NOVEL MUTATIONS AND DNA-BASED SCREENING IN NON-JEWISH CARRIERS OF TAY-SACHS-DISEASE

We have evaluated the feasibility of using PCR-based mutation screenin g for non-Jewish enzyme-defined carriers identified through Tay-Sachs disease-prevention programs. Although Tay-Sachs mutations are rare in the general population, non-Jewish individuals may be screened as spou ses of Jewish carriers or as relatives of probands. In order to define a panel of alleles that might account for the majority of mutations i n non-Jewish carriers, we investigated 26 independent alleles from 20 obligate carriers and 3 affected individuals. Eighteen alleles were re presented by 12 previously identified mutations, 7 that were newly ide ntified, and 1 that remains unidentified. We then investigated 46 enzy me-defined carrier alleles: 19 were pseudodeficiency alleles, and five mutations accounted for 15 other alleles. An eighth new mutation was detected among enzyme-defined carriers. Eleven alleles remain unidenti fied, despite the testing for 23 alleles. Some may represent false pos itives for the enzyme test. Our results indicate that predominant muta tions, other than the two pseudodeficiency alleles (739C-->T and 745C- ->T) and one disease allele (IVS9+1G-->A), do not occur in the general population. This suggests that it is not possible to define a collect ion of mutations that could identify an overwhelming majority of the a lleles in non-Jews who may require Tay-Sachs carrier screening. We con clude that determination of carrier status by DNA analysis alone is in efficient because of the large proportion of rare alleles. Notwithstan ding the possibility of false positives inherent to enzyme screening, this method remains an essential component of carrier screening in non -Jews. DNA screening can be best used as an adjunct to enzyme testing to exclude known HEXA pseudodeficiency alleles, the IVS9+1G-->A diseas e allele, and other mutations relevant to the subject's genetic herita ge.