Tay-sachs screening in the Jewish Ashkenazi population: DNA testing is the preferred procedure

A unique screening program for the identification of Tay-Sachs Disease (TSD) heterozygotes has been performed in the traditional Orthodox Ashkenazi Jewish (AJ) community since 1983. In recent years the program has utilized the biochemical assay for the determination of hexosaminidase A levels by the heat inactivation technique as well as by direct DNA analysis. The three mutations which were analyzed were those that have been shown to be prevalent among AJ TSD patients and carriers, namely the four nucleotide insertion mutation in exon 11 (1278+TATC), the splice mutation at the 5' end of intron 12 (1421+1g-->c), and the adult mutation, a Gly(269)-->Ser substitution in exon 5 (G269S). A total of 103,133 individuals were tested by biochemical analysis, and 38,197 of them were also assayed by DNA testing. Furthermore, 151 chromosomes from TSD patients or obligate heterozygotes were subjected to DNA analysis for one of the three mutations. DNA testing of the latter identified one of the three AJ mutations in every case, predicting a very high detection rate of heterozygotes in this community by this method. By contrast, the sensitivity of the enzyme assay ranged from 93.1% to 99.1% depending on the exclusion (inclusion) of inconclusive results as positive, while the specificity ranged from 88.1% to 98.8% depending on the inclusion (exclusion) of inconclusive results as positive. Our results strongly support the use of DNA testing alone as the most cost-effective and efficient approach to carrier screening for TSD in individuals of confirmed Ashkenazi Jewish ancestry. (C) 2001 Wiley-Liss, Inc.