ACOG has published two committee opinions on carrier screening. Committee Opinion 691 reviews the recommendations based on disorders. Committee Opinion 690 addresses the issues related to use of screening strategies such as expanded gene panel testing.
Spinal Muscular Atrophy (SMA) has joined cystic fibrosis (CF) as a recommendation for all women who are pregnant or considering pregnancy
Test all patients for CBC and RBC indices as part of antepartum care (ideally preconception)
Add Hgb electrophoresis if
Increased risk based on ethnicity: African, Middle Eastern, Southeast Asian, West Indian and Mediterranean ancestry
MCV is less than 80 fL with normal iron studies
Ashkenazi Jewish Testing (central and Eastern Europe descent)
Additional tests to ‘consider’ has been expanded to the following
Usher syndrome, Familial hyperinsulinism, Joubert and Maple syrup urine disease in addition to Bloom/Gaucher/Fanconi anemia/ML4/Neimann-Pick disease
Tay Sachs Disease
In addition to Ashkenazi Jews, offer if either partner is French-Canadian descent or Cajun
Screening can be performed using DNA-based testing (mutation analysis) or hexosaminidase enzyme in serum or leuckocytes (leukocyte only with oral contraceptives)
Enzyme testing picks up approximately 98% of carriers regardless of ethnicity
Mutation analysis is highly effective in at risk populations – detection rate is limited in other populations
Committee Opinion 690 reviews expanded carrier screening, including a discussion on counseling and what disorders should be included | Important summary statements include the following
Ethnic-specific, panethnic, 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. If obstetrician–gynecologists or other health care providers do not offer expanded carrier screening in their practice, screening recommendations for individual disorders should follow guidelines for carrier screening as outlined in Committee Opinion No. 691, Carrier Screening for Genetic Conditions.
Note: ACMG has published a document on preconception and prenatal carrier screening that includes a tiered approach to the selection of disorders | For the summary and links see ‘Related ObG Topics’ below)
Genetic Carrier Screening in Ashkenazi Jewish Patients
Offering carrier screening for various autosomal recessive conditions to patients of Ashkenazi Jewish or Central/Eastern European Jewish heritage has been a longstanding recommendation from ACOG and ACMG.
ACOG guidelines recommend, at a minimum, screening for the following disorders when offering genetic testing to those of Ashkenazi Jewish background
Tay Sachs Disease (1/30 carrier frequency)
Serum analysis in non-pregnant female, not taking oral contraceptives
Leukocyte analysis in pregnant female or female patient taking oral contraceptives
Cystic Fibrosis (1/29 carrier frequency)
Canavan disease (1/40 carrier frequency)
Familial Dysautonomia (1/32 carrier frequency)
ACOG has now included the following disorders where screening ‘should be considered’
Mucolipidosis IV (1/127 carrier frequency)
Niemann-Pick disease type A (1/90 carrier frequency)
Fanconi anemia group C (1/90 carrier frequency)
Bloom syndrome (1/100 carrier frequency)
Gaucher disease type I (1/15 carrier frequency)
Familial hyperinsulinism (1/68 carrier frequency)
Glycogen storage disease type 1 (1/64 carrier frequency)
Joubert Syndrome (1/110 carrier frequency)
Maple syrup urine disease (1/97 carrier frequency)
Usher Syndrome (type 1F: 1/147 | type III; 1/120)
Additional Clinical Considerations
Simultaneous testing of both partners can be considered if the patient is pregnant and timing is a concern
If the patient is pregnant and only one member of the couple is Ashkenazi Jewish, it is best to test that individual first, if possible
One Jewish grandparent is sufficient for testing
If patient is unsure of background, always offer testing
Even if a patient reports being screening previously, without documentation, she needs to be screened again
A positive family history may not always be present for autosomal recessive conditions, even when there is a high carrier frequency in the Ashkenazi population. Therefore, carrier screening should be offered to those who identify as having Eastern European Jewish/Ashkenazi ancestry. Guidelines have tended toward genetic screening for conditions that have a high carrier frequency in this population. However, due to technological advances, more disorders have been added to genetic screening panels and while some diseases have relatively high carrier rates, others may be less frequent but are considered severe conditions.
Informed consent for genetic testing at a minimum should include
A general description of the disorders
Some of these disorders may not always be severe
For example, cystic fibrosis can have relatively mild signs and symptoms
Residual risk for a disorder exists even if both partners have a negative carrier screening result, although less risk than prior to testing
A carrier of an autosomal recessive disorder is healthy but has a risk of passing the mutation to her offspring
Genetic counseling should be available for anyone who requests further information
When both partners are identified as carriers, there is a 25% chance that the fetus is carrying both mutations
Prenatal diagnosis with amniocentesis or chorionic villus sampling should be offered
Preimplantation Genetic Diagnosis (PGD) could be considered in couples when both are carriers for the same condition
Encourage patient to inform family members when they are confirmed carriers for any of the conditions for which they were tested
Testing for those of Jewish but non-Ashkenazi heritage
There are no guidelines specifically for Jews of Sephardic (descending from the Iberian/Spanish peninsula) or Mizrahi (Middle East, North Africa, Central Asia) heritage
Genetic testing panels that are comprehensive for Jewish individuals, regardless of area of origin, are now available and include over 90 disorders but most of these do not appear in the recommended ACOG list at this time
SMA variant in the Ashkenazi Jewish population
ACOG recommends that all women who are pregnant or considering pregnancy should be offered screening for SMA (see ‘Related ObG Topics’ below)
There are variants that tracks with silent carriers (i.e., found on chromosomes with duplications and not single-copy alleles) that can be incorporated into clinical carrier screening tests to improve residual risk estimates across all populations
Testing for one of these variants is available commercially in many laboratories and is especially effective in the Ashkenazi Jewish population to identify silent carriers
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