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Genetic analysis of de novo variants reveals sex differences in complex and isolated congenital diaphragmatic hernia and indicates MYRF as a candidate gene

Hongjian Qi, Lan Yu, Xueya Zhou, Alexander Kitaygorodsky, Julia Wynn, Na Zhu, Gudrun Aspelund, Foong Yen Lim, Timothy Crombleholme, Robert Cusick, Kenneth Azarow, Melissa Ellen Danko, Dai Chung, Brad W. Warner, George B. Mychaliska, Douglas Potoka, Amy J. Wagner, Mahmoud ElFiky, Deborah A. Nickerson, Michael J. Bamshad, Jay M. Wilson, Frances A. High, Mauro Longoni, Patricia Donahoe, Wendy K. Chung, Yufeng Shen
doi: https://doi.org/10.1101/206037
Hongjian Qi
1Department of Systems Biology, Columbia University, New York, NY, USA
2Department of Applied Mathematics and Applied Physics, Columbia University, New York, NY, USA
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Lan Yu
3Department of Pediatrics, Columbia University, New York, NY, USA
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Xueya Zhou
1Department of Systems Biology, Columbia University, New York, NY, USA
3Department of Pediatrics, Columbia University, New York, NY, USA
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Alexander Kitaygorodsky
1Department of Systems Biology, Columbia University, New York, NY, USA
4Department of Biomedical Informatics, Columbia University, New York, NY 10032
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Julia Wynn
3Department of Pediatrics, Columbia University, New York, NY, USA
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Na Zhu
1Department of Systems Biology, Columbia University, New York, NY, USA
3Department of Pediatrics, Columbia University, New York, NY, USA
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Gudrun Aspelund
5Department of Surgery, Columbia University Medical Center, New York, NY, USA
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Foong Yen Lim
6Cincinnati Children's Hospital, Cincinnati, OH, USA
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Timothy Crombleholme
6Cincinnati Children's Hospital, Cincinnati, OH, USA
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Robert Cusick
7Children's Hospital & Medical Center of Omaha, University of Nebraska College of Medicine, Omaha, NE, USA
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Kenneth Azarow
8Department of Surgery, Oregon Health&Science University, Portland, OR, USA
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Melissa Ellen Danko
9Monroe Carell Jr. Children's Hospital, Vanderbilt University Medical Center, Nashville, TN, USA
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Dai Chung
9Monroe Carell Jr. Children's Hospital, Vanderbilt University Medical Center, Nashville, TN, USA
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Brad W. Warner
10Washington University, St. Louis Children's Hospital, St. Louis, MO, USA
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George B. Mychaliska
11University of Michigan, CS Mott Children's Hospital, Ann Arbor, MI, USA
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Douglas Potoka
12Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
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Amy J. Wagner
13Medical College of Wisconsin, Milwaukee, WI, USA
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Mahmoud ElFiky
14Department of Pediatric Surgery, Faculty of Medicine, Cairo University, Cairo, Egypt
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Deborah A. Nickerson
15Center for Mendelian Genomics, University of Washington, Seattle, Washington, USA
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Michael J. Bamshad
15Center for Mendelian Genomics, University of Washington, Seattle, Washington, USA
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Jay M. Wilson
16Department of Surgery, Boston Children’s Hospital, Boston, MA, USA
17Department of Surgery, Harvard Medical School, MA, USA
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Frances A. High
16Department of Surgery, Boston Children’s Hospital, Boston, MA, USA
17Department of Surgery, Harvard Medical School, MA, USA
18Pediatric Surgical Research Laboratories, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
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Mauro Longoni
17Department of Surgery, Harvard Medical School, MA, USA
18Pediatric Surgical Research Laboratories, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
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Patricia Donahoe
17Department of Surgery, Harvard Medical School, MA, USA
18Pediatric Surgical Research Laboratories, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
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Wendy K. Chung
3Department of Pediatrics, Columbia University, New York, NY, USA
19Department of Medicine, Columbia University, New York, NY, USA
20Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
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Yufeng Shen
1Department of Systems Biology, Columbia University, New York, NY, USA
4Department of Biomedical Informatics, Columbia University, New York, NY 10032
21JP Sulzberger Columbia Genome Center, Columbia University, New York, NY, USA
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Abstract

Congenital diaphragmatic hernia (CDH) is one of the most common and lethal birth defects. Previous studies using exome sequencing support a significant contribution of coding de novo variants in complex CDH cases with additional anomalies and likely gene-disrupting (LGD) variants in isolated CDH cases. To further investigate the genetic architecture of CDH, we performed exome or genome sequencing in 283 proband-parent trios. Combined with data from previous studies, we analyzed a total of 357 trios, including 148 complex and 209 isolated cases. Complex and isolated cases both have a significant burden of deleterious de novo coding variants (1.7~fold, p= 1.2×10−5 for complex, 1.5~fold, p= 9.0×10−5 for isolated). Strikingly, in isolated CDH, almost all of the burden is carried by female cases (2.1~fold, p=0.004 for likely gene disrupting and 1.8~fold, p= 0.0008 for damaging missense variants); whereas in complex CDH, the burden is similar in females and males. Additionally, de novo LGD variants in complex cases are mostly enriched in genes highly expressed in developing diaphragm, but distributed in genes with a broad range of expression levels in isolated cases. Finally, we identified a new candidate risk gene MYRF (4 de novo variants, p-value=2×10−10), a transcription factor intolerant of mutations. Patients with MYRF mutations have additional anomalies including congenital heart disease and genitourinary defects, likely representing a novel syndrome.

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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.
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Posted November 12, 2017.
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Genetic analysis of de novo variants reveals sex differences in complex and isolated congenital diaphragmatic hernia and indicates MYRF as a candidate gene
Hongjian Qi, Lan Yu, Xueya Zhou, Alexander Kitaygorodsky, Julia Wynn, Na Zhu, Gudrun Aspelund, Foong Yen Lim, Timothy Crombleholme, Robert Cusick, Kenneth Azarow, Melissa Ellen Danko, Dai Chung, Brad W. Warner, George B. Mychaliska, Douglas Potoka, Amy J. Wagner, Mahmoud ElFiky, Deborah A. Nickerson, Michael J. Bamshad, Jay M. Wilson, Frances A. High, Mauro Longoni, Patricia Donahoe, Wendy K. Chung, Yufeng Shen
bioRxiv 206037; doi: https://doi.org/10.1101/206037
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Genetic analysis of de novo variants reveals sex differences in complex and isolated congenital diaphragmatic hernia and indicates MYRF as a candidate gene
Hongjian Qi, Lan Yu, Xueya Zhou, Alexander Kitaygorodsky, Julia Wynn, Na Zhu, Gudrun Aspelund, Foong Yen Lim, Timothy Crombleholme, Robert Cusick, Kenneth Azarow, Melissa Ellen Danko, Dai Chung, Brad W. Warner, George B. Mychaliska, Douglas Potoka, Amy J. Wagner, Mahmoud ElFiky, Deborah A. Nickerson, Michael J. Bamshad, Jay M. Wilson, Frances A. High, Mauro Longoni, Patricia Donahoe, Wendy K. Chung, Yufeng Shen
bioRxiv 206037; doi: https://doi.org/10.1101/206037

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