Sunday, February 10, 2019

Tay-Sachs disease in the Irish population

Branda KJ, Tomczak J, Natowicz MR. Heterozygosity for Tay-Sachs and Sandhoff diseases in non-Jewish Americans with ancestry from Ireland, Great Britain, or Italy. Genet Test. 2004 Summer;8(2):174-80.

Previous reports have found that non-Jewish Americans with ancestry from Ireland have an increased frequency of heterozygosity for Tay-Sachs disease (TSD), although frequency estimates are substantially different. Our goal in this study was to determine the frequency of heterozygosity for TSD and Sandhoff diseases (SD) among Irish Americans, as well as in persons of English, Scottish, and/or Welsh ancestry and in individuals with Italian heritage, who were referred for determination of their heterozygosity status and who had no known family history of TSD or SD or of heterozygosity for these conditions. Of 610 nonpregnant subjects with Irish background, 24 TSD heterozygotes were identified by biochemical testing, corresponding to a heterozygote frequency of 1 in 25 (4%; 95% CI, 1/39-1/17). In comparison, of 322 nonpregnant individuals with ancestry from England, Scotland, or Wales, two TSD heterozygotes were identified (1 in 161 or 0.62%; 95% CI, 1/328-1/45), and three TSD heterozygotes were ascertained from 436 nonpregnant individuals with Italian heritage (1 in 145 or 0.69%; 95% CI, 1/714-1/50). Samples from 21 Irish heterozygotes were analyzed for HEXA gene mutations. Two (9.5%) Irish heterozygotes had the lethal + 1 IVS-9 G --> A mutation, whereas 9 (42.8%) had a benign pseudodeficiency mutation. No mutation was found in 10 (47.6%) heterozygotes. These data allow for a frequency estimate of deleterious alleles for TSD among Irish Americans of 1 in 305 (95% CI, 1/2517-1/85) to 1 in 41 (95% CI, 1/72-1/35), depending on whether one, respectively, excludes or includes enzyme-defined heterozygotes lacking a defined deleterious mutation. Pseudodeficiency mutations were identified in both of the heterozygotes with ancestry from other countries in the British Isles, suggesting that individuals with ancestry from these countries do not have an increased rate of TSD heterozygosity. Four SD heterozygotes were found among individuals of Italian descent, a frequency of 1 in 109 (0.92%; 95% CI, 1/400-1/43). This frequency was higher than those for other populations, including those with Irish (1 in 305 or 0.33%; 95% CI, 1/252-1/85), English, Scottish, or Welsh (1 in 161 or 0.62%; 95% CI, 1/1328-1/45), or Ashkenazi Jewish (1 in 281 or 0.36%; 95% CI, 1/1361-1/96) ancestry. Individuals of Irish or Italian heritage might benefit from genetic counseling for TSD and SD, respectively.

van Bael M, Natowicz MR, Tomczak J, Grebner EE, Prence EM. Heterozygosity for Tay-Sachs disease in non-Jewish Americans with ancestry from Ireland or Great Britain. J Med Genet. 1996 Oct;33(10):829-32.


We performed a genetic epidemiological analysis of American non-Jewish people with ancestry from Ireland or Great Britain with regard to heterozgosity 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 for 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 heterozygotes by biochemical testing. Specimens from the biochemically identified Irish heterozygotes were analysed for seven different Hex A alpha subunit gene mutations; three (15.8%) had a lethal +1 IVS-9 G to A mutation, previously noted to be a common mutation among TSD heterozygotes of Irish ancestry. Eight of 19 (42.1%) had one of two benign or pseudodeficiency mutations, and no mutation was found in 42.1% of the heterozygotes analysed. These data indicate that non-Jewish Americans with Irish background have a significantly increased frequency of heterozygosity at the Hex A alpha 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 three TSD heterozygotes of non-Irish British Isles background; no mutations were found in the other two. The data allow for a frequency estimate of deleterious alleles for TSD among Irish Americans of 1 in 192 to 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.

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