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Am J Hum Genet. 2018 Jun 7;102(6):1078-1089. doi: 10.1016/j.ajhg.2018.04.004. Epub 2018 May 10.

Preconception Carrier Screening by Genome Sequencing: Results from the Clinical Laboratory.

Author information

1
Department of Molecular and Medical Genetics, Knight Diagnostic Laboratories, Oregon Health & Science University, Portland, OR 97239, USA.
2
Pathology, Division of Medical Genetics, University of Washington, Seattle, WA 98195, USA; Genome Sciences, Division of Medical Genetics, University of Washington, Seattle, WA 98195, USA.
3
Genome Sciences, Division of Medical Genetics, University of Washington, Seattle, WA 98195, USA.
4
Genome Sciences, Division of Medical Genetics, University of Washington, Seattle, WA 98195, USA; Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, WA 98195, USA.
5
Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, WA 98195, USA.
6
Pathology, Division of Medical Genetics, University of Washington, Seattle, WA 98195, USA.
7
Department of Medical Genetics, Kaiser Permanente Northwest, Portland, OR 97227, USA.
8
Center for Health Research, Kaiser Permanente Northwest, Portland, OR 97227, USA.
9
Department of Pediatrics, Division of Bioethics, University of Washington, Seattle, WA 98195, USA; Treuman Katz Center for Pediatric Bioethics, Seattle Children's Hospital, Seattle, WA 98101, USA.
10
Department of Molecular and Medical Genetics, Knight Diagnostic Laboratories, Oregon Health & Science University, Portland, OR 97239, USA. Electronic address: richarsu@ohsu.edu.

Abstract

Advances in sequencing technologies permit the analysis of a larger selection of genes for preconception carrier screening. The study was designed as a sequential carrier screen using genome sequencing to analyze 728 gene-disorder pairs for carrier and medically actionable conditions in 131 women and their partners (n = 71) who were planning a pregnancy. We report here on the clinical laboratory results from this expanded carrier screening program. Variants were filtered and classified using the latest American College of Medical Genetics and Genomics (ACMG) guideline; only pathogenic and likely pathogenic variants were confirmed by orthologous methods before being reported. Novel missense variants were classified as variants of uncertain significance. We reported 304 variants in 202 participants. Twelve carrier couples (12/71 couples tested) were identified for common conditions; eight were carriers for hereditary hemochromatosis. Although both known and novel variants were reported, 48% of all reported variants were missense. For novel splice-site variants, RNA-splicing assays were performed to aid in classification. We reported ten copy-number variants and five variants in non-coding regions. One novel variant was reported in F8, associated with hemophilia A; prenatal testing showed that the male fetus harbored this variant and the neonate suffered a life-threatening hemorrhage which was anticipated and appropriately managed. Moreover, 3% of participants had variants that were medically actionable. Compared with targeted mutation screening, genome sequencing improves the sensitivity of detecting clinically significant variants. While certain novel variant interpretation remains challenging, the ACMG guidelines are useful to classify variants in a healthy population.

KEYWORDS:

carrier couples; genome sequencing; medically actionable conditions; preconception carrier screening

PMID:
29754767
PMCID:
PMC5992121
DOI:
10.1016/j.ajhg.2018.04.004
[Indexed for MEDLINE]
Free PMC Article

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