Contribution of de novo and inherited rare CNVs to very preterm birth

Abstract

BackgroundThe genomic contribution to adverse health sequelae in babies born very preterm (<32 weeks’ gestation) is unknown. We conducted an investigation of rare CNVs in infants born very preterm as part of a study to determine the feasibility and acceptability of a larger, well-powered genome-wide investigation in the UK, with follow-up using linked National Health Service records and DNA storage for additional research.MethodsWe studied 488 parent–offspring trios. We performed genotyping using Illumina Infinium OmniExpress Arrays. CNV calling and quality control (QC) were undertaken using published protocols. We examined de novo CNVs in infants and the rate of known pathogenic variants in infants, mothers and fathers and compared these with published comparator data. We defined rare pathogenic CNVs as those consistently reported to be associated with clinical phenotypes.ResultsWe identified 14 de novo CNVs, representing a mutation rate of 2.9%, compared with 2.1% reported in control populations. The median size of these CNV was much higher than in comparator data (717 kb vs 255 kb). The rate of pathogenic CNVs was 4.3% in infants, 2.7% in mothers and 2% in fathers, compared with 2.3% in UK Biobank participants.ConclusionOur findings suggest that the rate of de novo CNVs, especially rare pathogenic CNVs, could be elevated in those born very preterm. However, we will need to conduct a much larger study to corroborate this conclusion.

Causes of preterm birth: Genetic factors in preterm birth and preterm infant phenotypes

“…22 Another complimenting study has revealed similar findings of a higher frequency of rare and de novo CNVs in very PN from the spontaneous PB phenotype. 21 Rare pathogenic de novo deletions in the protein-coding regions were associated with intellectual disability, psychoneurological symptoms, schizophrenia, and ASD and correlated with a spontaneous PB phenotype. 21 However, whether these genome rearrangements influence specific PN conditions and their outcomes, such as intraventricular hemorrhage, respiratory distress syndrome, infection, patent ductus arteriosus, necrotizing enterocolitis, BPD, and retinopathy of prematurity remains unclear, and the phenotypic expression of large CNVs may be clinically significant or more severe.…”

“…21 Rare pathogenic de novo deletions in the protein-coding regions were associated with intellectual disability, psychoneurological symptoms, schizophrenia, and ASD and correlated with a spontaneous PB phenotype. 21 However, whether these genome rearrangements influence specific PN conditions and their outcomes, such as intraventricular hemorrhage, respiratory distress syndrome, infection, patent ductus arteriosus, necrotizing enterocolitis, BPD, and retinopathy of prematurity remains unclear, and the phenotypic expression of large CNVs may be clinically significant or more severe. 21 Nowadays, with higher rates of PN survival, biological fitness still plays an important role in natural selection by eliminating harmful variants and reducing reproductive success.…”

“…20,21 Genomic regions with identified specific de novo variants are responsible for the early development of the central nervous system (CNS) and may lead to issues with CNS development and neuropsychiatric disorders, especially attention-deficit/hyperactivity disorder and autism spectrum disorders (ASD). 21,22 These DNA variants may not only induce PB but also play a key role in natural selection. 20 Epigenomes are an important intermediary between genes and their end product; proteins.…”

Trio-Based Low-Pass Genome Sequencing Reveals Characteristics and Significance of Rare Copy Number Variants in Prenatal Diagnosis

“…In addition, assignment of parental inheritance of CNVs is not only important for clinical interpretation, as rare de novo CNVs are more likely to be pathogenic ( Asadollahi et al, 2014 ), but also essential to provide prognostic information and recurrence risk ( Huijsdens-van Amsterdam et al, 2018 ). For instance, the incidence of de novo CNVs was 2.9% (14/488) in fetuses with early preterm birth ( Wong et al, 2020 ). However, due to triplication of the experimental cost for trio-based testing (simultaneous), parental inheritance assignment is often performed sequentially, when a candidate variant of interest has been identified in the proband.…”

Pilot study to establish a prospective neonatal cohort: Study of Preterm Infants and Neurodevelopmental Genes (SPRING)

“…Our secondary aim was to conduct a preliminary investigation to explore the hypothesis that the very preterm (VPT, <32 weeks gestation) population is enriched for rare pathogenic copy number variants; the results of this investigation were reported in a separate paper. 11…”