title: Fetal de novo mutations and preterm birth.
abstract: Preterm birth (PTB) affects ~12% of pregnancies in the US. Despite its high mortality and morbidity, the molecular etiology underlying PTB has been unclear. Numerous studies have been devoted to identifying genetic factors in maternal and fetal genomes, but so far few genomic loci have been associated with PTB. By analyzing whole-genome sequencing data from 816 trio families, for the first time, we observed the role of fetal de novo mutations in PTB. We observed a significant increase in de novo mutation burden in PTB fetal genomes. Our genomic analyses further revealed that affected genes by PTB de novo mutations were dosage sensitive, intolerant to genomic deletions, and their mouse orthologs were likely developmentally essential. These genes were significantly involved in early fetal brain development, which was further supported by our analysis of copy number variants identified from an independent PTB cohort. Our study indicates a new mechanism in PTB occurrence independently contributed from fetal genomes, and thus opens a new avenue for future PTB research.
authors.affiliation: Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University, School of Medicine, Stanford, CA, California, United States of America.|Department of Genetics, Center for Genomics and Personalized Medicine Stanford University, School of Medicine, Stanford, CA, California, United States of America.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Li
authors.affiliation: Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University, School of Medicine, Stanford, CA, California, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Oehlert
authors.affiliation: Department of Genetics, Center for Genomics and Personalized Medicine Stanford University, School of Medicine, Stanford, CA, California, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Snyder
authors.affiliation: Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University, School of Medicine, Stanford, CA, California, United States of America.
authors.forename: David K
authors.initials: DK
authors.lastname: Stevenson
authors.affiliation: Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University, School of Medicine, Stanford, CA, California, United States of America.
authors.forename: Gary M
authors.initials: GM
authors.lastname: Shaw
mesh_terms: D000818:Animals; D001921:Brain / Q000254:growth & development* / Q000378:metabolism / Q000473:pathology; D056915:DNA Copy Number Variations / Q000235:genetics; D005260:Female; D047109:Fetal Development / Q000235:genetics*; D005333:Fetus / Q000473:pathology; D016368:Frameshift Mutation / Q000235:genetics; D015894:Genome, Human; D006801:Humans; D051379:Mice; D011247:Pregnancy; D047928:Premature Birth / Q000235:genetics* / Q000473:pathology; D012307:Risk Factors; D017384:Sequence Deletion / Q000235:genetics