Clinical Review

New screening basics for the generalist

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Thanks to advances in genetics, we know the mutations responsible for a growing number of inherited disorders, but making use of that information in a generalist practice is a challenge, given all the other tasks we must manage.

Overall, you must determine the extent to which you will provide and interpret genetic testing and when to refer patients to a specialist. This article aims to simplify that decision by reviewing guidelines and key studies in 3 areas:

  • For genetic carrier screening for people of Ashkenazi Jewish heritage, add familial dysautonomia to the list of screened diseases.
  • Screening for Down syndrome is now possible in the first trimester.
  • Greater genetic risks may be present among children born as a result of assisted reproductive technology (ART), although it’s unclear whether the cause is their parents’ infertility or ART itself.

On the plus side, molecular DNA diagnostics are increasingly sophisticated, readily available, and cost-efficient. The downside: As the list of recommended studies grows, successful testing programs are harder to achieve because of the need to educate patients—and yourself—about each test.

Preconception testing may be especially advisable in women with infertility because it can identify carriers and detect conditions related to infertility or its treatment. With 1% of US births attributable to ART, the possibility of genetic effects continues to raise concern.

Add another disease to genetic carrier screening

ACOG Committee Opinion #298: Prenatal and preconception carrier screening for genetic diseases in individuals of Eastern European Jewish descent. Obstet Gynecol. 2004;104:425–428.

Add familial dysautonomia to carrier screening when patients—or their partners—are of Ashkenazi Jewish heritage. That’s the advice from an American College of Obstetricians and Gynecologists (ACOG) committee opinion. Also conduct previously recommended screening for Tay-Sachs disease, Canavan disease, and cystic fibrosis, and advise patients that testing is available for several other diseases as well (TABLE 1). For Tay-Sachs disease, screening also is urged for patients of French Canadian and Cajun descent.

ACOG emphasizes the importance of assessing these risks prior to pregnancy to allow time for the partner to be tested, if necessary.

Among the Ashkenazi Jewish population, DNA testing detects more than 95% of carriers of autosomal disorders by analyzing the small number of mutations responsible. Tay-Sachs was the first disease for which mutations were identified.

Familial dysautonomia is caused by a single mutation in the gene IKBKAP in more than 99% of affected patients. It has a carrier rate (1/32) similar to that of Tay-Sachs disease (1/30) and involves substantial morbidity of the autonomic and sensory nervous system, with symptoms such as abnormal sweating, pain/temperature insensitivity, and labile blood pressure. Treatment may relieve symptoms, but does not cure the disease.

Refer non-Ashkenazi partners of identified carriers. Although non-Ashkenazi partners are less likely to be carriers, the exact carrier frequency and detection rates for these people are unknown (except for Tay-Sachs disease and cystic fibrosis). In these situations, it may be wise to refer the patient and her partner for genetic counseling to clarify the sensitivity of DNA analysis and the advisability of possible alternative testing by enzyme analysis.

What a generalist should offer. Because the availability of genetic testing will continue to increase, ACOG recommends that generalists provide:

  • patient education on the disorders,
  • referral sources for additional counseling and prenatal diagnostic testing,
  • informed consent when obtaining samples for genetic testing, and
  • assurance of confidentiality.
Encourage carriers to share test results with family members who may be at risk. As ACOG points out, there is no precedent for health-care providers contacting other family members with genetic testing information unless a patient-provider relationship already exists.

Screen for Down syndrome in the first trimester

ACOG Committee Opinion #296: First-trimester screening for fetal aneuploidy. Obstet Gynecol. 2004;104:215–217.

Screening for Down syndrome is now available in the first trimester; ACOG recommends using ultrasound and maternal serum screening, with 3 criteria:

  • standardized, continuous quality assurance,
  • ability to counsel patients about the testing options, and
  • access to appropriate diagnostic testing.
Essential to the ACOG opinion was a collaborative study by Wapner et al1 on a first-trimester screening program in numerous US centers. The results: a 79% detection of trisomy 21 at 11 to 14 weeks’ gestation, with a screen-positive rate of 5%. This compares favorably with screening in the second trimester by a triple panel (maternal serum alpha-fetoprotein, beta-human chorionic gonadotropin, and estriol) or a quad panel (triple panel plus inhibin) (

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