Next-generation DNA sequencing of HEXA: a step in the right direction for carrier screening.
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.
Division of Genetics, Department of Pediatrics, Floating Hospital for Children, Tufts Medical Center Boston, Massachusetts.
Jodi D
JD
Hoffman
Good Start Genetics Inc. Cambridge, Massachusetts.
Valerie
V
Greger
Division of Genetics, Department of Pediatrics, University of MD School of Medicine Baltimore, Maryland.
Erin T
ET
Strovel
Division of Genetics, Department of Pediatrics, University of MD School of Medicine Baltimore, Maryland.
Miriam G
MG
Blitzer
Good Start Genetics Inc. Cambridge, Massachusetts.
Mark A
MA
Umbarger
Good Start Genetics Inc. Cambridge, Massachusetts.
Caleb
C
Kennedy
Good Start Genetics Inc. Cambridge, Massachusetts.
Brian
B
Bishop
Good Start Genetics Inc. Cambridge, Massachusetts.
Patrick
P
Saunders
Good Start Genetics Inc. Cambridge, Massachusetts.
Gregory J
GJ
Porreca
Dana Farber Cancer Institute Boston, Massachusetts.
Jaclyn
J
Schienda
Good Start Genetics Inc. Cambridge, Massachusetts.
Jocelyn
J
Davie
Good Start Genetics Inc. Cambridge, Massachusetts.
Stephanie
S
Hallam
Good Start Genetics Inc. Cambridge, Massachusetts.
Charles
C
Towne
Ethnic-based screening; Tay-Sachs disease.; genetic screening; hexosaminidase A; next-generation DNA sequencing