ObGyn Intelligence
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Carrier Screening Guide
The 113 genes ACMG recommends offering to all pregnant patients and those planning pregnancy (Tier 3: 97 autosomal recessive genes with carrier frequency of at least 1/200, plus 16 X-linked genes), with ACOG's recommendations marked alongside. [1] Frequencies are the maximum carrier frequency ACMG lists for any population, not the risk for an individual patient.
| Condition ↕ | Gene ↕ | Inheritance ↕ | Max carrier freq ↕ | ACMG source ↕ | ACOG ↕ |
|---|
ACMG Tier 4 covers genes with carrier frequency below 1/200, with no lower limit. ACMG reserves it for consanguineous pregnancies (second cousins or closer) and for cases where personal or family history warrants it, and does not recommend routine Tier 4 panels. [1] Tier 4 content differs from laboratory to laboratory, so the gene list and frequencies come from the panel the patient is offered.
Dominant and mitochondrial conditions (hereditary cancer, cardiac, thrombophilia genes and others) are not part of carrier screening and are no longer listed. Neither is MTHFR, which is not a carrier screening test.
The two documents clinicians use most do not say the same thing. ACOG Committee Opinions 690 and 691 (2017) remain ACOG's carrier screening documents; ACMG published its practice resource in 2021.
| ACOG [3,4] | ACMG [1] | |
|---|---|---|
| Offered to all | Cystic fibrosis and spinal muscular atrophy. CBC with red cell indices for hemoglobinopathies. | Tier 3: 97 autosomal recessive genes with carrier frequency of at least 1/200, plus 16 X-linked genes, including FMR1. |
| Ancestry | Ashkenazi Jewish: Tay-Sachs, Canavan, familial dysautonomia and cystic fibrosis; consider Usher syndrome, familial hyperinsulinism, Joubert syndrome, maple syrup urine disease, Bloom syndrome, Gaucher disease, Fanconi anemia, mucolipidosis IV and Niemann-Pick disease. Tay-Sachs also for French-Canadian and Cajun ancestry. Hemoglobin electrophoresis for African, Middle Eastern, Southeast Asian, West Indian or Mediterranean ancestry, or MCV below 80 fL with normal iron studies. | Screening should be ethnic and population neutral. ACMG calls restriction by ethnicity or self-identified ancestry inequitable and scientifically flawed. |
| Fragile X | Risk-based: family history of fragile X-related disorders or intellectual disability suggestive of fragile X, or personal history of ovarian insufficiency. | FMR1 is one of the 16 X-linked genes offered to all. |
| Panel strategy | Ethnic-specific, panethnic and expanded screening are all acceptable; each practice should offer one standard approach consistently. Conditions on expanded panels should have carrier frequency of at least 1/100, a well-defined phenotype, a significant effect on quality of life or health, early onset, and be diagnosable prenatally. | Tier 1 (CF and SMA) and Tier 2 (frequency 1/100 or more) are not recommended as the standard because they do not serve all groups equitably. Tier 4 for consanguinity or relevant history. ACMG recommends calling it "carrier screening," not "expanded carrier screening." |
| Consent | Screening is optional; a patient may decline any or all of it after counseling. | Reports must state the tier, gene content and testing approach, so the patient knows what was and was not screened. |
| Timing | Ideally before pregnancy. | Before conception or during pregnancy. |
| Repeat testing | Generally not repeated for the same condition; may be considered after significant changes in technology, with a genetics professional. | Readdress screening when the reproductive partner changes. |
A practice following ACOG alone offers CF, SMA and a CBC to everyone and adds conditions by ancestry and history. A practice following ACMG offers the full Tier 3 list to everyone. Both are defensible; what is not defensible is offering different patients different strategies without a reason. [3]
A carrier result means little until the reproductive partner's status is known.
For a woman who carries an X-linked condition, the partner's result does not change the risk: each son has a 50% chance of being affected. Offer genetic counseling, and testing to her relatives. [1] FMR1 premutation carriers also have their own risk of primary ovarian insufficiency, which belongs in pretest counseling. [1]
ASRM guidance (2021): [5]
A negative result lowers the chance of being a carrier. It never removes it.
SMA screening counts SMN1 copies. About 3% to 4% of people carry two SMN1 copies on one chromosome. If the other chromosome has none, the person is a "2+0" silent carrier whose two copies look normal on the test. A linked variant (c.*3+80T>G) raises the likelihood of a 2+0 carrier, particularly in Ashkenazi Jewish individuals. About 2% of affected alleles arise de novo. [9]
| Ancestry | Carrier frequency | Detection rate | Residual risk, 2 copies, linked variant absent | 2 copies, linked variant present |
|---|---|---|---|---|
| African American | 1/72 | 90% | 1/375 | 1/39 |
| Ashkenazi Jewish | 1/67 | 93% | 1/918 | Likely carrier |
| Asian | 1/59 | 93% | 1/907 | 1/61 |
| White | 1/47 | 95% | 1/921 | 1/69 |
| Hispanic | 1/68 | 93% | 1/906 | 1/99 |
Source: ARUP Laboratories. [9] Figures are laboratory-specific; use the values on the patient's own report.
ACOG recommends a CBC with red cell indices for every patient, ideally before pregnancy, and hemoglobin electrophoresis when ancestry places her at increased risk (African, Middle Eastern, Southeast Asian, West Indian or Mediterranean) or when MCV is below 80 fL with normal iron studies. [4] Alpha-thalassemia trait is not detected by electrophoresis and requires DNA testing. [4]
Hexosaminidase A enzyme testing detects about 98% of carriers regardless of ancestry. DNA testing performs well in high-risk populations but detects fewer carriers in others. Leukocyte enzyme testing is used for women taking oral contraceptives. [4]
For an autosomal recessive condition, each pregnancy has a 1 in 4 chance of being affected. The couple needs the options early enough to use them.
In Mackenzie's Mission, Australia's national program, 9,107 couples were screened for 1,281 genes associated with about 750 serious childhood-onset conditions. 1.9% of couples were newly found to have an increased chance; 78.3% of these couples had been assumed to be at general-population risk before screening. Of newly identified couples who were already pregnant, 64% had prenatal testing: of 29 tested pregnancies, 24 were unaffected and 5 affected. [6] Twelve months later, interviewed couples had used PGT-M and prenatal diagnosis to act on their result. [7]
When the woman is a carrier and the partner cannot be tested, a commercial cell-free DNA test estimates the fetal risk for CF, SMA, beta-hemoglobinopathies and alpha-thalassemia. In an industry-funded study of 528 pregnancies with outcomes (25 affected), sensitivity was 96.0% (95% CI 79.7 to 99.9) and positive predictive value 50.0%. [8] No professional society recommends it; ACOG has stated it lacks sufficient information to recommend single-gene cell-free DNA screening. [10] A high-risk result still requires diagnostic testing.