De novo variants in congenital diaphragmatic hernia identify MYRF as a new syndrome and reveal genetic overlaps with other developmental disorders

PLoS Genet. 2018 Dec 10;14(12):e1007822. doi: 10.1371/journal.pgen.1007822.

Hongjian Qi ¹ ², Lan Yu ³, Xueya Zhou ¹ ³, Julia Wynn ³, Haoquan Zhao ¹ ⁴, Yicheng Guo ¹, Na Zhu ¹ ³, Alexander Kitaygorodsky ¹ ⁴, Rebecca Hernan ³, Gudrun Aspelund ⁵, Foong-Yen Lim ⁶, Timothy Crombleholme ⁶, Robert Cusick ⁷, Kenneth Azarow ⁸, Melissa E Danko ⁹, Dai Chung ⁹, Brad W Warner ¹⁰, George B Mychaliska ¹¹, Douglas Potoka ¹², Amy J Wagner ¹³, Mahmoud ElFiky ¹⁴, Jay M Wilson ¹⁵ ¹⁶, Debbie Nickerson ¹⁷, Michael Bamshad ¹⁷, Frances A High ¹⁵ ¹⁶ ¹⁸, Mauro Longoni ¹⁶ ¹⁸, Patricia K Donahoe ¹⁶ ¹⁸, Wendy K Chung ³ ¹⁹ ²⁰, Yufeng Shen ¹ ⁴ ²¹

Affiliations

1 Department of Systems Biology, Columbia University Medical Center, New York, New York, United States of America.
2 Department of Applied Mathematics and Applied Physics, Columbia University, New York, New York, United States of America.
3 Department of Pediatrics Medical Center, Columbia University, New York, New York, United States of America.
4 Department of Biomedical Informatics, Columbia University Medical Center, New York, New York, United States of America.
5 Department of Surgery, Columbia University Medical Center, New York, New York, United States of America.
6 Cincinnati Children's Hospital, Cincinnati, Ohio, United States of America.
7 Children's Hospital & Medical Center of Omaha, University of Nebraska College of Medicine, Omaha, Nebraska, United States of America.
8 Department of Surgery, Oregon Health & Science University, Portland, Oregon, United States of America.
9 Monroe Carell Jr. Children's Hospital, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
10 Washington University, St. Louis Children's Hospital, St. Louis, Missouri, United States of America.
11 University of Michigan, CS Mott Children's Hospital, Ann Arbor, Michigan, United States of America.
12 Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
13 Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.
14 Department of Pediatric Surgery, Faculty of Medicine, Cairo University, Cairo, Egypt.
15 Department of Surgery, Boston Children's Hospital, Boston, Massachusetts, United States of America.
16 Department of Surgery, Harvard Medical School, Boston, Massachusetts, United States of America.
17 University of Washington, Seattle, Washington, United States of America.
18 Pediatric Surgical Research Laboratories, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
19 Department of Medicine, Columbia University, New York, New York, United States of America.
20 Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York, United States of America.
21 JP Sulzberger Columbia Genome Center, Columbia University Medical Center, New York, New York, United States of America.

PMID: 30532227 DOI: 10.1371/journal.pgen.1007822

Abstract

Congenital diaphragmatic hernia (CDH) is a severe birth defect that is often accompanied by other congenital anomalies. Previous exome sequencing studies for CDH have supported a role of de novo damaging variants but did not identify any recurrently mutated genes. To investigate further the genetics of CDH, we analyzed de novo coding variants in 362 proband-parent trios including 271 new trios reported in this study. We identified four unrelated individuals with damaging de novo variants in MYRF (P = 5.3x10(-8)), including one likely gene-disrupting (LGD) and three deleterious missense (D-mis) variants. Eight additional individuals with de novo LGD or missense variants were identified from our other genetic studies or from the literature. Common phenotypes of MYRF de novo variant carriers include CDH, congenital heart disease and genitourinary abnormalities, suggesting that it represents a novel syndrome. MYRF is a membrane associated transcriptional factor highly expressed in developing diaphragm and is depleted of LGD variants in the general population. All de novo missense variants aggregated in two functional protein domains. Analyzing the transcriptome of patient-derived diaphragm fibroblast cells suggest that disease associated variants abolish the transcription factor activity. Furthermore, we showed that the remaining genes with damaging variants in CDH significantly overlap with genes implicated in other developmental disorders. Gene expression patterns and patient phenotypes support pleiotropic effects of damaging variants in these genes on CDH and other developmental disorders. Finally, functional enrichment analysis implicates the disruption of regulation of gene expression, kinase activities, intra-cellular signaling, and Cytoskeleton organization as pathogenic mechanisms in CDH.

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