ACOG Opinion on Expanded Carrier Screening

SUMMARY:

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.

Key Highlights

  • Spinal Muscular Atrophy (SMA) has joined cystic fibrosis (CF) as a recommendation for all women who are pregnant or considering pregnancy
  • Hemoglobinopathies
    • 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)
    • Recommended testing remains for 4 disorders
      • Canavan; CF; Familial dysautonomia; Tay Sachs Disease
    • 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)

Learn More – Primary Sources:

ACOG Committee Opinion 690: Carrier Screening in the Age of Genomic Medicine

ACOG Committee Opinion 691 Carrier Screening for Genetic Conditions

Expanded Carrier Screening in Reproductive Medicine—Points to Consider: A Joint Statement of the ACMG, ACOG, NSGC, PQF, and SMFM

Genome sequencing and carrier testing:  decisions on categorization and whether to disclose  results of carrier testing

Locate a genetic counselor or genetics services:

Genetic Services Locator-ACMG

Genetic Services Locator-NSGC

Genetic Services Locator-CAGC

Locate a Maternal Fetal Medicine Specialist: SMFM

ACOG and Universal Screening for Cystic Fibrosis – What You Need to Know

CLINICAL ACTIONS:

Genetic screening for Cystic Fibrosis (CF) has been recommended by ACOG and ACMG for over a decade.

  • Offer CF screening to all women of reproductive age, not just those in higher risk groups
  • Document previous CF screening results
    • Genetic testing does not need to be repeated in subsequent pregnancies if already on record
  • Expanded mutation panels beyond the ‘ACMG 23’ can be considered to increase sensitivity
    • DNA sequencing of the CFTR gene is not considered ‘appropriate’ for routine carrier screening and should be reserved for particular circumstances in conjunction with genetic counseling (see below in key points)
  • Refer for genetic counseling if both partners are CF carriers
    • CF is an autosomal recessive disorder and if both partners are affected, the risk to offspring is ¼ or 25%

SYNOPSIS:

Initially, prenatal screening for CF was limited to women from high risk groups, non-Hispanic whites and those of Ashkenazi Jewish background. However, as it becomes more difficult to identify specific racial groups and ethnicities, ACOG guidance is clear that all women of reproductive age should be screened to determine their carrier status. There are several genetic tests currently available that can sequence the entire CFTR gene, providing a clinical report for hundreds of CF disease causing mutations.  While Committee Opinion 691 still mentions the original ACMG 23 mutation panel,  expanded mutation panel analysis can be considered to help improve test sensitivity particularly among non-Caucasians.

KEY POINTS:

  • Full gene sequencing of the CFTR gene should be reserved for patients who meet the following criteria:
    • Personal history of CF
    • Family history of CF
    • Males with CBAVD
    • Newborns with positive newborn screening results when mutation panel testing is negative
  • Newborn screening for CF in newborns does not replace maternal screening
    • A negative newborn screen for CF cannot identify parental carriers
  • Diagnosis code: Z31.430

Learn More – Primary Sources:

ACOG Committee Opinion 690: Carrier Screening in the Age of Genomic Medicine

ACOG Committee Opinion 691: Carrier Screening for Genetic Conditions

Expanded Carrier Screening in Reproductive Medicine—Points to Consider: A Joint Statement of the ACMG, ACOG, NSGC, PQF, and SMFM

Locate a Genetic Counselor or Genetics Services:

Genetic Services Locator-ACMG

Genetic Services Locator-NSGC

Genetic Services Locator-CAGC

Locate an MFM Specialist:

Locate a Maternal Fetal Medicine Specialist: SMFM

Practical obstetrics info for your women's healthcare practice

Second Trimester Echogenic Bowel: Important Ultrasound Finding with Varied Causes and Some Serious Implications

CLINICAL ACTIONS:

Fetal bowel can sometimes appear bright on prenatal ultrasound depending on the transducer used and machine settings. However, echogenic bowel in the fetus is not a significant finding unless the bowel appears as bright as bone (the brightness of the iliac wing can be used a reference).  If the ultrasound report does confirm echogenic fetal bowel, further management should include

  • Aneuploidy screening
    • No previous aneuploidy screening
      • NIPS or quad screening
    • Negative aneuploidy screening
      • No further aneuploidy evaluation
  • Further work-up
    • Offer cystic fibrosis screening if not yet performed in current or prior pregnancy
    • Evaluate for cytomegalovirus (CMV) infection with IgG and IgM titers
    • Follow-up fetal growth scan in the third trimester to evaluate for growth restriction
    • If aneuploidy screening is positive, offer confirmatory diagnostic testing, referral for high-risk OB consultation and genetic counseling

SYNOPSIS:

Fetal echogenic bowel is present in up to 1.8% of second trimester ultrasound exams. It can be due to congenital cytomegalovirus infection, cystic fibrosis, intra-amniotic bleeding, fetal growth restriction, aneuploidy or gastrointestinal obstruction. Therefore, further work-up is warranted.

KEY POINTS:

  • Echogenic bowel is associated with aneuploidy (3 to 5%), the most common is Down syndrome (Trisomy 21)
  • If all identifiable causes are ruled out, fetal growth should be evaluated, as there is an association with fetal growth restriction
  • When isolated, normal fetal outcomes are likely. Pediatrics should be informed of the prenatal findings and work-up

Learn More – Primary Sources:

ACOG Practice Bulletin No. 226: Screening for Fetal Chromosomal Abnormalities

ACOG Practice Bulletin No. 162: Prenatal Diagnostic Testing for Genetic Disorders

Outcome of infants presenting with echogenic bowel in the second trimester of pregnancy

Society for Maternal-Fetal Medicine Consult Series #57: Evaluation and management of isolated soft ultrasound markers for aneuploidy in the second trimester

Locate a genetic counselor, genetics services or high risk OB:

Genetic Services Locator-ACMG 

Genetic Services Locator-NSGC

Genetic Services Locator-CAGC

Locate a Maternal Fetal Medicine Specialist: SMFM

Genetic Carrier Screening in Ashkenazi Jewish Patients

CLINICAL ACTIONS:

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

SYNOPSIS:

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.

KEY POINTS:

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

Learn More – Primary Sources:

ACOG Committee Opinion 690: Carrier Screening for Genetic Conditions

ACOG Committee Opinion 691: Carrier Screening in the Age of Genomic Medicine 

Expanded Carrier Screening in Reproductive Medicine—Points to Consider: A Joint Statement of the ACMG, ACOG, NSGC, PQF, and SMFM

ACMG Practice Guidelines : Carrier Screening in Individuals of Ashkenazi Jewish Descent

An Ashkenazi Jewish SMN1 haplotype specific to duplication alleles improves pan-ethnic carrier screening for spinal muscular atrophy

Locate a genetic counselor or genetics services:

Genetic Services Locator-ACMG

Genetic Services Locator-NSGC

Genetic Services Locator-CAGC