Clinical Chemistry
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Clinical Chemistry 53: 392-398, 2007. First published January 26, 2007; 10.1373/clinchem.2006.082727
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(Clinical Chemistry. 2007;53:392-398.)
© 2007 American Association for Clinical Chemistry, Inc.

Molecular Diagnostics and Genetics

Evaluation of the Risk for Tay-Sachs Disease in Individuals of French Canadian Ancestry Living in New England

Dianna C. Martin1, Brian L. Mark2, Barbara L. Triggs-Raine1,3,4 and Marvin R. Natowicz5,a

Departments of1 Biochemistry and Medical Genetics, 2 Microbiology, and 3 Pediatrics and Child Health, University of Manitoba, Winnipeg, MB, Canada.
4 Manitoba Institute for Child Health, Winnipeg, MB, Canada.
5 Genomic Medicine Institute and Departments of Neurology, Pathology and Laboratory Medicine and Pediatrics, Cleveland Clinic, Cleveland, OH.

aAddress correspondence to this author at: Genomic Medicine Institute, Cleveland Clinic Foundation NE-5, 9500 Euclid Avenue, Cleveland, OH 44195. Fax 216-636-0009; e-mail Natowim{at}ccf.org.

Background: The assessment of risk for Tay-Sachs disease (TSD) in individuals of French Canadian background living in New England is an important health issue. In preliminary studies of the enzyme-defined carrier frequency for TSD among Franco-Americans in New England, we found frequencies (1:53) higher than predicted from the incidence of infantile TSD in this region. We have now further evaluated the risk for TSD in the Franco-American population of New England.

Methods: Using a fluorescence-based assay for ß-hexosaminidase activity, we determined the carrier frequencies for TSD in 2783 Franco-Americans. DNA analysis was used to identify mutations causing enzyme deficiency in TSD carriers.

Results: We determined the enzyme-defined carrier frequency for TSD as 1:65 (95% confidence interval 1:49 to 1:90). DNA-based analysis of 24 of the enzyme-defined carriers revealed 21 with sequence changes: 9 disease-causing, 4 benign, and 8 of unknown significance. Six of the unknowns were identified as c.748G>A p.G250S, a mutation we show by expression analysis to behave similarly to the previously described c.805G>A p.G269S adult-onset TSD mutation. This putative adult-onset TSD c.748G>A p.G250S mutation has a population frequency similar to the common 7.6 kb deletion mutation that occurs in persons of French Canadian ancestry.

Conclusions: We estimate the frequency of deleterious TSD alleles in Franco-Americans to be 1:73 (95% confidence interval 1:55 to 1:107). These data provide a more complete data base from which to formulate policy recommendations regarding TSD heterozygosity screening in individuals of French Canadian background.






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