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

Oligogenic inheritance of congenital heart disease involving a NKX2-5 modifier

Casey A. Gifford, Sanjeev S. Ranade, Ryan Samarakoon, Hazel T. Salunga, T. Yvanka de Soysa, Yu Huang, Ping Zhou, Aryé Elfenbein, Stacia K. Wyman, Yen Kim Bui, Kimberly R. Cordes Metzler, Philip Ursell, Kathryn N. Ivey, Deepak Srivastava
doi: https://doi.org/10.1101/266726
Casey A. Gifford
1Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA
2Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA 94158, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sanjeev S. Ranade
1Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA
2Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA 94158, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ryan Samarakoon
1Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA
2Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA 94158, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hazel T. Salunga
1Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA
2Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA 94158, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
T. Yvanka de Soysa
1Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA
2Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA 94158, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yu Huang
1Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ping Zhou
1Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Aryé Elfenbein
1Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA
2Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA 94158, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Stacia K. Wyman
1Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yen Kim Bui
1Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA
2Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA 94158, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kimberly R. Cordes Metzler
1Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA
2Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA 94158, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Philip Ursell
3Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kathryn N. Ivey
1Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA
2Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA 94158, USA
4Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94143, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Deepak Srivastava
1Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA
2Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA 94158, USA
4Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94143, USA
5Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94143, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: dsrivastava@gladstone.ucsf.edu
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Supplementary material
  • Preview PDF
Loading

Abstract

Complex genetic inheritance is thought to underlie many human diseases, yet experimental proof of this model has been elusive. Here, we show that a human congenital heart defect, left ventricular non-compaction (LVNC), can be caused by a combination of rare, inherited heterozygous missense single nucleotide variants. Whole exome sequencing of a nuclear family revealed novel single nucleotide variants of MYH7 and MKL2 in an asymptomatic father while the offspring with severe childhood-onset LVNC harbored an additional missense variant in the cardiac transcription factor, NKX2-5, inherited from an unaffected mother. Mice bred to compound heterozygosity for the orthologous missense variants in Myh7 and Mkl2 had mild cardiac pathology; the additional inheritance of the Nkx2-5 variant yielded a more severe LVNC-like phenotype in triple compound heterozygotes. RNA sequencing identified genes associated with endothelial and myocardial development that were dysregulated in hearts from triple heterozygote mice and human induced pluripotent stem cell–derived cardiomyocytes harboring the three variants, with evidence for NKX2-5’s contribution as a modifier on the molecular level. These studies demonstrate that the deployment of efficient gene editing tools can provide experimental evidence for complex inheritance of human disease.

One sentence summary A combination of three inherited heterozygous missense single nucleotide variants underlying a familial congenital heart defect.

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-ND 4.0 International license.
Back to top
PreviousNext
Posted February 20, 2018.
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.
Oligogenic inheritance of congenital heart disease involving a NKX2-5 modifier
(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
Oligogenic inheritance of congenital heart disease involving a NKX2-5 modifier
Casey A. Gifford, Sanjeev S. Ranade, Ryan Samarakoon, Hazel T. Salunga, T. Yvanka de Soysa, Yu Huang, Ping Zhou, Aryé Elfenbein, Stacia K. Wyman, Yen Kim Bui, Kimberly R. Cordes Metzler, Philip Ursell, Kathryn N. Ivey, Deepak Srivastava
bioRxiv 266726; doi: https://doi.org/10.1101/266726
Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
Citation Tools
Oligogenic inheritance of congenital heart disease involving a NKX2-5 modifier
Casey A. Gifford, Sanjeev S. Ranade, Ryan Samarakoon, Hazel T. Salunga, T. Yvanka de Soysa, Yu Huang, Ping Zhou, Aryé Elfenbein, Stacia K. Wyman, Yen Kim Bui, Kimberly R. Cordes Metzler, Philip Ursell, Kathryn N. Ivey, Deepak Srivastava
bioRxiv 266726; doi: https://doi.org/10.1101/266726

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

  • Genetics
Subject Areas
All Articles
  • Animal Behavior and Cognition (2543)
  • Biochemistry (4994)
  • Bioengineering (3497)
  • Bioinformatics (15279)
  • Biophysics (6926)
  • Cancer Biology (5427)
  • Cell Biology (7771)
  • Clinical Trials (138)
  • Developmental Biology (4558)
  • Ecology (7180)
  • Epidemiology (2059)
  • Evolutionary Biology (10261)
  • Genetics (7532)
  • Genomics (9826)
  • Immunology (4899)
  • Microbiology (13304)
  • Molecular Biology (5165)
  • Neuroscience (29569)
  • Paleontology (203)
  • Pathology (842)
  • Pharmacology and Toxicology (1470)
  • Physiology (2153)
  • Plant Biology (4780)
  • Scientific Communication and Education (1015)
  • Synthetic Biology (1343)
  • Systems Biology (4022)
  • Zoology (771)