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Vol. 19: Spring 2001
Prenatal Diagnosis

Prenatal Diagnosis of Single Gene Disorders

The number of genetic disorders that can be diagnosed prenatally is constantly expanding, and internet resources should be consulted for the most up-to-date information. In many instances, a diagnosis is based on molecular techniques, which can identify specific mutations. Examples include autosomal recessive disorders such as cystic fibrosis, X-linked disorders such as Factor VIII deficiency (Hemophilia A), and autosomal dominant disorders such as Huntington disease. Other disorders, such as Smith-Lemli-Opitz syndrome, an autosomal recessive disorder caused by abnormal cholesterol synthesis, can be diagnosed by biochemical methods from cells obtained by chorionic villus sampling or amniocentesis. The purpose of this section is to review the general approach to prenatal diagnosis of any genetic condition. 

The first step: Recording the family history

Ideally, the process begins by obtaining a detailed family history prior to conception. If a positive family history of a specific disorder is identified, a referral to a genetic specialist may be appropriate to confirm the diagnosis. If both partners are of an ethnic group known to have a high carrier frequency for a particular disease, carrier testing is indicated. For example, carrier testing for the following seven conditions is offered to parents of Ashkenazi Jewish descent: Tay-Sachs disease, Canavan disease, cystic fibrosis, Gaucher disease, Bloom syndrome, Fanconi anemia (Group C) and Niemann-Pick disease (Type A).

For several reasons, the best time to offer carrier testing is also prior to conception. First, decisions about whether to conceive or to use gamete donors may depend on an accurate risk assessment. Second, being told that one is a carrier of a genetic disorder may have emotional consequences, and these may be exaggerated if a current pregnancy is involved. Third, the time needed to obtain the results of carrier testing can be lengthy. For an autosomal recessive disorder, it may be more cost-effective to test only one partner rather than the couple. If the tested individual is not a carrier, then the pregnancy is essentially not at risk. However, if a second trimester pregnancy is involved, time may be a constraint, and both parents will need to be tested simultaneously. 

Genetic counseling can be beneficial for the couple concerned about genetic risks to their offspring. In many cases, when a genetic disorder has been diagnosed in a family member, the couple imagines their risk to be much higher than it actually is. 

Example: Ms. L had a brother and a sister with cystic fibrosis (CF). Her brother is deceased, and her sister is awaiting a lung transplant. She and her husband are both Caucasians of Northern European descent. What is their risk of having a child with CF? Ms. L has a risk of 2/3 to be a carrier, and Mr. L has a risk of 1 in 25, if there is no history of CF in his family. CF is inherited as an autosomal recessive disorder, so the overall risk of having an affected child is 2/3 x 1/25 x 1/4, or 1/150. While this risk is approximately 17 times higher than the general population risk for Caucasian couples with no family history of CF, the risk is still less than 1%. In this case, it makes sense to offer CF mutation analysis to Mr. L first, if time is not critical. If no mutation is identified, his risk is reduced to less than 1 in 200, and the overall risk of having an affected child drops to less than 1 in 1200. 

For some genetic conditions, such as Charcot-Marie-Tooth disease, more than one inheritance pattern has been described. Pedigree analysis can sometimes help to identify the mode of inheritance in a particular family. 

Confirming the diagnosis in the affected individual

Another critical step in the process is obtaining medical records, to confirm the diagnosis in the affected relative. Many specialized referral laboratories require that documentation of the diagnosis accompany the specimen being sent for prenatal diagnosis. For example, if the diagnosis involves a metabolic disease, the enzyme levels in the affected child and the carrier parents may provide information, which would be helpful in interpreting the results from the prenatal sample. 

The lab that made the diagnosis of the affected individual would be the best lab to test the prenatal specimen or perform carrier tests on other family members. This is not always possible, since insurance companies may dictate where a sample must be sent.

Determining whether prenatal diagnosis is possible

After the genetic diagnosis has been confirmed and the risk has been assessed, the next step is to determine whether prenatal testing is available. A very valuable resource is GeneTests(tm), formerly called Helix at www.genetests.org. This is a comprehensive database of genetic laboratories funded by the National Library of Medicine of the NIH, and the Maternal and Child Health Bureau. It is available without cost to any health professional, although one must register as a user in order to access the information. 

GeneTests(tm) lists over 700 genetic diseases and over 450 laboratories, which provide DNA and other genetic testing. One can search by disease name, and a list of labs performing testing will appear. The listing will indicate whether testing is for research only, clinical, and/or prenatal. A contact person is also listed for each lab, so that the specific case can be discussed before sending a sample. For instance, the cost and turn-around time may differ between two labs testing for the same disease. GeneTests(tm) also offers a genetics clinic directory, which can be searched by location or type of clinic. 

It is important to note that there are still many recognized single gene disorders for which no carrier testing or prenatal diagnosis is currently available. Since change occurs so rapidly in this field, families should be encouraged to regularly contact their genetics center to see if advances have occurred for the disorder in question. This is especially true if they are considering a pregnancy. 

When and how?

Once it has been established that prenatal diagnosis is an option for a pregnant woman, the next question concerns the gestational age at which the diagnosis can be made. If a DNA test is available, usually CVS will be the preferred method to obtain the sample. When both parents are carriers of a recessive disease, they have a 25% risk with each pregnancy. The slightly increased risk of fetal loss with CVS, as compared to amniocentesis, is usually acceptable to them in order to obtain a result in the first trimester. As discussed elsewhere in this publication, CVS is usually performed at 10-13 weeks from the last menstrual period. However, if the pregnancy is beyond the first trimester, amniocentesis remains a viable option. Patients need to be informed about when to expect results, since some testing may take several weeks.

Non-invasive techniques

If no biochemical or molecular diagnosis is available, it is important to determine whether any anatomic features of the disorder could possibly be identified by fetal ultrasound, and at what gestational age one would first look. In such cases, serial ultrasound examinations may be required. For example, ultrasound has been useful in the prenatal diagnosis of alpha-thalassemia in at-risk fetuses. The diagnosis has been suspected as early as 12-13 weeks, based on an increased cardio-thoracic ratio. (Lam, et al., 1999).

Research currently continues on the isolation and characterization of fetal cells in the maternal circulation, but this is not yet clinically available. 

Analysis of maternal urine has shown promise in evaluating for Smith-Lemli-Opitz syndrome, an autosomal recessive disorder of cholesterol metabolism. When a woman is carrying an affected fetus, disease-specific sterols are present in her urine. (Shackelton, et al., 1999).

Practical considerations

Preparations must be made before offering prenatal diagnosis for rare disorders, as the process can be time-consuming. Special arrangements must be made in advance with the referral laboratory. Proper pre-authorization from the insurance company should be sought, recognizing that carrier testing is often denied as a covered benefit, even when clearly indicated. The shipping and handling requirements may be complicated, as when the sample must be shipped on dry ice. The lab may also require special consent forms. 

For all these reasons, it is important to work with a genetic consultant when an at-risk couple is identified. Failure to do the necessary groundwork has resulted in situations where a physician has performed an amniocentesis on a patient, only to learn that there is no prenatal diagnosis available for the disorder in question. 

The Genetic Drift Newsletter is not copyrighted. Readers are free to duplicate all or parts of its contents. The Genetic Drift Newsletter is published semiannually by the Mountain States Regional Genetic Services Network for associates & those interested in Human Genetics. In accordance with accepted publication standards, we request acknowledgement in print of any article reproduced in another publication. The views expressed in the newsletter do not necessarily reflect local, state, or federal policy. For additional information, contact Carol Clericuzio, M.D., Editor, Department of Pediatrics, The University of New Mexico, Albuquerque, NM, 87131

Prenatal Diagnosis - Table of Contents

Prenatal Diagnosis of Single Gene Disorders
Down Syndrome Maternal Serum Screening
Fetal Ultrasound
Chorionic Villus Sampling
Percutaneous Umbilical Blood Sampling
Preimplantation Genetic Diagnosis
The Future of Prenatal Diagnosis
TABLE: Timetable for Prenatal Diagnostic/Screening Procedures



Bob McCurdy