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. 2013 Nov;1(4):260-8.
doi: 10.1002/mgg3.37. Epub 2013 Sep 16.

Next-generation DNA sequencing of HEXA: a step in the right direction for carrier screening

Jodi D Hoffman  1 , Valerie Greger  2 , Erin T Strovel  3 , Miriam G Blitzer  3 , Mark A Umbarger  2 , Caleb Kennedy  2 , Brian Bishop  2 , Patrick Saunders  2 , Gregory J Porreca  2 , Jaclyn Schienda  4 , Jocelyn Davie  2 , Stephanie Hallam  2 , Charles Towne  2
Affiliations

Next-generation DNA sequencing of HEXA: a step in the right direction for carrier screening

Jodi D Hoffman et al. Mol Genet Genomic Med. 2013 Nov.

Abstract

Tay-Sachs disease (TSD) is the prototype for ethnic-based carrier screening, with a carrier rate of ∼1/27 in Ashkenazi Jews and French Canadians. HexA enzyme analysis is the current gold standard for TSD carrier screening (detection rate ∼98%), but has technical limitations. We compared DNA analysis by next-generation DNA sequencing (NGS) plus an assay for the 7.6 kb deletion to enzyme analysis for TSD carrier screening using 74 samples collected from participants at a TSD family conference. Fifty-one of 74 participants had positive enzyme results (46 carriers, five late-onset Tay-Sachs [LOTS]), 16 had negative, and seven had inconclusive results. NGS + 7.6 kb del screening of HEXA found a pathogenic mutation, pseudoallele, or variant of unknown significance (VUS) in 100% of the enzyme-positive or obligate carrier/enzyme-inconclusive samples. NGS detected the B1 allele in two enzyme-negative obligate carriers. Our data indicate that NGS can be used as a TSD clinical carrier screening tool. We demonstrate that NGS can be superior in detecting TSD carriers compared to traditional enzyme and genotyping methodologies, which are limited by false-positive and false-negative results and ethnically focused, limited mutation panels, respectively, but is not ready for sole use due to lack of information regarding some VUS.

Keywords: Ethnic-based screening; Tay-Sachs disease.; genetic screening; hexosaminidase A; next-generation DNA sequencing.

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Figures

Figure 1
Figure 1
The study design and outcome. Enzyme analysis and DNA analysis results are shown for all study participants. The white boxes show the number of positives, negatives, inconclusives, and the number of alleles for each mutation category. Note that a pseudoallele results in a false positive in the enzyme analysis, while a B1 variant produces a false-negative result. VUS, variant of unknown significance.
See this image and copyright information in PMC

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