Faculty Collaboration Database

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;14(12):e1007822

Date

12/12/2018

Pubmed ID

30532227

Pubmed Central ID

PMC6301721

DOI

10.1371/journal.pgen.1007822

Scopus ID

2-s2.0-85058925741 (requires institutional sign-in at Scopus site)   71 Citations

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.

Author List

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

Author

Amy Wagner MD Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Child, Preschool
DNA Copy Number Variations
Developmental Disabilities
Female
Genetic Variation
Heart Defects, Congenital
Hernias, Diaphragmatic, Congenital
Humans
Infant, Newborn
Longitudinal Studies
Male
Membrane Proteins
Mutation
Mutation, Missense
Phenotype
Sequence Analysis, RNA
Syndrome
Transcription Factors
Whole Genome Sequencing