Open AccessNext‐generation DNA sequencing of HEXA : a step in the right direction for carrier screening
Author(s) -
Hoffman Jodi D.,
Greger Valerie,
Strovel Erin T.,
Blitzer Miriam G.,
Umbarger Mark A.,
Kennedy Caleb,
Bishop Brian,
Saunders Patrick,
Porreca Gregory J.,
Schienda Jaclyn,
Davie Jocelyn,
Hallam Stephanie,
Towne Charles
Publication year - 2013
Publication title -
molecular genetics and genomic medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.765
H-Index - 29
ISSN - 2324-9269
DOI - 10.1002/mgg3.37
Subject(s) - genotyping , obligate , hexa , carrier testing , genetics , dna sequencing , asymptomatic carrier , dna , biology , medicine , genotype , gene , disease , biochemistry , pregnancy , ecology , fetus , prenatal diagnosis
T ay‐ S achs disease ( TSD ) is the prototype for ethnic‐based carrier screening, with a carrier rate of ~1/27 in A shkenazi J ews and F rench C anadians. 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 .