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

Hongjian Qi, Lan Yu, Xueya Zhou, Julia Wynn, Haoquan Zhao, Yicheng Guo, Na Zhu, Alexander Kitaygorodsky, Rebecca Hernan, Gudrun Aspelund, Foong Yen Lim, Timothy Crombleholme, Robert Cusick, Kenneth Azarow, Melissa E. Danko, Dai Chung, Brad W. Warner, George B. Mychaliska, Douglas Potoka, Amy J. WagnerMahmoud ElFiky, Jay M. Wilson, Debbie Nickerson, Michael Bamshad, Frances A. High, Mauro Longoni, Patricia K. Donahoe, Wendy K. Chung, Yufeng Shen

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere1007822
JournalPLoS genetics
Volume14
Issue number12
DOIs
StatePublished - Dec 2018

Fingerprint

hernia
gene
Genes
genes
diaphragm
Diaphragm
gene expression
phenotype
transcription factors
Urogenital Abnormalities
Exome
Phenotype
cell communication
Congenital Heart Defects
cardiovascular disease
gene expression regulation
Gene Expression Regulation
heart diseases
abnormality
cytoskeleton

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

De novo variants in congenital diaphragmatic hernia identify MYRF as a new syndrome and reveal genetic overlaps with other developmental disorders. / Qi, Hongjian; Yu, Lan; Zhou, Xueya; Wynn, Julia; Zhao, Haoquan; Guo, Yicheng; Zhu, Na; Kitaygorodsky, Alexander; Hernan, Rebecca; Aspelund, Gudrun; Lim, Foong Yen; Crombleholme, Timothy; Cusick, Robert; Azarow, Kenneth; Danko, Melissa E.; Chung, Dai; Warner, Brad W.; Mychaliska, George B.; Potoka, Douglas; Wagner, Amy J.; ElFiky, Mahmoud; Wilson, Jay M.; Nickerson, Debbie; Bamshad, Michael; High, Frances A.; Longoni, Mauro; Donahoe, Patricia K.; Chung, Wendy K.; Shen, Yufeng.

In: PLoS genetics, Vol. 14, No. 12, e1007822, 12.2018.

Research output: Contribution to journalArticle

Qi, H, Yu, L, Zhou, X, Wynn, J, Zhao, H, Guo, Y, Zhu, N, Kitaygorodsky, A, Hernan, R, Aspelund, G, Lim, FY, Crombleholme, T, Cusick, R, Azarow, K, Danko, ME, Chung, D, Warner, BW, Mychaliska, GB, Potoka, D, Wagner, AJ, ElFiky, M, Wilson, JM, Nickerson, D, Bamshad, M, High, FA, Longoni, M, Donahoe, PK, Chung, WK & Shen, Y 2018, 'De novo variants in congenital diaphragmatic hernia identify MYRF as a new syndrome and reveal genetic overlaps with other developmental disorders', PLoS genetics, vol. 14, no. 12, e1007822. https://doi.org/10.1371/journal.pgen.1007822
Qi, Hongjian ; Yu, Lan ; Zhou, Xueya ; Wynn, Julia ; Zhao, Haoquan ; Guo, Yicheng ; Zhu, Na ; Kitaygorodsky, Alexander ; Hernan, Rebecca ; Aspelund, Gudrun ; Lim, Foong Yen ; Crombleholme, Timothy ; Cusick, Robert ; Azarow, Kenneth ; Danko, Melissa E. ; Chung, Dai ; Warner, Brad W. ; Mychaliska, George B. ; Potoka, Douglas ; Wagner, Amy J. ; ElFiky, Mahmoud ; Wilson, Jay M. ; Nickerson, Debbie ; Bamshad, Michael ; High, Frances A. ; Longoni, Mauro ; Donahoe, Patricia K. ; Chung, Wendy K. ; Shen, Yufeng. / De novo variants in congenital diaphragmatic hernia identify MYRF as a new syndrome and reveal genetic overlaps with other developmental disorders. In: PLoS genetics. 2018 ; Vol. 14, No. 12.
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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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AU - Qi, Hongjian

AU - Yu, Lan

AU - Zhou, Xueya

AU - Wynn, Julia

AU - Zhao, Haoquan

AU - Guo, Yicheng

AU - Zhu, Na

AU - Kitaygorodsky, Alexander

AU - Hernan, Rebecca

AU - Aspelund, Gudrun

AU - Lim, Foong Yen

AU - Crombleholme, Timothy

AU - Cusick, Robert

AU - Azarow, Kenneth

AU - Danko, Melissa E.

AU - Chung, Dai

AU - Warner, Brad W.

AU - Mychaliska, George B.

AU - Potoka, Douglas

AU - Wagner, Amy J.

AU - ElFiky, Mahmoud

AU - Wilson, Jay M.

AU - Nickerson, Debbie

AU - Bamshad, Michael

AU - High, Frances A.

AU - Longoni, Mauro

AU - Donahoe, Patricia K.

AU - Chung, Wendy K.

AU - Shen, Yufeng

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N2 - 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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