J Mol Diagn. 2013 Dec 26. pii: S1525-1578(13)00251-1. doi: 10.1016/j.jmoldx.2013.10.006. [Epub ahead of print]
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.
Hallam S1, Nelson H2, Greger V2, Perreault-Micale C2, Davie J2, Faulkner N2, Neitzel D2, Casey K2, Umbarger MA2, Chennagiri N2, Kramer AC2, Porreca GJ2,Kennedy CJ2.
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 and in the Ashkenazi Jewish population), 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 the CFTR, G6PC, CLRN1, MCOLN1, ABCC8, BCKDHB, and IKBKAP genes.
Copyright © 2013 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.
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