INTRODUCTION — Historically, the approach to preconception and prenatal carrier screening has been selective (ie, targeted or condition-directed), based primarily on race/ethnicity and personal/family history. Increasingly, however, patients are being offered a broader approach to carrier screening, which is possible because of rapid advancements in genetic testing technologies and decreasing costs. Expanded carrier screening refers to the practice of simultaneously screening for a large number of conditions in a panethnic approach (ie, without regard to race or ethnicity) [1]. Although the information from expanded carrier screening can inform patient and provider decision-making, it can also present practical and ethical challenges that need to be considered.
This topic will discuss issues related to expanded carrier screening in women planning pregnancy or who are pregnant. Genetic screening in specific populations and for specific conditions are reviewed separately:
●(See "Down syndrome: Overview of prenatal screening".)
●(See "Prenatal screening and diagnosis for fragile X syndrome".)
●(See "Cystic fibrosis: Carrier screening".)
GOALS OF PRECONCEPTION/PRENATAL CARRIER SCREENING — The goals of preconception/prenatal carrier screening are to:
●Identify individuals at risk of transmitting a heritable disorder to offspring.
●Provide appropriate reproductive counseling, prenatal care, and newborn management of a potentially affected child.
●Enhance the individual's reproductive autonomy (eg, preconception planning, preimplantation genetic testing, prenatal diagnosis, and pregnancy management).
RATIONALE FOR EXPANDED CARRIER SCREENING — The rationale for expanded rather than traditional carrier screening is that many individuals are unaware of their reproductive risk for transmitting a disorder(s) to offspring because:
●They have no family history of the genetic disorder(s) that they carry and many of the conditions are rare.
●They are of a multiethnic background or not aware of their full ancestry or true ethnicity.
●They have a normal second-trimester ultrasound examination. Although single gene disorders can be associated with abnormal 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 patients at risk for affected offspring that might otherwise not have been identified by a fetal ultrasound finding in the absence of a known family history.
IS EXPANDED CARRIER SCREENING PREFERABLE TO TRADITIONAL SELECTIVE SCREENING? — In 2019, an American College of Obstetricians and Gynecologists’ committee opinion concluded that carrier screening performed either by expanded carrier screening or traditional ethnic-based testing is an acceptable strategy as one approach is not clearly superior to the other [2]. Obstetric providers should determine a standard approach for their practice, but with consideration of the individual patient's desire for information based on their personal values and preferences. (See 'Choosing a screening panel' below.)
WHICH DISORDERS ARE SCREENED FOR? — Increasing population intermixing confounds what people believe to be their ethnicity, thus carrier screening panels should be inclusive of diverse populations.
Commercial laboratories offer test panels that screen for only a few, or 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 pathogenic variants within a disorder that contribute to the highest detection of carriers; however, there is no accepted standard or guideline for laboratories to determine which disorders to include in a panel. Panels can differ within the same laboratory and between laboratories. It is important that any laboratory panel include a transparent description of the process used for including/excluding specific genes.
Guidelines from professional organizations typically recommend that the condition being screened for should be a health problem associated with one or more of the following [2-5]. For disorders meeting these criteria, the disease frequency should be known so that residual risk can be calculated.
●Cognitive disability.
●Need for surgical or medical intervention.
●Poor quality of life.
●Prenatal diagnosis that could lead to prenatal intervention to improve perinatal outcome, delivery interventions to optimize newborn and infant outcome, parental education regarding special medical needs and intervention after birth.
The American College of Obstetricians and Gynecologists provides some guidance, based on the well-established approach to selection of disorders evaluated by newborn screening. This approach considers the carrier frequency and prevalence of the disorder, well-defined disorders known to have a detrimental effect on quality of life (eg, associated with neurocognitive impairment or medical handicaps), and disorders with early onset or available intervention. Screening for adult-onset disorders, conditions for which the natural history is unknown or poorly established, or disorders that occur with a very low frequency is discouraged [2].
In 2021, the American College of Medical Genetics and Genomics (ACMG) recommended offering all pregnant patients and those planning a pregnancy carrier screening for autosomal recessive and X-linked conditions; these conditions (described by ACMG as "tier 3" conditions) were defined as having a carrier frequency ≥1/200 [6]. Lists of these conditions were provided in the practice resource.
CONDITIONS THAT SHOULD NOT BE SCREENED FOR — Professional societies discourage screening for disorders that typically have:
●An adult-onset phenotype and molecular testing cannot distinguish between childhood or adult onset (eg, alpha 1 antitrypsin deficiency).
●Variants with high allele frequencies and low penetrance of a phenotype (eg, methylene tetrahydrofolate reductase variants).
●Better screening performance with nonmolecular screening techniques (eg, hereditary hemochromatosis has low penetrance when molecular variants are identified).
The techniques used in expanded carrier screening test panels are not appropriate for hemoglobinopathy screening and Tay Sachs screening within the non-Ashkenazi Jewish population. Within the Ashkenazi community, gene sequencing of the common alleles is reasonable as it will detect >98 percent of Tay Sachs carriers.
●Hemoglobin electrophoresis and measurement of mean corpuscular volume should be used 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, but may not include less common genes such as alpha thalassemia). (See "Prenatal screening and testing for hemoglobinopathy".)
●Genetic testing for Tay Sachs disease may target the three common pathogenic variants most often causative of disease within the known Ashkenazi Jewish population. Hexosaminidase-A 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 disease more common in people of Ashkenazi Jewish descent and others with a family history of these disorders", section on 'Tay-Sachs disease'.)
TECHNIQUES — The process of pathogenic variant screening depends on the laboratory's technology.
●Some laboratories offer complete sequencing of a gene (ie, assessment of the entire DNA sequence of the gene) via next-generation methodologies. (See "Next-generation DNA sequencing (NGS): Principles and clinical applications".)
●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. The panel may include pathogenic variants for which there are few supportive data other than a single published report.
INFORMED CONSENT — The process of informed consent provides an opportunity to discuss limitations and benefits of testing. The information should be given in an unbiased manner using language appropriate to the literacy of the patient and culturally sensitive. (See "Genetic counseling: Family history interpretation and risk assessment", section on 'Informed consent for genetic testing'.)
Benefits
Identification of carriers regardless of race/ethnicity — Genetic conditions do not occur exclusively in specific ethnic groups. Furthermore, it is increasingly difficult to assign a single 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 [7].
●In the largest observational study of routine recessive disease carrier screening (a multiethnic population of >23,000 individuals), 76 percent of carriers would have been missed by ACOG's traditional ethnic-based guideline in place at the time of the study [8]. 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.
Simultaneous testing for a large number of genetic conditions — Mendelian disorders account for 20 percent of infant mortality and 18 percent of infant hospitalizations in the United States [9]. A single laboratory panel can screen for hundreds of Mendelian disorders simultaneously. Screening for hundreds of disorders on one test panel could provide a potentially cost-effective means of identifying carriers for rare Mendelian disorders in the general population [10]. Preconception or prenatal identification of carriers could lead to reduction in diagnostic cost and time, earlier treatment, avoidance of unnecessary treatments, and prevention of disease in offspring [11,12].
Harms and limitations — There are no data demonstrating an improvement in reproductive outcome, despite the benefits described above.
Identification of conditions of limited impact, uncertain prevalence, or 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.
Including the above types of disorders in a reproductive screening panel is in direct conflict with accepted clinical criteria for reproductive screening programs. Guidelines typically recommend only screening for disorders with one or more of the following characteristics [2-5]:
●A well-defined genotype and phenotype.
●A high carrier frequency that is known within the screened population.
●A deleterious effect on quality of life (eg, causing cognitive or physical impairment, requiring significant surgical treatment or medical treatment throughout life, decreased life expectancy).
●Fetal, neonatal, or early childhood onset amenable to prenatal diagnosis and, ideally, potential antenatal/postnatal intervention to improve 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 [13].
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 [8,14,15]. 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 [8].
Use of panels with low-frequency conditions or a large number of genes may have downstream costs for additional laboratory testing or sequencing, increases the time and complexity of counseling, and thus may increase patient anxiety. (See 'Choosing a 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 [16]. 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.
Identification of variants with personal health risks — Although the primary goal of screening is to identify risks of offspring, rarely disorders that pose a personal health risk for the carrier may be detected.
Identification of X-linked conditions — Before the 2021 ACMG practice resource described above [6] (see 'Which disorders are screened for?' above), screening for X-linked conditions within a panel had never been previously recommended, aside from Fragile X syndrome for patients with a family history of autism or premature ovarian insufficiency. There is no peer-reviewed study to determine the frequency of X-linked genes across populations, which ACMG acknowledged in the supplementary material. Furthermore, there are no data or guidance on how to accurately provide pretest counseling to women who may discover unanticipated information about their health beyond reproductive risk for the pregnancy when X-linked conditions are included.
PRETEST AND POSTTEST COUNSELING — Pretest and posttest counseling are essential to the process of carrier testing in clinical practice. Women with risk factors for genetic conditions are often best served by referral to a provider with genetics expertise in order to meet the patient's need for information and the obstetric provider's workflow pressures in the office. Risk factors for single gene disorders include:
●Family history of a genetic condition.
●Family history of an individual(s) with features that may constitute a genetic diagnosis (eg, intellectual disability, multiple miscarriages, birth defects).
●Underlying maternal medical conditions.
Guidelines for genetic counseling, including interpretation of the family history and risk assessment, are reviewed in detail separately. (See "Genetic counseling: Family history interpretation and risk assessment".)
In addition to the pretest and posttest counseling describe below, providers with genetics expertise can:
●Review the clinical features and variability of conditions for which testing may be available.
●Calculate the patient's a priori risk for specific conditions in the planned screening panel based on family history or maternal health.
●Describe the technology of the planned tests and test performance (sensitivity/specificity, positive/negative predictive value).
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 [3].
Pretest counseling — Pretest counseling and informed consent should include a broad discussion of types of conditions included in the carrier screening panel and limitations of genetic screening. The goals of pretest counseling are to provide education, personalized and nondirective information about testing options, and facilitate informed consent. The major components of pretest counseling, as recommended by a variety of professional organizations, include [2,3,17,18]:
●Make it clear at the beginning of the discussion that genetic testing is optional.
●Review the baseline risk of having a child with a birth defect or intellectual disability, which is 3 to 4 percent in the general population [19].
●Explain that screening and diagnostic testing options are available to all women and clarify the difference between the two types of testing.
●Use neutral and nonjudgmental language to broadly describe the types of conditions screened for by the chosen panel and explain that some conditions may have poorly-defined phenotypes.
●Review 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.)
●Discuss that positive results can have implications related to the current/future health status of the patient herself and other 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'.)
●Explain 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).
●Explain 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 carrier screening.
●Address the issue of cost prior to testing so the patient may obtain coverage information from her insurer. Cost may be an important a factor in the decision-making process for an individual patient.
●Discuss 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 regulations.
Posttest counseling
●Provide posttest counseling in a nondirective and objective manner by the process that was outlined with the patient during pretest counseling [17,20].
●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. 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 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.
•Discuss options for prenatal diagnosis, if the patient is pregnant and results of parental screening indicate the fetus is at risk of the genetic condition (not an asymptomatic carrier).
•Discuss reproductive options. For pregnant patients: pregnancy management, delivery planning, pregnancy termination. For preconception patients: preimplantation genetic testing, use of noncarrier donor gametes, adoption planning.
•Discuss potential implications for other family members [3,17].
CHOOSING A SCREENING PANEL — No uniform or standardized process has been identified for best practice in expanded carrier screening. Clinicians have many choices when choosing a panel for expanded carrier screening. For each panel, the laboratory should provide information on the carrier frequency in the general population and in specific ethnic groups for the conditions offered within the panel so that the clinician and patient can determine whether or not the panel is appropriate. Although ethnicity is increasingly difficult to characterize, some patients are certain of their ethnicity and want targeted information.
The American College of Obstetricians and Gynecologists has published an example of an expanded panel with this information [2].
The American College of Medical Genetics and Genomics (ACMG) has lists of autosomal recessive and X-linked conditions having a carrier frequency ≥1/200 in their practice resource [6].
IS RESCREENING RECOMMENDED BEFORE A SUBSEQUENT PREGNANCY? — Carrier rescreening typically is not offered or recommended unless the patient's medical history or family history has changed [3]. However, screening panels and molecular techniques have changed over time, with potential differences in the conditions screened and 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 this cohort of patients with previous targeted or 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 — Patients 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 [21]. 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.
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 screening and diagnosis".)
SUMMARY AND RECOMMENDATIONS
●Definition – Expanded carrier screening refers to the practice of simultaneously screening for a large number of conditions in a panethnic approach. (See 'Introduction' above.)
●Technique – Screening is performed using targeted high-throughput pathogenic variant analysis for specific pathogenic variants known to be associated with a particular disease or sequence analysis via next-generation methodologies. (See 'Techniques' above.)
●Rationale and goals – The majority of carrier individuals have no family history of the genetic condition(s) that they carry; therefore, they are unaware of their reproductive risk for transmitting the condition(s) to offspring. In addition, many individuals are of a multiethnic background or not aware of their full ancestry or true ethnicity. The major goal of expanded rather than traditional carrier screening is to increase identification of individuals at risk for transmitting a disorder(s) to offspring and enhance their reproductive options. (See 'Rationale for expanded carrier screening' above and 'Goals of preconception/prenatal carrier screening' above.)
●Benefits – The two major benefits of expanded carrier screening are: identification of carriers regardless of their race/ethnicity and the ability to screen for many Mendelian disorders in a single test. (See 'Benefits' above.)
●Harms and limitations – Various strategies for expanded carrier screening panels have been proposed but no uniform or standardized process has been identified for best practice and there is a paucity of data supporting an improvement in reproductive outcome. Individual patients, however, may desire this information based on personal values and preferences. (See 'Harms and limitations' above.)
Limitations of expanded carrier screening are that (see 'Identification of conditions of limited impact, uncertain prevalence, or poorly defined phenotype' above and 'Identification of variants of uncertain clinical significance' above):
•Panels offered by commercial laboratories include some conditions that result in only mild to moderate (rather that severe) health complications (eg, MTHFR), 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 and unanticipated or incidental findings may be reported.
●Counseling – Pretest and posttest counseling are essential to the process of carrier testing in clinical practice, and includes many components (table 1). (See 'Pretest and posttest counseling' above.)
Women with risk factors for genetic conditions are often best served by referral to a provider with genetics expertise. (See 'Pretest and posttest counseling' above.)
●Conditions screened for – Guidelines from professional organizations typically recommend the condition being screened for should be a health problem associated with one or more of the following (see 'Choosing a screening panel' above):
•Cognitive disability.
•Need for surgical or medical intervention.
•Poor quality of life.
•Prenatal diagnosis that could lead to improvement in perinatal or postnatal outcome.
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 penetrance of a phenotype, better screening performance with nonmolecular screening techniques. The techniques used in expanded carrier screening test panels may not be appropriate for hemoglobinopathy screening and are not appropriate for Tay Sachs screening within the Ashkenazi Jewish population. (See 'Conditions that should not be screened for' above.)
