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Molecular Genetic Testing in Mainstream Medicine Vol. 14: Spring, 1997 |
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Molecular Genetic Testing in Mainstream Medicine Vol. 14: Spring, 1997 |
The focus of this section will be on direct DNA tests that can be performed on amniotic fluid samples to assist the physician in prenatal management of pregnancies at risk for maternal-fetal incompatibility. The most frequent cause of allo-immune hemolytic disease is Rhesus (Rh) blood group incompatibility between the mother and her fetus. However, a number of other red blood cell antigens can also lead to similar problems, including the Kell system. Here we will focus on the Rh system because this is the most frequent cause of problems and the best described system, to date. The following three points deserve emphasis:
The Rh blood group locus consists of two closely linked genes on chromosome 1: the RhD gene and the RhCc/Ee gene. The difference between RhD positive and RhD negative individuals is the presence or absence of the RhD gene. RhD negative individuals lack both copies of the RhD gene, while RhD positive individuals have one or two copies of the RhD gene. The Rh E/e and C/c antigens are determined by the RhCc/Ee gene. The E and e alleles differ by a single amino acid in the protein; the C and c alleles differ at four positions in the protein.
At-risk pregnancies include those in which the pregnant woman is RhD negative and has an RhD antibody titer (usually due to sensitization during a previous pregnancy or occasionally due to a previous incompatible transfusion). If the father is RhD negative then the pregnancy should not be at risk; however the possibility of non-paternity should be kept in mind. Similarly, any pregnant woman who is homozygous RhCC, Rhcc, RhEE or Rhee may have antibodies to the antigen that she does not possess and therefore carry an at- risk pregnancy.
Approximately 15% of the U.S. Caucasian population are RhD negative. However, not all RhD negative women have antibodies to the RhD antigen. Therefore, RhD negative women should be tested for the presence of this antibody at an early stage in their pregnancy. Approximately 56% of RhD positive men are heterozygous; i.e. they have only one copy of the RhD gene. Serological testing and the DNA test described below cannot distinguish individuals with one copy of the gene from those with two copies. Fortuntely, if the fetus is RhD negative then incompatibility is not an issue. For the reasons explained above, the best way to determine if the fetus is at risk is to perform RhD testing on a fetal sample. Testing on an amniotic fluid sample is clearly preferrable to a fetal blood (PUBS) sample because the procedure poses less of a risk to the fetus.
The testing assesses the presence or absence of the RhD gene. The test is greater than 99% accurate and gives either an RhD positive or RhD negative result. The RhC/c test looks at the specific sites in the RhCc/Ee gene that differ between the RhC and Rhc alleles. The results are reported as a genotype. The RhE/e test looks at the single difference between the E and e alleles in the RhCc/Ee gene and the results are reported as RhE negative or RhE positive. RhC and RhE testing are believed to be greater than 99% accurate.
A typical sample is 5-10 ml of unspun amniotic fluid shipped at ambient temperature. Fetal blood, CVS tissue and cultured amniocytes or CVS cells are also appropriate samples and may be sent for analysis if a procedure is performed for other reasons. Note that bloody amniotic fluid samples may be difficult to amplify and may lead to false negative results due to maternal cell contamination.
A pregnant woman presents at her OB/GYN office for a prenatal visit. Routine blood work determines that she is RhD negative and her partner is RhD positive. The pregnant woman is then determined to have an RhD serum antibody titer. The pregnancy is typically followed until approximately 22 weeks when fetal monitoring by amniocentesis begins. Part of the amniotic fluid sample is sent for an OD450 analysis to determine if blood degradation products are present in the amniotic fluid (this is a screening test for fetal erythroblastosis) and part is sent for fetal DNA typing. If the fetus is determined to be RhD positive, further monitoring of the OD450 by serial amniocentesis is required. However, if the fetus is determined to be RhD negative, the fetus is judged to be at low risk for Rh disease and can be followed by non- invasive procedures such as sonography.
Contributed by Stephanie Hallam, Ph.D. (UT)
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 Genetics 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
Table of Contents
Molecular Genetic Testing in Mainstream Medicine:
Introduction
Venous Thrombosis and the Factor V (Leiden) Mutation
DNA Testing for Hereditary Hemochromatosis
APO E Genotype Testing for Broad Beta Disease (Type III Hyperlipoproteinemia)
Fetal Rh Testing for Maternal-Fetal Incompatibility
Type 1 (insulin-dependent) Diabetes Mellitus
Adult Onset Neurodegenerative Disorders: CAG Triplet Repeat Expansion Mutations
Genetic Testing for Prader-Willi and Angelman Syndromes
Clinical and Applied Molecular Genetics Laboratories
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