Tay-Sachs disease preconception screening in Australia: self-knowledge of being an Ashkenazi Jew predicts carrier state
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ORIGINAL ARTICLE
Tay-Sachs disease preconception screening in Australia: self-knowledge of being an Ashkenazi Jew predicts carrier state better than does ancestral origin, although there is an increased risk for c.1421+1G>C mutation in individuals with South African heritage Raelia Lew & Leslie Burnett & Anné Proos
Received: 4 January 2011 / Accepted: 30 June 2011 / Published online: 15 July 2011 # Springer-Verlag 2011
Abstract The Australasian Community Genetics Program provided a preconception screening for Tay-Sachs disease (TSD) to 4,105 Jewish high school students in Sydney and Melbourne over the 12-year period 1995–2007. By correlating the frequencies of mutant HEXA, MIM *606869 (gene map locus 15q23-q24) alleles with subjects’ nominated ethnicity (Ashkenazi/Sephardi/Mixed) and grandparental birthplaces, we established that Ashkenazi ethnicity is a better predictor of TSD carrier status than grandparental ancestral origins. Screening self-identified Ashkenazi subjects detected 95% of TSD carriers (carrier frequency 1:25). Having mixed Ashkenazi and non-Ashkenazi heritage reduced the carrier frequency (1:97). South African heritage conveyed a fourfold risk of c.1421+ 1G> C mutation compared with other AJ subjects (odds ratio (OR), 4.19; 95% confidence interval (CI), 1.83–9.62, p=0.001), but this was the only specific case of ancestral origin improving
diagnostic sensitivity over that based on determining Ashkenazi ethnicity. Carriers of c.1278insTATC mutations were more likely to have heritage from Western Europe (OR, 1.65 (95% CI, 1.04–2.60), p=0.032) and South Eastern Europe (OR, 1.77 (95% CI, 1.14–2.73), p=0.010). However, heritage from specific European countries investigated did not significantly alter the overall odds of TSD carrier status.
Nonstandard abbreviations are used in this paper.
Introduction
R. Lew (*) : L. Burnett : A. Proos Department of Obstetrics and Gynaecology, Queen Elizabeth II Research Institute for Mothers and Infants, University of Sydney NSW 2006, Sydney, Australia e-mail: [email protected] L. Burnett : A. Proos Pacific Laboratory Medicine Services (PaLMS), Pathology North, Royal North Shore Hospital, St. Leonards, Sydney, NSW 2065, Australia R. Lew Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia
Keywords Tay-Sachs disease . Australia . South Africa . Jewish . Screening Abbreviations AJ Ashkenazi Jewish TSD Tay-Sachs Disease
Tay-Sachs disease (TSD) is a fatal neurodegenerative lysosomal sphingolipid storage disorder caused by mutations of HEXA MIM *606869 (gene map locus 15q23-q24). The HEXA gene product is the α-subunit of βhexosaminidase, a dimeric enzyme involved in the lysosomal degradation of GM2 gangliosides. TSD carrier frequency is approximately 1:25 in individuals of Ashkenazi Jewish (AJ) descent (Kolodny 2009). TSD incidence in Jewish people is one in 3,900 births, compared to one in 320,000 births in the general population (Triggs-Raine et al. 2001). Several mutant HEXA alleles have been demonstrated in the AJ population (Arpaia et al. 1988)
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