POPULATION-SPECIFIC SCREENING BY MUTATION ANALYSIS FOR DISEASES FREQUENT IN ASHKENAZI JEWS

We describe a partially automated DNA mutation assay for detecting the most frequent mutations in the alpha-subunit of beta-hexosaminidase A , the acid beta-glucosidase and the cystic fibrosis transmembrane cond uctance regulator genes for the Ashkenazi Jewish population. The assay detects carriers for Tay-Sachs disease, Gaucher disease, and cystic f ibrosis with sensitivities of at least 92%, 96%, and 97%, respectively . Among 1,364 young adults of Ashkenazic ancestry in the Dor Yeshurim community who were tested, 52 were Tay-Sachs carriers, 110 were Gauche r carriers, and 62 were cystic fibrosis carriers. Ten individuals were carriers for two diseases, and three unsuspected cases were diagnosed with Gaucher disease based on mutation test results. In addition to T ay Sachs mutation data, results for hexosaminidase A activity were als o available. All of 1,254 samples normal by enzyme quantitation were a lso negative for the three alpha-subunit mutations tested, and all of 43 samples with 'inconclusive' enzyme results were negative by DNA. On ly 52 of 67 samples positive by enzyme assay were also positive for on e of the three mutations tested for Tay Sachs disease. The data sugges t a high degree of false positivity inherent in enzyme identification of carriers, There are no correlative methods to assess the sensitivit y of Gaucher and CF carrier testing. The results show that population screening can be carried out efficiently by DNA analysis, with the acc rual of carrier information for three separate diseases conducted as a single test. Furthermore, the DNA method for Tay Sachs screening appe ars to exceed the specificity of hexosaminidase A enzyme testing. (C) 1996 Wiley-Liss, Inc.