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Hum Genet. 2018 Feb;137(2):183-193. doi: 10.1007/s00439-018-1871-6. Epub 2018 Feb 7.

Robust identification of mosaic variants in congenital heart disease.

Author information

1
Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
2
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
3
Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
4
Department of Systems Biology, Columbia University Medical Center, New York, NY, USA.
5
Department of Biomedical Informatics, Columbia University Medical Center, New York, NY, USA.
6
Department of Genetics, Harvard Medical School, Boston, MA, USA.
7
Cardiovscular Research Center, Massachusetts General Hospital, Boston, MA, USA.
8
Division of Cardiac Surgery, The Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
9
Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
10
Division of Cardiology, The Children's Hospital of Philadelphia, The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
11
Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
12
Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA.
13
Howard Hughes Medical Institute, Yale University, New Haven, CT, USA.
14
Yale Center for Mendelian Genomics, New Haven, CT, USA.
15
Yale Center for Genome Analysis, Yale University, New Haven, CT, USA.
16
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.
17
Department of Pediatrics, Columbia University Medical Center, New York, NY, USA.
18
Department of Medicine, Columbia University Medical Center, New York, NY, USA.
19
Department of Medicine (Cardiology), Brigham and Women's Hospital, Boston, MA, USA.
20
The Howard Hughes Medical Institute, Chevy Chase, MD, USA.
21
Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. bruce.gelb@mssm.edu.
22
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. bruce.gelb@mssm.edu.
23
Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA. bruce.gelb@mssm.edu.

Abstract

Mosaicism due to somatic mutations can cause multiple diseases including cancer, developmental and overgrowth syndromes, neurodevelopmental disorders, autoinflammatory diseases, and atrial fibrillation. With the increased use of next generation sequencing technology, multiple tools have been developed to identify low-frequency variants, specifically from matched tumor-normal tissues in cancer studies. To investigate whether mosaic variants are implicated in congenital heart disease (CHD), we developed a pipeline using the cancer somatic variant caller MuTect to identify mosaic variants in whole-exome sequencing (WES) data from a cohort of parent/affected child trios (n = 715) and a cohort of healthy individuals (n = 416). This is a novel application of the somatic variant caller designed for cancer to WES trio data. We identified two cases with mosaic KMT2D mutations that are likely pathogenic for CHD, but conclude that, overall, mosaicism detectable in peripheral blood or saliva does not account for a significant portion of CHD etiology.

PMID:
29417219
PMCID:
PMC5997246
[Available on 2019-02-07]
DOI:
10.1007/s00439-018-1871-6

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