From the Guidelines
The best way to predict Tay-Sachs disease in a fetus with a mother of Ashkenazi Jewish background and family history of Tay-Sachs is through molecular testing of both parents for the HEXA gene mutation, specifically the three most common mutations (1278insTATC, 1421+1G>C, and G269S) that account for over 95% of Tay-Sachs cases in this population. This approach is recommended because it allows for the detection of the specific genetic mutations that cause Tay-Sachs disease, providing a more accurate diagnosis than enzyme activity testing alone 1.
Key Considerations
- The carrier frequency of Tay-Sachs disease among Ashkenazi Jews is approximately 1 in 31.7, making it a significant concern for this population 1.
- Molecular testing can detect over 98% of obligate Jewish carriers and 93% of Jewish carriers identified by enzymatic screening, making it a highly effective screening tool 1.
- If both parents are found to be carriers, prenatal diagnostic testing should be performed to determine if the fetus is affected, either through chorionic villus sampling (CVS) at 10-13 weeks of pregnancy or amniocentesis at 15-20 weeks 1.
Testing Options
- Molecular testing of both parents for the HEXA gene mutation is the recommended approach, as it provides a high degree of accuracy in detecting the specific genetic mutations that cause Tay-Sachs disease 1.
- Enzyme activity testing of the father or affected family member may not provide the same level of accuracy as molecular testing, and is not recommended as the primary screening method 1.
- Preimplantation genetic diagnosis (PGD) with in vitro fertilization is another option for couples known to be carriers who wish to prevent having an affected child 1.
Importance of Genetic Counseling
- Genetic counseling should accompany all testing to help understand the 25% risk of having an affected child when both parents are carriers, and to discuss options if the fetus is diagnosed with Tay-Sachs disease 1.
- Counseling can also help couples understand the residual risks associated with molecular testing, and make informed decisions about their reproductive options 1.
From the Research
Predicting Tay Sachs in the Fetus
To predict if the fetus is affected by Tay Sachs, considering the mother's Ashkenazi Jewish background and family history of Tay Sachs, the following options are available:
- Molecular testing of the mother: This is the preferred method for ascertaining carriers in Ashkenazi Jews, as DNA testing identifies 99.9% of carriers 2.
- Enzyme activity testing of the father: If the father is not of Ashkenazi Jewish descent, enzyme assay should be done initially, and positive or indeterminate results should be confirmed by DNA mutation analysis 2.
- Enzyme activity testing in the affected family member: This method can be used to identify carriers, but it may not be as accurate as molecular testing, especially in individuals with pseudodeficiency alleles 2, 3.
Recommended Approach
The recommended approach is to offer carrier testing to couples when at least one individual is of Ashkenazi Jewish descent, and ideally, testing should be done prior to conception 2. If the couple is already pregnant, both partners should have enzyme testing and DNA testing sent concomitantly to expedite counseling and action 2. Prenatal diagnosis can be accomplished within 24-48 hours from sampling using biochemical and DNA-based methods in peripheral and umbilical cord blood, amniotic fluid, and chorionic villi samples 4.
Key Considerations
Key considerations include:
- Carrier testing should be offered to couples when at least one individual is of Ashkenazi Jewish descent 2.
- Molecular testing is the preferred method for ascertaining carriers in Ashkenazi Jews 2.
- Enzyme activity testing can be used to identify carriers, but it may not be as accurate as molecular testing 2, 3.
- Prenatal diagnosis can be used to detect Tay Sachs disease in the fetus 4, 5.