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

The 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.

We 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.

We 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.

Our 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.