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

Park, Noh Jin; Craig, Morgan; Sharma, Rajesh; Li, Yuanyin; Lobo, Raynah; Redman, Joy B.; Salazar, Denise; Sun, Weimin; Neidich, Julie; Strom, Charles M.

doi:10.1203/pdr.0b013e3181c6e318

Cited by 23 publications

(21 citation statements)

References 17 publications

(11 reference statements)

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“…Indeed, the one enzyme positive-DNA negative sample that we were able to follow up by sequence analysis has one non-AJ parent. As mentioned, the Thr259Ala mutation that we identified in this family was reported in a study of non-AJ TSD carriers and lateonset patients (Park et al 2010). Although in that report the authors speculated that this Thr259Ala could be a benign polymorphism, we suggest that it may instead be disease causing.…”

Section: Discussionmentioning

confidence: 48%

“…An oligonucleotide ligation assay on the Prism Genetic Analyzer was developed by the laboratory to interrogate position 775, and this confirmed the same nucleotide change in the mother but not the father (data not shown). This A775G (Thr259Ala) mutation also was uncovered recently after HEXA sequencing of a non-AJ carrier (Park et al 2010), suggesting that it may not be a rare familial mutation. We analyzed further the Thr259Ala change to gain insight as to whether it could represent a deleterious mutation.…”

Section: Resultsmentioning

confidence: 84%

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Platelet Hexosaminidase A Enzyme Assay Effectively Detects Carriers Missed by Targeted DNA Mutation Analysis

et al. 2012

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Biochemical testing of hexosaminidase A (HexA) enzyme activity has been available for decades and has the ability to detect almost all Tay-Sachs disease (TSD) carriers, irrespective of ethnic background. This is increasingly important, as the gene pool of those who identify as Ashkenazi Jewish is diversifying. Here we describe the analysis of a cohort of 4,325 individuals arising from large carrier screening programs and tested by the serum and/or platelet HexA enzyme assays and by targeted DNA mutation analysis. Our results continue to support the platelet assay as a highly effective method for TSD carrier screening, with a low inconclusive rate and the ability to detect possible disease-causing mutation carriers that would have been missed by targeted DNA mutation analysis. Sequence analysis performed on one such platelet assay carrier, who had one non-Ashkenazi Jewish parent, identified the amino acid change Thr259Ala (A775G). Based on crystallographic modeling, this change is predicted to be deleterious, as threonine 259 is positioned proximal to the HexA alpha subunit active site and helps to stabilize key residues therein. Accordingly, if individuals are screened for TSD in broad-based programs by targeted molecular testing alone, they must be made aware that there is a more sensitive and inexpensive test available that can identify additional carriers. Alternatively, the enzyme assays can be offered as a first tier test, especially when screening individuals of mixed or non-Jewish ancestry.

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Section: Discussionmentioning

confidence: 48%

Section: Resultsmentioning

confidence: 84%

Platelet Hexosaminidase A Enzyme Assay Effectively Detects Carriers Missed by Targeted DNA Mutation Analysis

et al. 2012

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“…) and c.118delT (Park et al. ) appear to be rare alleles; they are considered pathogenic because of their truncating nature. Of note, these five variants would not have been detected by utilizing popular genotyping approaches, like the one described in Lazarin et al.…”

Section: Resultsmentioning

confidence: 99%

“…Full‐exon sequencing is not always sensitive enough to detect every disease allele in TSD patients or obligate carriers (Park et al. ; Gort et al. ).…”

Section: Discussionmentioning

confidence: 99%

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

Hoffman

Greger

Strovel

et al. 2013

Molec Gen & Gen Med

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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.

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“…However, mixed ethnicity, adoption, and unknown ancestry compromise the application of the ethnicity‐based approach. The birth of babies with classically ‘Jewish’ disorders to non‐Jewish families exemplifies the pitfalls of defining genetic risks based on patients' self‐report and increasingly nebulous social constructs of race and ethnicity 16. The ACOG statement on CF carrier screening acknowledges the difficulty of assigning a single ethnicity to individuals as a justification for offering pan‐ethnic screening 3.…”

Section: Introductionmentioning

confidence: 99%

Changing trends in carrier screening for genetic disease in the United States

Nazareth¹,

Lazarin²,

Goldberg³

2015

Prenatal Diagnosis

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Genetic disease is the leading cause of infant death in the United States, accounting for approximately 20% of annual infant mortality. Advances in genomic medicine and technological platforms have made possible low cost, pan‐ethnic expanded genetic screening that enables obstetric care providers to offer screening for over 100 recessive genetic diseases. However, the rapid integration of genomic medicine into routine obstetric practice has raised some concerns about the practical implementation of such testing. These changing trends in carrier screening, along with concerns and potential solutions, will be addressed. © 2015 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.

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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

Cited by 23 publications

References 17 publications

Platelet Hexosaminidase A Enzyme Assay Effectively Detects Carriers Missed by Targeted DNA Mutation Analysis

Platelet Hexosaminidase A Enzyme Assay Effectively Detects Carriers Missed by Targeted DNA Mutation Analysis

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

Changing trends in carrier screening for genetic disease in the United States

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