DETECTION OF MICRODELETIONS BY NON-INVASIVE …

DETECTION OF MICRODELETIONS BY NON-INVASIVE PRENATAL TESTING

by Erica Marie Bednar B.S., The Ohio State University, 2011

Submitted to the Graduate Faculty of the Human Genetics Department in the Graduate School of Public Health in partial fulfillment of the requirements for the degree of

Master of Science

University of Pittsburgh 2013

UNIVERSITY OF PITTSBURGH GRADUATE SCHOOL OF PUBLIC HEALTH

This thesis was presented by

Erica Marie Bednar

It was defended on March 19, 2013 and approved by

Robert Ferrell, Ph.D., Professor, Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh

David Finegold, M.D., Professor, Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh

Mary Dunkel, M.S., Certified Genetic Counselor, Magee-Womens Hospital of Pittsburgh, PA Thesis Director: David Peters, Ph.D., Associate Professor, Division of Reproductive Genetics, Magee-Womens Research Institute of Pittsburgh, PA

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Copyright ? by Erica Marie Bednar 2013

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DETECTION OF MICRODELETIONS BY NON-INVASIVE PRENATAL TESTING Erica Bednar, M.S.

University of Pittsburgh, 2013

ABSTRACT

Background: Non-invasive prenatal testing (NIPT) is currently offered for the detection of Trisomy 21, 13, 18 and sex chromosome aneuploidy. The test is unique because it reaches nearly diagnostic levels of accuracy, otherwise achieved only by invasive procedures like chorionic villus sampling or amniocentesis, but requires only a sample of maternal blood. The NIPT technology continues to advance and a greater variety of genomic alterations can be detected. This research study describes the detection of two different fetal microdeletions using NIPT, which includes whole genome next-generation sequencing, and targeted region capture and sequencing methods. Methods: Whole genome next-generation sequencing, and targeted region capture and sequencing methods, were used on samples of maternal plasma obtained from pregnancies with confirmed microdeletions. The DNA of these samples was compared to control DNA libraries to identify the fetal microdeletions. Results: We were able to identify statistically significant differences between samples to detect fetal microdeletions on chromosome 12p12.1-p11.22 from maternal plasma samples. Identification of a fetal microdeletion on 5p15.33 from maternal plasma samples was achieved, but highlighted the difficulties in detection, and future challenges for NIPT.

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Conclusion: Our research has demonstrated the ability to detect microdeletions by whole genome next-generation sequencing and targeted region capture and sequencing methods of NIPT. The findings indicate the ability of NIPT to detect a wide range of genomic alterations, which will impact prenatal care in the future if the technology improves. Development and expansion of NIPT has significant public health implications due to its high levels of accuracy as compared to current screening, and safety for the pregnancy as compared to current diagnostic testing options. NIPT could have major ethical implications, and could impact the role of prenatal genetic counselors and physicians.

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