Background and methods: The prevention of Tay-Sachs disease (GM2 gangliosidosis, type 1) depends on the identification of carriers of the gene for this autosomal recessive disorder. We compared the enzyme-based test widely used in screening for Tay-Sachs disease with a test based on analysis of DNA. We developed methods to detect the three mutations in the HEXA gene that occur with high frequency among Ashkenazi Jews: two mutations cause infantile Tay-Sachs disease, and the third causes the adult-onset form of the disease. DNA segments containing these mutation sites were amplified with the polymerase chain reaction and analyzed for the presence of the mutations.
Results: Among 62 Ashkenazi obligate carriers of Tay-Sachs disease, the three specific mutations accounted for all but one of the mutant alleles (98 percent). In 216 Ashkenazi carriers identified by the enzyme test, DNA analysis showed that 177 (82 percent) had one of the identified mutations. Of the 177, 79 percent had the exon 11 insertion mutation, 18 percent had the intron 12 splice-junction mutation, and 3 percent had the less severe exon 7 mutation associated with adult-onset disease. The results of the enzyme tests in the 39 subjects (18 percent) who were defined as carriers but in whom DNA analysis did not identify a mutant allele were probably false positive (although there remains some possibility of unidentified mutations). In addition, of 152 persons defined as noncarriers by the enzyme-based test, 1 was identified as a carrier by DNA analysis (i.e., a false negative enzyme-test result).
Conclusions: The increased specificity and predictive value of the DNA-based test make it a useful adjunct to the diagnostic tests currently used to screen for carriers of Tay-Sachs disease. Although some false positive results may be desirable on an enzyme-based test that is used in screening, the DNA test allows precise definition of the carrier state for the known mutations.