missed by ACOG's traditional ethnic-based guideline in place at the time of the study (2013) [7]. With panethnic screening, 24 percent of individuals were identified as carriers for at least one disorder, and 5.2 percent were carriers for multiple disorders on the 108 disorder panel.

Identification of carriers with a negative family history and normal fetal sonogram — Carriers may not be identified with traditional screening because:

●They have no family history of the genetic disorder(s) that they carry. This is common for rare disorders. With expanded carrier screening, a single laboratory panel can screen for hundreds of Mendelian disorders simultaneously, which could provide a potentially cost-effective means of identifying carriers for rare Mendelian disorders in the general population [8]. Although relatively rare, Mendelian disorders have been reported to account for 20 percent of infant mortality and 18 percent of infant hospitalizations in the United States [9]. Disorders with significant health disabilities also impact the individual's and family's quality of life.

●They have a normal second-trimester fetal ultrasound examination. Although some single gene disorders can be associated with abnormal fetal findings on routine second-trimester ultrasound examination, many are not, or the findings are subtle or transient. Expanded carrier screening provides an opportunity to identify individuals at risk for an affected offspring who might otherwise not have been identified by a fetal ultrasound finding in the absence of a known family history.

Other benefits — Other benefits of panethnic expanded screening are that [10]:

●It avoids potential ethnic/racial stigmatization.

●It removes patient and clinician responsibility for recognizing higher risk status.

Harms and limitations — Harms and limitations of a panethnic expanded carrier screening strategy compared with traditional carrier screening are discussed below.

Unproven improvement in reproductive outcome — At the population level, panethnic expanded carrier screening has not been proven to improve reproductive outcomes (eg, increased frequency of live birth) compared with single condition screening offered to high-risk groups based on ancestry and family history. Clinical validation studies of population screening using large panels are needed.

Identification of conditions of limited impact, uncertain prevalence, or variable, poorly defined phenotype — The preconception/prenatal panels that commercial laboratories offer for expanded carrier screening include some disorders that result in only mild to moderate (rather than severe) health complications (eg, methylenetetrahydrofolate reductase [MTHFR] gene variant), have significant variations in or poorly defined phenotype (eg, hereditary hemochromatosis), or have onset in adulthood (eg, BRCA1/BRCA2 testing for hereditary breast and ovarian cancer susceptibility). In addition, the frequency of some conditions is unknown in the general population or within specific ethnic groups, rendering calculation of residual risk after a positive test inconclusive.

As the number of disorders included on a panel increases, the likelihood of identifying a carrier increases. As a result, more than half of patients screened with large panels may be found to be carriers for one or more disorders [7,11,12]. In one study in which nearly 24,000 patients were screened using a panel with 417 pathogenic variants associated with 108 recessive disorders, on average, 24 percent of individuals were positive for at least one condition and, when stratified by self-reported ethnicity, the frequency ranged from 44 percent of Ashkenazi Jewish individuals to 8.5 percent of East Asian individuals [7].

Use of panels with low-frequency conditions or a large number of genes may have downstream costs for additional laboratory testing. This increases the time and complexity of counseling, and thus may increase patient anxiety. (See 'Choosing a laboratory and screening panel' below.)

Identification of variants of uncertain clinical significance — Sequencing technologies may identify variants of uncertain clinical significance (VUS), which are a change in the gene with unknown significance to function and/or health. These are more likely to be identified if the laboratory performs diagnostic sequencing in lieu of detection for specific pathogenic variants. With additional bioinformatics and data, a VUS could eventually be reclassified to be either deleterious or benign.

Although most laboratories do not reveal VUS in clinical reports, this practice is without oversight and not uniform. Variant interpretation is subjective, with laboratories developing their own tools, data mining of public repositories, and functional analysis with minimal guidance from governing bodies (eg, the American College of Medical Genetics and Genomics [ACMG] or the Association for Molecular Pathology) on variant interpretation, clinical validity, or utility [13]. VUS can cause patient anxiety despite counseling, which is complex and time-consuming. Potential psychosocial consequences from medical uncertainty of a VUS result is important to consider in both pre- and posttest counseling.

Lack of detection of private or unique pathogenic variants — Targeted high-throughput pathogenic variant analysis for specific pathogenic variants known to be associated with a particular disease has the potential to miss pathogenic variants that are private or unique within a family or ethnic group. Although the majority of laboratories now use comprehensive sequencing to minimize this risk, a few continue to use targeted variant analysis; therefore, providers should identify the molecular technology utilized by their chosen laboratory.

Identification of variants with personal health risks for the carrier — Although the primary goal of screening is to identify risks for offspring, disorders that pose a personal health risk for the carrier may be detected [14,15]. For example, carriers of the fragile X premutation are at increased risk for premature ovarian insufficiency and early-onset ataxia syndrome. Carriers of BRCA1/BRCA2 are at increased risk for hereditary breast and ovarian cancer and other conditions.

Identification of X-linked conditions — The frequency of X-linked genes across populations is not known. There are no data or guidance on how to accurately provide pretest counseling to individuals who may discover unanticipated information about their health beyond reproductive risk for the pregnancy when X-linked conditions are included in an expanded panel.

Other

●The cost-effectiveness of a panethnic expanded approach to carrier screening has not been established compared with traditional targeted screening. It requires more resources for counseling, which can make implementation costly and difficult.

●Preconception carrier screening is not always possible because it is estimated that 20 percent of pregnancies are unplanned. Carrier screening during pregnancy has time pressures regarding scheduling, testing, and obtaining results to maximize reproductive options.

SCREENING PANELS

Which conditions should be included in carrier screening panels? — Guidelines from professional organizations typically recommend screening for conditions that are associated with one or more of the following [16-19]:

●A well-defined genotype and phenotype.

●A high carrier frequency that is known within the screened population. The disease frequency should be known so that residual risk can be calculated.

●A deleterious effect on quality of life:

•Cognitive or physical impairment

•Need for significant surgical treatment or medical intervention throughout life

•Decreased life expectancy

●Fetal, neonatal, or early childhood onset.

●Test availability for fetal diagnosis.

●Availability of prenatal interventions to improve perinatal outcome and/or availability of delivery interventions to optimize newborn and infant outcome.

In a 2017 review of conditions included on commercial expanded carrier screening panels available in the United States, only 27 percent of the conditions included in the panels overall met these criteria for inclusion [20].

Which conditions should not be screened for? — Experts generally discourage genetic carrier screening for the following conditions. Including these types of disorders in a reproductive screening panel is in direct conflict with accepted clinical criteria for reproductive screening programs.

●Conditions with adult onset. Some adult-onset conditions may sometimes present during childhood (eg, alpha-1 antitrypsin deficiency). For these conditions, ideally molecular testing should be available that can distinguish between childhood and adult onset.

●Conditions for which the natural history is unknown or poorly established.

●Conditions that occur with a very low frequency.

●Conditions with variants that have high allele frequencies but low penetrance of a phenotype (eg, methylene tetrahydrofolate reductase variants).

●Conditions in which screening performance may be better with nonmolecular screening techniques (eg, screening for sickle cell trait by hemoglobin electrophoresis).

•The techniques used in expanded carrier screening test panels are not yet recommended to replace alternative screening modalities, specifically for hemoglobinopathy screening and for Tay Sachs screening in individuals not of Ashkenazi Jewish ancestry. Please note that for individuals of Ashkenazi ancestry, gene sequencing of the common alleles is reasonable as it will detect >98 percent of Tay Sachs carriers.

•Mean corpuscular volume, mean corpuscular hemoglobin, and protein chemistry methods are used as first-line tests for hemoglobinopathy screening because of limitations of molecular testing (eg, molecular testing panels for screening include the more common hemoglobinopathy genes in the population, such as sickle cell and beta thalassemia). However, hemoglobin electrophoresis may not be able to detect pathogenic variants in specific families with beta thalassemia, alpha thalassemia silent carrier, or ascertain the arrangements of the deletions (cis or trans) in alpha thalassemia. (See "Hemoglobinopathy: Screening and counseling in the reproductive setting and fetal diagnosis".)

•Although emerging data suggest clinical validity for gene sequencing of hexosaminidase A (HEXA) associated with Tay Sachs disease, HEXA enzyme testing remains a recommended strategy for those with non-Jewish or mixed ancestry [21-23]. Genetic testing for Tay Sachs disease may target the three common pathogenic variants most often causative of disease within the known Ashkenazi Jewish population. HEXA enzyme testing is the optimal method to identify carriers in panethnic population screening, non-Jewish individuals, or individuals with mixed ancestry (fewer than four Ashkenazi Jewish grandparents). (See "Preconception and prenatal carrier screening for genetic disorders more common in people of Ashkenazi Jewish descent and others with a family history of these disorders", section on 'Tay-Sachs disease'.)

Choosing a laboratory and screening panel — Clinicians and patients have many choices when choosing a laboratory and panel for expanded carrier screening. Panel composition markedly varies among laboratories (and even within the same laboratory), no laboratory offers a panel that is clearly superior, and there is no accepted standard or guideline for laboratories to determine which disorders to include. Commercial laboratories offer test panels that screen for anywhere from a few to up to several hundred disorders. The majority are autosomal recessive, but some may be X-linked or autosomal dominant single gene disorders. Selection of the disorders in the panel is generally based on gene frequency and inclusion of the pathogenic variants associated with a disorder that contribute to the highest detection of carriers; however, the panel may include pathogenic variants for which there are few supportive data other than a single published report.

When choosing a laboratory and panel:

●It is important to ensure that the laboratory provides a clear description of the process used for including/excluding specific genes in the panel. For each panel, the laboratory should provide information on the carrier frequency in the general population and in specific racial/ethnic groups for the conditions offered within the panel so that the clinician and patient can determine whether or not the panel is appropriate.

The American College of Obstetricians and Gynecologists has published an example of an expanded panel with this information [16].

The American College of Medical Genetics and Genomics (ACMG) has lists of autosomal recessive conditions having a carrier frequency ≥1 in 200 and X-linked conditions in their practice resource [24]. This results in a panel of 113 conditions.

●The method used for gene identification should also be provided because it may influence the residual risk for a negative result. Some laboratories offer complete sequencing of a gene (ie, assessment of the entire DNA sequence of the gene) via next-generation methodologies. Some laboratories offer targeted high-throughput pathogenic variant analysis to detect specific deleterious changes in a gene or genes (ie, genotype) known to be associated with a particular disease. Although race/ethnicity is increasingly difficult to characterize, some patients are certain of their race/ethnicity and want targeted information. (See "Next-generation DNA sequencing (NGS): Principles and clinical applications".)

PATIENT COUNSELING

Pretest counseling — Pretest counseling and informed consent should include a broad discussion of the benefits and limitations of genetic screening and the types of conditions included in the carrier screening panel. The goals of pretest counseling are to provide education, personalized and nondirective information about testing options, and facilitate informed consent. Referral to a provider with genetics expertise can meet the patient's need for information and mitigate the obstetric provider's workflow pressures in the office.

The major components of pretest counseling, as recommended by a variety of professional organizations, include [16,17,21,25]:

●Making it clear at the beginning of the discussion that genetic testing is optional.

●Reviewing the baseline risk of having a child with a congenital anomaly or intellectual disability, which is 3 to 4 percent in the general population [26].

●Explaining that screening and diagnostic testing options are available to all individuals and clarifying the difference between the two types of testing.

●Explaining that there are >1000 known autosomal recessive conditions and that every individual is likely to be a carrier for at least one of these conditions; however, the chances that both prospective parents are carriers for the same condition is extremely low for most of these conditions.

●Using neutral and nonjudgmental language to broadly describe the types of conditions screened for by the chosen panel and explaining that some conditions may have poorly-defined or variable phenotypes. However, it is neither practical nor necessary to fully explain all of the clinical and test characteristics of each condition in a panel that contains dozens or even hundreds of conditions [17].

●Reviewing the risks, benefits, and limitations of screening, including the possibility for variants of unknown clinical significance and unanticipated and incidental findings, including rare but recognized health risks to an identified carrier. (See 'Harms and limitations' above.)

●Discussing that positive results can have implications related to the current/future health status of the patient and their family members (eg, detecting that the patient has an autosomal dominant gene for a late-onset disorder). (See "Genetic testing", section on 'Disclosure to family members'.)

●Explaining the concept of residual risk (ie, that a negative carrier screen result reduces the likelihood that the patient is a carrier, but there remains a residual risk that may or may not be quantifiable based on the prevalence or pathogenic variant frequency of the condition).

●Explaining that a positive or high-risk screening result does not mean that the fetus is affected. Paternal screening, prenatal diagnostic testing, and/or postnatal diagnostic testing may be necessary to make a definitive diagnosis. Discuss possible consequences if the biologic father is not available for testing and refer patients to a provider with genetic expertise for counseling on reproductive risk and diagnostic testing options.

●Addressing the issue of cost prior to testing. Cost and insurance coverage vary and cost may be an important a factor in the decision-making process for an individual patient. The patient can obtain cost coverage information from their insurer to avoid unexpected large costs.

●Discussing how and when results will be confidentially disclosed. Results of expanded carrier screening are genetic information that is confidential. Providers are obligated to follow all Health Insurance Portability and Accountability Act (HIPAA) regulations.

Posttest counseling

●Provide posttest counseling in a nondirective and objective manner by the process that was outlined with the patient during pretest counseling [25,27].

●Discuss negative predictive value or residual risk for negative or low-risk test results.

●Discuss implications of positive or high-risk screening results; written information can be helpful:

•Explain the significance of the result, including information about the condition and options for ongoing management.

•For autosomal recessive conditions, the biologic father should be screened. The father could elect to limit testing to the gene or genes with pathogenic variants identified in the mother, and should undergo sequencing of the entire gene (not targeted mutation analysis) to obtain comprehensive reproductive information. If both parents are identified as carriers of an autosomal recessive condition, genetic counseling by a certified genetics professional is indicated.

If the biologic father has a negative carrier screen for an autosomal recessive condition and the mother has a positive screen, the likelihood of an affected pregnancy is significantly reduced but not eliminated and further testing is not usually offered. Residual risk should be determined, if possible.

Genetic counseling by a certified genetics professional is also indicated for autosomal dominant and X-linked conditions.

•When results of parental screening indicate offspring are at risk for the genetic condition (not an asymptomatic carrier), issues include:

-Preconception planning, which may involve preimplantation genetic testing (which requires conception by in vitro fertilization) or use of noncarrier donated gametes. Remaining childless, adoption, and accepting the chance of having an affected child are other options.

-Prenatal (fetal) diagnosis is an option during pregnancy, and involves amniocentesis or chorionic villus sampling.

-Management of pregnancies with an affected fetus, including prenatal care, delivery planning, and newborn care. Pregnancy termination is also an option.

•Discuss potential implications for other family members [17,25].

IS RESCREENING RECOMMENDED BEFORE A SUBSEQUENT PREGNANCY? — Carrier rescreening typically is not offered or recommended unless the individual's/couple's medical history or family history has changed [17]. However, screening panels and molecular techniques have changed over time, with potential differences in the conditions screened for and the interpretation of both pathogenic or benign results. Ongoing research is necessary to best determine on a population level how expanded carrier testing should be integrated into clinical care for the cohort of patients with previous targeted or racial/ethnic-based testing.

If a patient requests repeat carrier screening, we recommend referral to a provider with genetics expertise to review previous testing and determine the limitations and benefits of this request.

DIRECT-TO-CONSUMER GENETIC TESTING — Individuals who are considering direct-to-consumer genetic testing should receive counseling to review the test's potential benefits, risks, and limitations. A general discussion of issues regarding concerns about the accuracy, interpretation, and value of such testing is presented separately. (See "Personalized medicine", section on 'Direct-to-consumer testing'.)

The American College of Obstetricians and Gynecologists has published guidance for obstetrician-gynecologists who encounter patients who present with direct-to-consumer genetic test results [28]. Such patients should be counseled by a health care professional with the appropriate knowledge, training, and experience in interpreting test results. Confirmatory testing in a clinical laboratory is generally recommended prior to any medical intervention.

SELECTED MEDICAL SOCIETY GUIDELINES

●American College of Obstetricians and Gynecologists (ACOG) – In 2020, an ACOG committee opinion concluded that ethnic-specific, panethnic, and expanded carrier screening are all acceptable strategies [16]. ACOG suggested that obstetric providers determine a standard approach for their practice, but consider an individual's desire for genetic information based on their personal values and preferences. Patients who request a screening strategy other than the one used by their health care provider should have the option of utilizing that strategy after receiving counseling on its limitations, benefits, and alternatives.

For individuals who choose expanded carrier screening, ACOG advises the disorders selected for inclusion in a panel should meet several consensus-determined criteria: carrier frequency ≥1 in 100, 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 [16]. In addition, prenatal diagnosis for the disorder should be available.

●American College of Medical Genetics and Genomics (ACMG) – In 2021, the ACMG recommended offering all pregnant patients and those planning a pregnancy carrier screening paradigms that are panethnic and population nonselective to promote equity and inclusion [24]. They pointed out that screening based on socially defined ethnic constructs or by self-identified ancestry is both inequitable and scientifically flawed, thus carrier screening should go beyond commonly recognized at-risk groups and include diverse populations. They also recommended an expanded approach: screening for 97 autosomal recessive and 16 X-linked conditions that have a carrier frequency ≥1 in 200 (described by ACMG as "tier 3" conditions). Lists of these conditions were provided in the practice resource and includes 113 conditions.

●Other – (See 'Society guideline links' below.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Prenatal genetic screening and diagnosis".)

SUMMARY AND RECOMMENDATIONS

●Terminology – Panethnic expanded carrier screening refers to the practice of simultaneously screening for a large number of genetic conditions without regard for racial/ethnic risk factors in the population. This information informs preconception planning and pregnancy management. (See 'Terminology' above and 'Introduction' above.)

●Offer genetic carrier screening – Relevant professional societies recommend offering generic carrier screening to all pregnant individuals and those planning pregnancy. In the context of shared decision-making, patients should be informed of the range of available information from carrier screening panels and the limitations and benefits of the various options, and then pursue testing based on their desire for information. (See 'Introduction' above.)

●Counseling – Pretest and posttest counseling are essential to the process of carrier screening in clinical practice, and include many components (table 1). (See 'Patient counseling' above.)

●Benefits – Genetic disorders are not isolated to certain populations. A major benefit of a panethnic expanded screening strategy compared with traditional strategies is identification of carriers who are not fully aware of their racial/ethnic ancestry or who are of multiracial/multiethnic ancestry and thus unaware of their reproductive risk for transmitting a heritable condition to their offspring. Another benefit is the ability to screen for many Mendelian disorders in a single test, including rare disorders where a family history of the condition is often absent. (See 'Benefits' above.)

●Harms and limitations – Some limitations include (see 'Harms and limitations' above):

•Panels offered by commercial laboratories include some conditions that result in only mild to moderate (rather that severe) health complications (eg, methylenetetrahydrofolate reductase [MTHFR] gene variant), have significant variations in or poorly defined phenotype (eg, hereditary hemochromatosis), or have onset in adulthood (eg, BRCA1/BRCA2 testing for hereditary breast and ovarian cancer)

•The frequency of some conditions is unknown in the general population or within specific ethnic groups, rendering calculation of residual risk after a positive test inconclusive

•Variants of uncertain clinical significance (VUS) and unanticipated or incidental findings may be reported

•Lack of detection of private or unique pathogenic variants

•Identification of variants with personal health risks for the carrier

●Screening panels – Various strategies for expanded carrier screening panels have been proposed but no uniform or standardized process has been identified for best practice. General guidelines have been developed describing the types of conditions that could be included and should not be included. In general, screening is most appropriate for adult-onset conditions with a well-defined genotype and phenotype, a high carrier frequency that is known within the screened population, cognitive or physical impairment, need for significant surgical treatment or medical intervention throughout life, and/or decreased life expectancy.

Professional societies discourage screening for disorders that typically have an adult-onset phenotype and molecular testing cannot distinguish between childhood or adult onset, variants with high allele frequencies and low phenotypic penetrance, or better screening performance with nonmolecular screening techniques. (See 'Which conditions should be included in carrier screening panels?' above and 'Which conditions should not be screened for?' above.)