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Open Access Methodology article

Sensitive and specific detection of mosaic chromosomal abnormalities using the Parent-of-Origin-based Detection (POD) method

Joseph D Baugher1, Benjamin D Baugher2, Matthew D Shirley1 and Jonathan Pevsner1345*

Author Affiliations

1 Program in Biochemistry, Cellular and Molecular Biology, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA

2 The Johns Hopkins University Applied Physics Laboratory, Laurel, MD, 20723, USA

3 Program in Human Genetics, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA

4 Department of Neurology, Hugo W. Moser Research Institute at Kennedy Krieger Institute, 707N. Broadway, Baltimore, MD, 21205, USA

5 Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA

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BMC Genomics 2013, 14:367  doi:10.1186/1471-2164-14-367

Published: 31 May 2013

Abstract

Background

Mosaic somatic alterations are present in all multi-cellular organisms, but the physiological effects of low-level mosaicism are largely unknown. Most mosaic alterations remain undetectable with current analytical approaches, although the presence of such alterations is increasingly implicated as causative for disease.

Results

Here, we present the Parent-of-Origin-based Detection (POD) method for chromosomal abnormality detection in trio-based SNP microarray data. Our software implementation, triPOD, was benchmarked using a simulated dataset, outperformed comparable software for sensitivity of abnormality detection, and displayed substantial improvement in the detection of low-level mosaicism while maintaining comparable specificity. Examples of low-level mosaic abnormalities from a large autism dataset demonstrate the benefits of the increased sensitivity provided by triPOD. The triPOD analyses showed robustness across multiple types of Illumina microarray chips. Two large, clinically-relevant datasets were characterized and compared.

Conclusions

Our method and software provide a significant advancement in the ability to detect low-level mosaic abnormalities, thereby opening new avenues for research into the implications of mosaicism in pathogenic and non-pathogenic processes.

Keywords:
Mosaicism; Parent-of-origin; Trio; Parent–child; Software; Microarray; Autism; Cleft; HapMap