Carrier testing is part of routine prenatal care and is ideally done before conception. The extent of carrier testing is related to how the woman and her partner weigh factors such as
The probability of a fetal abnormality based on risk factors and the results of any previous testing
The probability of a complication from invasive fetal testing
The importance of knowing the results (eg, would the pregnancy be terminated if an abnormality was diagnosed, would not knowing the results cause anxiety)
For these reasons, the decision is individual, and recommendations often cannot be generalized to all women, even those with similar risk.
A screening history is part of the evaluation. The history is summarized as a pedigree (see figure Symbols for constructing a family pedigree). Information should include the health status and presence of genetic disorders or carrier status of both parents, of first-degree relatives (parents, siblings, offspring), and of second-degree relatives (aunts, uncles, grandparents), as well as ethnic and racial background and consanguineous matings. Outcomes of previous pregnancies are noted. If genetic disorders are suspected, relevant medical records must be reviewed.
Testing potential parents for a genetic carrier state that may result in affected offspring is best done before conception; however, many people wait until after conception to have carrier screening. Traditionally, screening tests are offered to parents at risk of being asymptomatic carriers for certain common mendelian disorders (see table Preconception or Prenatal Genetic Screening of Potential Parents). Because parent ethnicity is often complex and not well-defined and because prenatal genetic testing is becoming much less expensive and quicker, some clinicians are starting to screen all potential (and expectant) parents, regardless of ethnicity (called universal carrier screening). Therefore, current approaches to carrier screening include offering all patients the same larger list of conditions to be evaluated. Often, dozens of genes and disorders (some with more severe phenotypic consequences than others) are included (1). Increasing the amount of testing and evaluation is expected to increase the complexity of pre-test counseling. The American College of Medical Genetics and Genomics recommends a tiered carrier screening system based on carrier frequency and has provided tables listing disorders to be included in carrier screening panels (2).
(See also Prenatal Genetic Counseling.)
General references
1. American College of Obstetricians and Gynecologists/Committee on Genetics: Committee opinion no. 690: Carrier Screening in the age of genomic medicine. Obstet Gynecol 129 (3):e35–e40, 2017. doi: 10.1097/AOG.0000000000001951
2. Gregg AR, Aarabi M, Klugman S, et al: Screening for autosomal recessive and X-linked conditions during pregnancy and preconception: A practice resource of the American College of Medical Genetics and Genomics (ACMG). [published correction appears in Genet Med 2021 Aug 27]. Genet Med 23(10):1793-1806, 2021. doi:10.1038/s41436-021-01203-z
Prenatal Testing to Detect Fetal Genetic Abnormalities
After conception, pregnant women should be offered noninvasive screening tests for fetal chromosomal disorders using one of several methods (eg, ell-free DNA serum tests, analyte screening) (1). If such a screening test is positive, it may be followed up with fetal diagnostic genetic testing, which are invasive tests using a sample of fetal cells (see table Indications for Fetal Genetic Diagnostic Tests). These diagnostic tests provide a definitive diagnosis of genetic abnormalities. Additionally, if screening of either parent (done before or after conception) detects a genetic abnormality, pregnant patients may choose to do fetal genetic diagnostic tests (eg, chorionic villous sampling or amniocentesis) without first doing a noninvasive fetal screening test (eg, cfDNA or serum screening).
Screening tests for fetal chromosomal disorders include screening for fetal Down syndrome, trisomy 18, and trisomy 13 with analysis of cell-free DNA (cfDNA) in maternal plasma, which can be done as early as 10 weeks gestation. Another screening method, called analyte screening, uses multiple maternal serum markersneural tube defects, Down syndrome (and other chromosomal abnormalities), and some other birth defects. Analyte screening is done at 15 to 20 weeks gestation.
Fetal genetic diagnostic tests are usually recommended if risk of a fetal chromosomal abnormality is increased (see table Indications for Fetal Genetic Diagnostic Tests). Fetal genetic diagnostic tests, unlike screening tests, are usually invasive and involve fetal risk. Thus, in the past, these tests were not routinely recommended for women without risk factors or a known genetic abnormality in one of the parents. However, because fetal genetic diagnostic tests are now more widely available and safety has improved, it is recommended to offer fetal genetic testing to all pregnant patients, regardless of risk.
Fetal genetic diagnostic tests include chorionic villus sampling, amniocentesis, or, rarely, percutaneous umbilical blood sampling. In addition, for pregnancies conceived through assisted reproductive technologies (eg, in vitro fertilization), preimplantation genetic diagnosis is an option.
Fetal genetic diagnostic tests can detect all trisomies, many other chromosomal abnormalities, and several hundred mendelian abnormalities. Submicroscopic chromosomal abnormalities are missed by traditional karyotype testing and can be identified only by microarray technologies, such as array comparative genomic hybridization and single nucleotide polymorphism (SNP)-based arrays. Array comparative genomic hybridization in prenatal testing is most frequently used to evaluate fetuses with structural abnormalities. Arrays detect numeric chromosome abnormalities (eg, trisomies) as well as unbalanced structural chromosome disorders, such as microdeletions. Studies have reported about 6% incidence of array abnormalities that would have been missed with traditional karyotyping in structurally abnormal fetuses.
Preimplantation genetic diagnosis may be available for partners who are using in vitro fertilization.
Preconception or Prenatal Genetic Testing of Potential Parents
Ancestry* | Disorder | Parental Genetic Carrier Screening Tests | Prenatal Fetal Genetic Diagnostic Tests (if parental carrier testing is positive) |
|---|---|---|---|
All | DNA analysis of at least the 23 most common CFTRpathogenic gene variants (formerly termed mutations), each of which is present in ≥ 0.1% of the US population | PGD, CVS, or amniocentesis for genotype determination* | |
Ashkenazi Jewish† | Canavan disease | DNA analysis to detect the most common pathogenic gene variants | PGD, CVS, or amniocentesis for DNA analysis |
Familial dysautonomia | DNA analysis to detect the most common pathogenic gene variants | PGD, CVS, or amniocentesis for DNA analysis | |
Measurement of serum hexosaminidase A to check for deficiency or DNA analysis | PGD, CVS, or amniocentesis for DNA analysis | ||
African | Hemoglobin electrophoresis | PGD, CVS, or amniocentesis for genotype determination (direct DNA analysis) | |
Cajun | Tay-Sachs disease | Measurement of serum hexosaminidase A to check for deficiency or DNA analysis | PGD, CVS, or amniocentesis for DNA analysis |
Southeast Asian, Asian Indian, African, Mediterranean, Middle Eastern | CBC; if MCV is < 80 fL, hemoglobin electrophoresis or DNA analysis | PGD, CVS, or amniocentesis for genotype determination (direct DNA analysis or linkage analysis) | |
Southeast Asian, Cambodian, Chinese, Filipino, Laotian, Vietnamese | CBC; if MCV is < 80 fL, hemoglobin electrophoresis or DNA analysis | PGD, CVS, or amniocentesis for genotype determination (direct DNA analysis or linkage analysis) | |
* Definitive diagnosis is not always possible; sensitivity varies by ancestry. Some ancestries are included in this table; this is not a comprehensive list. See Committee Opinion No. 691: Carrier Screening for Genetic Conditions. Obstet Gynecol 129(3):e41-e55, 2017. doi:10.1097/AOG.0000000000001952 for more information. | |||
† For people with Ashkenazi Jewish ancestry, some experts also recommend screening for Gaucher disease, Niemann-Pick disease type A, Fanconi syndrome group C, Bloom syndrome, and mucolipidosis IV. | |||
CBC = complete blood count; CFTR = cystic fibrosis transmembrane conductance regulator; CVS = chorionic villus sampling; PGD = preimplantation genetic diagnosis; MCV = mean corpuscular volume. | |||
Indications for Fetal Genetic Diagnostic Tests
Indication | Comments |
|---|---|
Desire for testing | ACOG recommends that all pregnant women be offered noninvasive and invasive testing to assess fetal karyotype, regardless of maternal age. |
Previous recurrent spontaneous abortions | Chromosome analysis may be indicated for both parents. |
Chromosomal abnormality in a previous child | Chromosome analysis may be indicated for both parents. |
Paternal age > 50 | Testing is controversial because, although older paternal age increases risk of some pathogenic gene variants, the number and loci of possible de novo pathogenic gene variants are extensive, making testing problematic. However, exome testing, which is under study, may be useful because it uses a single laboratory test to identify many pathogenic gene variants. |
Parental chromosomal disorder | Based on specific abnormality, not all parental chromosomal rearrangements are associated with risks to offspring. |
Suspected parental sex-linked mendelian disorder | Specific pathogenic gene variant of parents must be known to offer testing. |
Autosomal recessive mendelian disorder diagnosed or suspected in both parents | Specific pathogenic gene variant of parents must be known to offer testing. |
Abnormal cell-free DNA analysis from maternal plasma | Chorionic villus sampling during the first trimester or amniocentesis during the second trimester is done. |
Levels of maternal serum markers* suggesting trisomy 21 or trisomy 18 | Chorionic villus sampling during the first trimester or amniocentesis during the second trimester is done. |
Elevated maternal alpha-fetoprotein and indeterminate ultrasound results | Amniocentesis is done. |
Structural abnormalities in the fetus (including increased nuchal translucency in the first trimester) noted during ultrasonography | Risk of fetal chromosomal abnormality depends on specific anatomic findings. |
* Measured during the first or second trimester. | |
ACOG = American College of Obstetricians and Gynecologists. | |
Testing references
1. American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins—Obstetrics; Committee on Genetics; Society for Maternal-Fetal Medicine: Screening for fetal chromosomal abnormalities: ACOG Practice Bulletin, Number 226. Obstet Gynecol. 2020;136(4):e48-e69. doi:10.1097/AOG.0000000000004084
