title: Validation for clinical use of, and initial clinical experience with, a novel approach to population-based carrier screening using high-throughput, next-generation DNA sequencing.
abstract: Traditional carrier screening assays are designed to look for only the most common mutations within a gene owing to cost considerations. Although this can yield high detection rates in specific populations for specific genes (such as cystic fibrosis in Caucasians), they are suboptimal for other ethnicities or for patients of mixed or unknown ethnic background. Next-generation DNA sequencing provides an opportunity to provide carrier screening using more comprehensive mutation panels that are limited primarily by information about the clinical impact of detected sequence changes. We describe a next-generation DNA sequencing-based assay capable of reliably screening patient samples in a timely and comprehensive manner. The analytic accuracy in a research setting has been documented. Here, we describe the additional studies performed to ensure the accuracy (analytic validity) and robustness of our assay for use in clinical practice and provide data from our experience offering this testing. Our clinical experience using this approach to screen 11,691 in vitro fertilization patients has identified 449 mutant alleles: 447 in carriers and 2 in an affected individual. In total, we found 87 distinct mutations in 14 different genes. Approximately one quarter of the mutations found are not included in traditional, limited, mutation panels, including 16 known mutations unique to our panel, and novel truncating mutations in several genes.
authors.affiliation: Good Start Genetics, Inc., Cambridge, Massachusetts. Electronic address: shallam@gsgenetics.com.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Hallam
authors.affiliation: Good Start Genetics, Inc., Cambridge, Massachusetts.
authors.forename: Heather
authors.initials: H
authors.lastname: Nelson
authors.affiliation: Good Start Genetics, Inc., Cambridge, Massachusetts.
authors.forename: Valerie
authors.initials: V
authors.lastname: Greger
authors.affiliation: Good Start Genetics, Inc., Cambridge, Massachusetts.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Perreault-Micale
authors.affiliation: Good Start Genetics, Inc., Cambridge, Massachusetts.
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Davie
authors.affiliation: Good Start Genetics, Inc., Cambridge, Massachusetts.
authors.forename: Nicole
authors.initials: N
authors.lastname: Faulkner
authors.affiliation: Good Start Genetics, Inc., Cambridge, Massachusetts.
authors.forename: Dana
authors.initials: D
authors.lastname: Neitzel
authors.affiliation: Good Start Genetics, Inc., Cambridge, Massachusetts.
authors.forename: Kristie
authors.initials: K
authors.lastname: Casey
authors.affiliation: Good Start Genetics, Inc., Cambridge, Massachusetts.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Umbarger
authors.affiliation: Good Start Genetics, Inc., Cambridge, Massachusetts.
authors.forename: Niru
authors.initials: N
authors.lastname: Chennagiri
authors.affiliation: Good Start Genetics, Inc., Cambridge, Massachusetts.
authors.forename: Alexander C
authors.initials: AC
authors.lastname: Kramer
authors.affiliation: Good Start Genetics, Inc., Cambridge, Massachusetts.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Porreca
authors.affiliation: Good Start Genetics, Inc., Cambridge, Massachusetts.
authors.forename: Caleb J
authors.initials: CJ
authors.lastname: Kennedy
mesh_terms: D003550:Cystic Fibrosis / Q000175:diagnosis / Q000235:genetics; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics; D004252:DNA Mutational Analysis / Q000379:methods / Q000592:standards; D005820:Genetic Testing / Q000379:methods* / Q000592:standards*; D006579:Heterozygote; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods* / Q000592:standards*; D006801:Humans; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013661:Tay-Sachs Disease / Q000175:diagnosis / Q000235:genetics; D054820:beta-Hexosaminidase alpha Chain / Q000235:genetics
chemical_list: D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C518253:HEXA protein, human; D054820:beta-Hexosaminidase alpha Chain