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.

Mutations in fetal genes involved in innate immunity and host defense against microbes increase risk of preterm premature rupture of membranes (PPROM)

“…The mutations that we identified could be spontaneous, or inherited from the father or mother (Li et al. ). We speculate that maternal inheritance may be most likely in the setting of PPROM, since an enhanced maternal reproductive tract inflammatory response to bacteria or viruses, or deficiency in endogenous antimicrobial defenses would presumably act in synergy with similar defects in the fetus when both mother and fetus are heterozygous for damaging mutations (Plunkett et al.…”

Recent advances in the genetics of preterm birth

“…While this study was underpowered to detect specifically associated genes and did not distinguish between medically indicated and spontaneous preterm birth, it did provide evidence that those born preterm have an increased rate of de novo variants at a genome‐wide level. Also when damaging de novo variants were observed in those born preterm, they were more likely to occur in genes that do not tolerate mutations well, and that are expressed in early fetal brain development (Li et al., ). While not definitive, this study does provide evidence that suggests further investigation of rare de novo genetic variants in preterm birth will be important.…”

“…The final study we consider here adopted a whole-genome sequencing approach (Li, Oehlert, Snyder, Stevenson, & Shaw, 2017). Rather than focus on cases and controls, the authors used 816 parent-proband trios (295 with preterm birth) to identify de novo genetic variants.…”

PsyMuKB: A De Novo Variant Knowledge Base Integrating Transcriptional and Translational Information to Identify Isoform-specific Mutations in Developmental Disorders

“…A total of 876,175 of them are DNMs, including SNVs and small indels, affecting 732,879 unique sites across the genome (Figure 2A). About 61.5% of variants come from controls, including healthy sibling of patients (n=162,800) from various DNP disorder studies, an uncharacterized cohort study (n=340,192) [41] and a fetal sample (preterm and non-preterm) study (n=36,441) [42]. DNM variants were collected from various studies based on four major clinical phenotypes: psychiatric disorders, neurological disorders, birth defect diseases, and control studies (Figure 2A) (Figure 2A).…”