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.
Abstract
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.
Abstract
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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