@article {658,
	title = {De novo variants in congenital diaphragmatic hernia identify MYRF as a new syndrome and reveal genetic overlaps with other developmental disorders.},
	journal = {PLoS Genet},
	volume = {14},
	year = {2018},
	month = {2018 12},
	pages = {e1007822},
	abstract = {<p>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.</p>},
	keywords = {Child, Preschool, Developmental Disabilities, DNA Copy Number Variations, 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 Exome Sequencing, Whole Genome Sequencing},
	issn = {1553-7404},
	doi = {10.1371/journal.pgen.1007822},
	author = {Qi, Hongjian and Yu, Lan and Zhou, Xueya and Wynn, Julia and Zhao, Haoquan and Guo, Yicheng and Zhu, Na and Kitaygorodsky, Alexander and Hernan, Rebecca and Aspelund, Gudrun and Lim, Foong-Yen and Crombleholme, Timothy and Cusick, Robert and Azarow, Kenneth and Danko, Melissa E and Chung, Dai and Warner, Brad W and Mychaliska, George B and Potoka, Douglas and Wagner, Amy J and ElFiky, Mahmoud and Wilson, Jay M and Nickerson, Debbie and Bamshad, Michael and High, Frances A and Longoni, Mauro and Donahoe, Patricia K and Chung, Wendy K and Shen, Yufeng}
}
@article {69,
	title = {De Novo and Rare Variants at Multiple Loci Support the Oligogenic Origins of Atrioventricular Septal Heart Defects.},
	journal = {PLoS Genet},
	volume = {12},
	year = {2016},
	month = {2016 Apr},
	pages = {e1005963},
	abstract = {<p>Congenital heart disease (CHD) has a complex genetic etiology, and recent studies suggest that high penetrance de novo mutations may account for only a small fraction of disease. In a multi-institutional cohort surveyed by exome sequencing, combining analysis of 987 individuals (discovery cohort of 59 affected trios and 59 control trios, and a replication cohort of 100 affected singletons and 533 unaffected singletons) we observe variation at novel and known loci related to a specific cardiac malformation the atrioventricular septal defect (AVSD). In a primary analysis, by combining developmental coexpression networks with inheritance modeling, we identify a de novo mutation in the DNA binding domain of NR1D2 (p.R175W). We show that p.R175W changes the transcriptional activity of Nr1d2 using an in vitro transactivation model in HUVEC cells. Finally, we demonstrate previously unrecognized cardiovascular malformations in the Nr1d2tm1-Dgen knockout mouse. In secondary analyses we map genetic variation to protein-interaction networks suggesting a role for two collagen genes in AVSD, which we corroborate by burden testing in a second replication cohort of 100 AVSDs and 533 controls (p = 8.37e-08). Finally, we apply a rare-disease inheritance model to identify variation in genes previously associated with CHD (ZFPM2, NSD1, NOTCH1, VCAN, and MYH6), cardiac malformations in mouse models (ADAM17, CHRD, IFT140, PTPRJ, RYR1 and ATE1), and hypomorphic alleles of genes causing syndromic CHD (EHMT1, SRCAP, BBS2, NOTCH2, and KMT2D) in 14 of 59 trios, greatly exceeding variation in control trios without CHD (p = 9.60e-06). In total, 32\% of trios carried at least one putatively disease-associated variant across 19 loci,suggesting that inherited and de novo variation across a heterogeneous group of loci may contribute to disease risk. </p>},
	keywords = {Animals, Female, Heart Septal Defects, Heterozygote, Homozygote, Humans, Male, Mice, Mice, Knockout, Mutation, Pedigree},
	issn = {1553-7404},
	doi = {10.1371/journal.pgen.1005963},
	author = {Priest, James R and Osoegawa, Kazutoyo and Mohammed, Nebil and Nanda, Vivek and Kundu, Ramendra and Schultz, Kathleen and Lammer, Edward J and Girirajan, Santhosh and Scheetz, Todd and Waggott, Daryl and Haddad, Francois and Reddy, Sushma and Bernstein, Daniel and Burns, Trudy and Steimle, Jeffrey D and Yang, Xinan H and Moskowitz, Ivan P and Hurles, Matthew and Lifton, Richard P and Nickerson, Debbie and Bamshad, Michael and Eichler, Evan E and Mital, Seema and Sheffield, Val and Quertermous, Thomas and Gelb, Bruce D and Portman, Michael and Ashley, Euan A}
}
