Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

Early post-zygotic mutations contribute to congenital heart disease

Alexander Hsieh, Sarah U. Morton, Jon A.L. Willcox, Joshua M. Gorham, Angela C. Tai, Hongjian Qi, Steven DePalma, David McKean, Emily Griffin, Kathryn B. Manheimer, Daniel Bernstein, Richard W. Kim, Jane W. Newburger, George A. Porter Jr., Deepak Srivastava, Martin Tristani-Firouzi, Martina Brueckner, Richard P. Lifton, Elizabeth Goldmuntz, Bruce D. Gelb, Wendy K. Chung, Christine E. Seidman, J. G. Seidman, Yufeng Shen
doi: https://doi.org/10.1101/733105
Alexander Hsieh
1Columbia University Medical Center, New York, NY, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sarah U. Morton
2Boston Children’s Hospital, Boston, Massachusetts, USA
3Harvard Medical School, Boston, Massachusetts, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jon A.L. Willcox
3Harvard Medical School, Boston, Massachusetts, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Joshua M. Gorham
3Harvard Medical School, Boston, Massachusetts, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Angela C. Tai
3Harvard Medical School, Boston, Massachusetts, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hongjian Qi
1Columbia University Medical Center, New York, NY, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Steven DePalma
3Harvard Medical School, Boston, Massachusetts, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
David McKean
3Harvard Medical School, Boston, Massachusetts, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Emily Griffin
1Columbia University Medical Center, New York, NY, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kathryn B. Manheimer
4Icahn School of Medicine at Mount Sinai, New York, New York, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Daniel Bernstein
5Stanford University, Palo Alto, California, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Richard W. Kim
6Children’s Hospital Los Angeles, Los Angeles, California, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jane W. Newburger
2Boston Children’s Hospital, Boston, Massachusetts, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
George A. Porter Jr.
7University of Rochester Medical Center, Rochester, New York, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Deepak Srivastava
8Gladstone Institutes and University of California San Francisco, San Francisco, California, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Martin Tristani-Firouzi
9University of Utah School of Medicine, Salt Lake City, Utah, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Martina Brueckner
10Yale University School of Medicine, New Haven, Connecticut, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Richard P. Lifton
14Rockefeller University, New York, NY, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Elizabeth Goldmuntz
13Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Bruce D. Gelb
4Icahn School of Medicine at Mount Sinai, New York, New York, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Wendy K. Chung
1Columbia University Medical Center, New York, NY, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Christine E. Seidman
3Harvard Medical School, Boston, Massachusetts, USA
11Brigham and Women’s Hospital, Boston, Massachusetts, USA
12Howard Hughes Medical Institute, Harvard University, Boston, Massachusetts, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
J. G. Seidman
3Harvard Medical School, Boston, Massachusetts, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yufeng Shen
1Columbia University Medical Center, New York, NY, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: ys2411@cumc.columbia.edu
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Supplementary material
  • Preview PDF
Loading

Abstract

Background The contribution of somatic mosaicism, or genetic mutations arising after oocyte fertilization, to congenital heart disease (CHD) is not well understood. Further, the relationship between mosaicism in blood and cardiovascular tissue has not been determined.

Results We developed a computational method, Expectation-Maximization-based detection of Mosaicism (EM-mosaic), to analyze mosaicism in exome sequences of 2530 CHD proband-parent trios. EM-mosaic detected 326 mosaic mutations in blood and/or cardiac tissue DNA. Of the 309 detected in blood DNA, 85/97 (88%) tested were independently confirmed, while 7/17 (41%) candidates of 17 detected in cardiac tissue were confirmed. MosaicHunter detected an additional 64 mosaics, of which 23/46 (50%) among 58 candidates from blood and 4/6 (67%) of 6 candidates from cardiac tissue confirmed. Twenty-five mosaic variants altered CHD-risk genes, affecting 1% of our cohort. Of these 25, 22/22 candidates tested were confirmed. Variants predicted as damaging had higher variant allele fraction than benign variants, suggesting a role in CHD. The frequency of mosaic variants above 10% mosaicism was 0.13/person in blood and 0.14/person in cardiac tissue. Analysis of 66 individuals with matched cardiac tissue available revealed both tissue-specific and shared mosaicism, with shared mosaics generally having higher allele fraction.

Conclusions We estimate that ~1% of CHD probands have a mosaic variant detectable in blood that could contribute to cardiac malformations, particularly those damaging variants expressed at higher allele fraction compared to benign variants. Although blood is a readily-available DNA source, cardiac tissues analyzed contributed ~5% of somatic mosaic variants identified, indicating the value of tissue mosaicism analyses.

Footnotes

  • alh2194{at}cumc.columbia.edu (A.H.), Sarah.Morton{at}childrens.harvard.edu (S.U.M.), Jon_Willcox{at}hms.harvard.edu (J.A.L.W.), jgorham{at}genetics.med.harvard.edu (J.M.G.), angela_tai{at}hms.harvard.edu (A.C.T.), hq2130{at}columbia.edu (H.Q.), depalma{at}genetics.med.harvard.edu (S.D.), dmckean{at}genetics.med.harvard.edu (D.M.), eg2871{at}cumc.columbia.edu (E.G.), kathryn.manheimer{at}icahn.mssm.edu (K.B.M.), danb{at}stanford.edu (D.B.), rikim{at}chla.usc.edu (R.W.K.), jane.newburger{at}cardio.chboston.org (J.W.N.), george_porter{at}urmc.rochester.edu (G.A.P.), deepak.srivastava{at}gladstone.ucsf.edu (D.S.), martin.tristani{at}utah.edu (M.T.F.), martina.brueckner{at}yale.edu (M.B.), rickl{at}mail.rockefeller.edu (R.P.L.) Goldmuntz{at}email.chop.edu (E.G.) bruce.gelb{at}mssm.edu (B.D.G.) wkc15{at}cumc.columbia.edu (W.K.C.) cseidman{at}genetics.med.harvard.edu (C.E.S.), seidman{at}genetics.med.harvard.edu (J.G.S.), ys2411{at}cumc.columbia.edu (Y.S.)

  • Abbreviations

    ASD
    Autism Spectrum Disorder
    CHD
    Congenital Heart Disease
    dnSNV
    de novo SNV
    Dmis
    Deleterious Missense mutation
    DPsite
    Total Read Depth at a variant site
    DPsample
    Sample-wide Average Read Depth
    ExAC
    Exome Aggregation Consortium
    FDR
    False Discovery Rate
    gnomAD
    Genome Aggregation Database
    HHE
    High Heart Expression
    LOF
    Loss-of-Function
    LR
    Likelihood Ratio
    MAF
    Minor Allele Fraction
    N
    Total Read Depth
    Nalt
    Alternate Allele Read Depth
    OR
    Odds Ratio
    PCGC
    Pediatric Cardiac Genomics Consortium
    pLI
    Probability of Loss-of-Function Intolerance
    PV4
    P-value for strand bias, baseQ bias, mapQ bias and tail distance bias (SAMtools)
    SNV
    Single Nucleotide Variant
    VAF
    Variant Allele Fraction
    WES
    Whole Exome Sequencing
  • Copyright 
    The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
    Back to top
    PreviousNext
    Posted August 13, 2019.
    Download PDF

    Supplementary Material

    Email

    Thank you for your interest in spreading the word about bioRxiv.

    NOTE: Your email address is requested solely to identify you as the sender of this article.

    Enter multiple addresses on separate lines or separate them with commas.
    Early post-zygotic mutations contribute to congenital heart disease
    (Your Name) has forwarded a page to you from bioRxiv
    (Your Name) thought you would like to see this page from the bioRxiv website.
    CAPTCHA
    This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
    Share
    Early post-zygotic mutations contribute to congenital heart disease
    Alexander Hsieh, Sarah U. Morton, Jon A.L. Willcox, Joshua M. Gorham, Angela C. Tai, Hongjian Qi, Steven DePalma, David McKean, Emily Griffin, Kathryn B. Manheimer, Daniel Bernstein, Richard W. Kim, Jane W. Newburger, George A. Porter Jr., Deepak Srivastava, Martin Tristani-Firouzi, Martina Brueckner, Richard P. Lifton, Elizabeth Goldmuntz, Bruce D. Gelb, Wendy K. Chung, Christine E. Seidman, J. G. Seidman, Yufeng Shen
    bioRxiv 733105; doi: https://doi.org/10.1101/733105
    Digg logo Reddit logo Twitter logo Facebook logo Google logo LinkedIn logo Mendeley logo
    Citation Tools
    Early post-zygotic mutations contribute to congenital heart disease
    Alexander Hsieh, Sarah U. Morton, Jon A.L. Willcox, Joshua M. Gorham, Angela C. Tai, Hongjian Qi, Steven DePalma, David McKean, Emily Griffin, Kathryn B. Manheimer, Daniel Bernstein, Richard W. Kim, Jane W. Newburger, George A. Porter Jr., Deepak Srivastava, Martin Tristani-Firouzi, Martina Brueckner, Richard P. Lifton, Elizabeth Goldmuntz, Bruce D. Gelb, Wendy K. Chung, Christine E. Seidman, J. G. Seidman, Yufeng Shen
    bioRxiv 733105; doi: https://doi.org/10.1101/733105

    Citation Manager Formats

    • BibTeX
    • Bookends
    • EasyBib
    • EndNote (tagged)
    • EndNote 8 (xml)
    • Medlars
    • Mendeley
    • Papers
    • RefWorks Tagged
    • Ref Manager
    • RIS
    • Zotero
    • Tweet Widget
    • Facebook Like
    • Google Plus One

    Subject Area

    • Bioinformatics
    Subject Areas
    All Articles
    • Animal Behavior and Cognition (3512)
    • Biochemistry (7352)
    • Bioengineering (5329)
    • Bioinformatics (20277)
    • Biophysics (10026)
    • Cancer Biology (7749)
    • Cell Biology (11319)
    • Clinical Trials (138)
    • Developmental Biology (6440)
    • Ecology (9958)
    • Epidemiology (2065)
    • Evolutionary Biology (13336)
    • Genetics (9362)
    • Genomics (12592)
    • Immunology (7714)
    • Microbiology (19046)
    • Molecular Biology (7447)
    • Neuroscience (41063)
    • Paleontology (300)
    • Pathology (1231)
    • Pharmacology and Toxicology (2139)
    • Physiology (3164)
    • Plant Biology (6866)
    • Scientific Communication and Education (1274)
    • Synthetic Biology (1898)
    • Systems Biology (5318)
    • Zoology (1089)