Development and Performance of a Comprehensive Targeted Sequencing Assay for Pan-Ethnic Screening of Carrier Status

Identifying individuals as carriers of severe disease traits enables informed decision making about reproductive options. Although carrier screening has traditionally been based on ethnicity, the increasing ethnic admixture in the general population argues for the need for pan-ethnic carrier screeni...

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Bibliographic Details
Published in:The Journal of molecular diagnostics : JMD 2014-05, Vol.16 (3), p.350-360
Main Authors: Tanner, Alice K, Valencia, C. Alexander, Rhodenizer, Devin, Espirages, Marina, Da Silva, Cristina, Borsuk, Lisa, Caldwell, Sara, Gregg, Edward, Grimes, Elizabeth, Lichanska, Agnieszka M, Morris, Leah, Purkayastha, Anjan, Weslowski, Brian, Tibbetts, Clark, Lorence, Matthew C, Hegde, Madhuri
Format: Article
Language:English
Subjects:
Adult
DNA Mutational Analysis - methods
Ethnic Groups - genetics
Female
Genetic Testing - methods
Heterozygote
High-Throughput Nucleotide Sequencing
Humans
Mutation
Oligonucleotide Array Sequence Analysis - methods
Pathology
Polymerase Chain Reaction
Pregnancy
Prenatal Diagnosis - methods
Sensitivity and Specificity
Sequence Analysis, DNA - methods
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Summary:Identifying individuals as carriers of severe disease traits enables informed decision making about reproductive options. Although carrier screening has traditionally been based on ethnicity, the increasing ethnic admixture in the general population argues for the need for pan-ethnic carrier screening assays. Highly multiplexed mutation panels allow for rapid and efficient testing of hundreds of mutations concurrently. We report the development of the Pan-Ethnic Carrier Screening assay, a targeted sequencing assay for routine screening that simultaneously detects 461 common mutations in 91 different genes underlying severe, early-onset monogenic disorders. Mutation selection was aided by the use of an extensive mutation database from a clinical laboratory with expertise in newborn screening and lysosomal storage disease testing. The assay is based on the Affymetrix GeneChip microarray platform but generates genomic DNA sequence as the output. Analytical sensitivity and specificity, using genomic DNA from archived control cultures and from clinical specimens, was found to be >99% for all mutation types. This targeted sequencing assay has advantages over multiplex PCR and next-generation sequencing assays, including accuracy of mutation detection over a range of mutation types and ease of analysis and reporting of results.
ISSN:1525-1578
1943-7811
DOI:10.1016/j.jmoldx.2013.12.003