OJGen  Vol.3 No.1 , March 2013
Tay-Sachs carrier screening in the genomics age: Gene sequencing versus enzyme analysis in non-Jewish individuals
ABSTRACT

Purpose: To compare the sensitivity of Hexosaminidase A (HexA) enzyme-based testing to gene sequencing for carrier detection in non-Jewish individuals. Methods: Blood samples were obtained from parents and relatives of affected patients at an annual Tay-Sachs and Allied Diseases Foundation meeting. A family history was taken for each individual. Samples were analyzed for leukocyte HexA activity, serum HexA activity and subjected to extensive gene sequencing. The results from these analyses were combined with our previously published data describing 34 obligate Tay-Sachs disease (TSD) carriers. Results: Twelve additional TSD carriers were detected in this study. Gene sequencing successfully identified all 12 carriers whereas enzyme analysis identified 11 of 12 carriers. This individual is a carrier of the B1 variant that is known to cause false negative results with enzyme testing. Combined data from 46 non-Jewish TSD carriers revealed that gene sequencing had a higher sensitivity rate than HexA enzyme-based testing (94% versus 87%) in non-Jewish TSD carriers. In our series, approximately 4% of non-Jewish TSD carriers have this mutation. Conclusions: HexA gene sequencing provides a higher sensitivity for TSD carrier detection than HexA based enzyme analysis in non-Jewish patients primarily due to the presence of individuals with the B1 variant.


Cite this paper
Strom, C. , Park, N. , Morgan, C. , Lobo, R. , Crossley, B. , Sharma, R. , Bonilla-Guerrero, R. and Salazar, D. (2013) Tay-Sachs carrier screening in the genomics age: Gene sequencing versus enzyme analysis in non-Jewish individuals. Open Journal of Genetics, 3, 61-66. doi: 10.4236/ojgen.2013.31007.
References
[1]   Kaback, G., Lim-Steele, J., Dabholkar, D., Brown, D., Levy, N. and Zeiger K. (1993) Tay-Sachs disease—Carrier screening, prenatal diagnosis, and the molecular era. An international perspective, 1970 to 1993. The international TSD data collection network. JAMA, 270, 2307-2315. doi:10.1001/jama.1993.03510190063028

[2]   O’Brien, J.S., Okada, S., Chen, A. and Fillerup, D.L. (1970) Tay-Sachs disease. Detection of heterozygotes and homozygotes by serum hexosaminidase assay. The New England Journal of Medicine, 283, 15-20. doi:10.1056/NEJM197007022830104

[3]   ACOG Committee on Genetics. (2005) Screening for Tay-Sachs disease. Obstetrics & Gynecology, 106, 893-894.

[4]   Navon, R., Mark, Z., Mashiah, S. and Padeh, B. (1973) Determination of Tay-Sachs genotypes in pregnant women. Clinical Genetics, 4, 286-287. doi:10.1111/j.1399-0004.1973.tb01158.x

[5]   Nitowsky, H.M., Davis, J., Nakagawa, S. and Fox, D. (1979) Human hexosaminidase isozymes. IV. Effects of oral contraceptive steroids on serum hexosaminidase activity. American Journal of Obstetrics & Gynecology, 134, 642-647.

[6]   Bach, G., Tomczak, J., Risch, N. and Ekstein, J. (2001) Tay-Sachs screening in the Jewish Ashkenazi population: DNA testing is the preferred procedure. American Journal of Medical Genetics, 99, 70-75. doi:10.1002/1096-8628(20010215)99:1<70::AID-AJMG1120>3.0.CO;2-0

[7]   Triggs-Raine, B.L., Mules, E.H., Kaback, M.M., LimSteele, J.S., Dowling, C.E., Akerman, B.R., Natowicz, M.R., Grebner, E.E., Navon, R. and Welch, J.P. (1992) A pseudodeficiency allele common in non-Jewish TaySachs carriers: Implications for carrier screening. The American Journal of Human Genetics, 51, 793-801.

[8]   Cao, Z., Natowicz, M.R., Kaback, M.M., Lim-Steele, J.S., Prence, E.M., Brown, D., Chabot, T. and Triggs-Raine, B.L. (1993) A second mutation associated with apparent b-hexosaminidase A pseudodeficiency: Identification and frequency estimation. The American Journal of Human Genetics, 53, 1198-1205.

[9]   Kytzia, H.J. and Sandhoff, K. (1985) Evidence for two different active sites on human beta-hexosaminidase A. Interaction of GM2 activator protein with beta-hexosaminidase A. Journal of Biological Chemistry, 260, 7568-7572.

[10]   Rozenberg, R., Kok, F. and Burin, M.G. (2006) Diagnosis and molecular characterization of non-classic forms of Tay-Sachs disease in Brazil. Journal of Child Neurology, 21, 540-544.

[11]   Grebner, E.E. and Tomczak, J. (1991) Distribution of three a-chain b-hexosaminidase A mutations among TaySachs carriers. The American Journal of Human Genetics, 48, 604-607.

[12]   Tutor, J.C. (2004) Biochemical characterization of the GM2 gangliosidosis B1 variant. Brazilian Journal of Medical and Biological Research, 37, 777-783. doi:10.1590/S0100-879X2004000600001

[13]   Whitley, C.B., Anderson, R.A. and McIvor, R.S. (1992) Heterozygosity for the “DN allele” (G533->A) of the bhexosaminidase a subunit gene identified by direct DNA sequencing in a family with the B1 variant of GM2-gangliosidosis. Neuropediatrics, 23, 96-101. doi:10.1055/s-2008-1071320

[14]   Triggs-Raine, B.L., Feigenbaum, A.S., Natowicz, M., Skomorowski, M.A., Schuster, S.M., Clarke, J.T., Mahuran, D.J., Kolodny, E.H. and Gravel, R.A. (1990) Screening for carriers of Tay-Sachs disease among Ashkenazi Jews. A comparison of DNA-based and enzyme-based tests. The New England Journal of Medicine, 323, 6-12. doi:10.1056/NEJM199007053230102

[15]   Park, N.J., Morgan, C., Sharma, R., et al. (2010) Improving accuracy of Tay-Sachs carrier screening of the non-Jewish population: Analysis of 34 carriers and six late-onset patients with HEXA enzyme and DNA sequence analysis, Pediatric Research, 67, 217-220. doi:10.1203/PDR.0b013e3181c6e318

[16]   Huang, D., Chen, C., Sun, W., Strom, C.M. and Bender, R.A. (2004) High-throughput gene sequencing assay development for hereditary nonpolyposis colon cancer. Clinical Colorectal Cancer, 4, 275-279. doi:10.3816/CCC.2004.n.027

[17]   Strom, C.M., Janeczko, R.A., Anderson, B., et al. (2005) Technical validation of a multiplex platform to detect thirty mutations in eight genetic diseases prevalent in individuals of Ashkenazi Jewish descent. Genetics in Medicine, 7, 633-639. doi:10.1097/01.gim.0000187120.93597.16

[18]   Snyder, R.A. and Brady, R.O. (1969) The use of white cells as a source of diagnostic material for lipid storage diseases. Clinica Chimica Acta, 25, 331-338. doi:10.1016/0009-8981(69)90275-7

[19]   Lowry, O.H., Rosebrough, N.J., Farral, A.L. and Randall, R.J. (1951) Protein measurement with the Folin phenol reagent. Journal of Biological Chemistry, 193, 265-275.

[20]   O’Brien, J.S., Okada, S., Chen, A. and Fillerup, D.L. (1970) Tay-Sachs disease: Detection of heterozygotes and homozygotes by serum hexosaminidase assay. The New England Journal of Medicine, 283, 15-20.

[21]   PolyPhen-2. http://genetics.bwh.harvard.edu/pph2/ , accessed 11/29/11

[22]   Chelly, A. S., Lacorte, J.-M., Poenara, L. and Kahn, A. (2004) Seven novel Tay-Sachs mutations detected by chemical mismatch cleavage of PCR-amplified DNA fragments. Genomics, 11, 124-134.

 
 
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