HETEROZYGOSITY FOR TAY-SACHS-DISEASE IN NON-JEWISH AMERICANS WITH ANCESTRY FROM IRELAND OR GREAT-BRITAIN

We performed a genetic epidemiological analysis of American non-Jewish people with ancestry from Ireland or Great Britain with regard to het erozygosity for Tay-Sachs disease (TSD). This study was prompted by a recent report that the frequency of heterozygosity for TSD among Irish Americans was 1 in 8, a frequency much higher than that recognised fo r any other population group. We identified 19 of 576 (3.3%) people of Irish background as TSD heterozygotes by the standard thermolability assay for beta-hexosaminidase A (Hex A) activity. Three of 289 people of non-Irish British Isles background (1%) were also identified as het erozygotes by biochemical testing. Specimens from the biochemically id entified Irish heterozygotes were analysed for seven different Hex A c t subunit gene mutations; three (15.8%) had a lethal +1 IVS-9 G to A m utation, previously noted to be a common mutation among TSD heterozygo tes of Irish ancestry. Eight of 19 (42.1%) had one of two benign or ps eudodeficiency mutations, and no mutation was found in 42.1% of the he terozygotes analysed. These data indicate that non-Jewish Americans wi th Irish background have a significantly increased frequency of hetero zygosity at the Hex A a subunit gene locus, but that approximately 42% of the biochemically ascertained heterozygotes have clinically benign mutations. A pseudodeficiency mutation was identified in one of the t hree TSD heterozygotes of non-Irish British Isles background; no mutat ions were found in the other two. The data allow for a frequency estim ate of deleterious alleles for TSD among Irish Americans of 1 in 192 t o 1 in 52. Non-Jewish Americans with ancestry from Great Britain have a minimal, if any, increase in rate of heterozygosity at the TSD gene locus relative to the general population.