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Copy number variants and preterm birth: findings from the pilot Study of Preterm Infants and Neurodevelopment Genes (SPRING)

Hilary S Wong1, Megan Wadon2, Neena Modi3, George Kirov2, Michael O’Donovan2, Anita Thapar2 
Department of Paediatrics, University of Cambridge; (2) MRC Centre for Neuropsychiatric Genetics and Genomics, University of Cardiff; (3) Section of Neonatal Medicine, Imperial College London .
Introduction (include hypothesis) 
Genetic risk variants may contribute to preterm birth and the neurodevelopmental outcome of infants born preterm [1]. In the pilot Study of Preterm Infants and Neurodevelopment Genes (SPRING), we aimed to (i) evaluate the feasibility of establishing a prospective very preterm (VPT, <32 weeks gestation) neonatal cohort for genetic investigations, (ii) explore the acceptability to parents of long-term DNA storage and longitudinal follow-up through routine data linkage, and (iii) examine the hypothesis that the VPT population is enriched for copy number variants (CNV). We present the preliminary results from the genetics analyses in this abstract. 
Methods (include source of funding and ethical approval if required) 
We invited participation from VPT families in 60 English neonatal units and collected blood samples from participants (0.5ml from infant, 5ml from parents). We sought parent consent for DNA storage and to ascertain future outcomes through routine data linkage and recall. DNA were extracted from the blood samples using Nucleon BACC3 genomic DNA extraction kits. Genotyping was performed using Illumina Infinium OmniExpress Arrays. We examined CNVs in two ways: firstly, de novo CNVs in infants were identified and compared with published comparator data (frequency of 2.0% in 3208 parent-proband trios); secondly, we analysed VPT infants, mothers and fathers for the presence of 51 pathogenic CNVs associated with clinical phenotypes. For comparison, we used a previous analysis of the UK Biobank by GK and MOD that found a frequency of 2.3% for the same list of CNVs [2]. The study was funded by the Medical Research Council (MR/N025288/1) and approved by the Wales Multi-Centre Research Ethics Committee (16/WA/0324). 
The families of 883 VPT infants consented to participate, exceeding our target of 500 families. The parents of 874 (99.0%) infants agreed to DNA storage, 796 (90.1%) agreed to future data linkage and 794 (89.9%) agreed to be recalled. Genomic analysis was conducted on the first 488 parent-proband trio samples that passed quality control. This cohort had a median (range) gestational age of 28.7 (22+6–31+6) weeks and birthweight of 1100g (445g–2230g). Fourteen de novo CNVs (6 duplications, 8 deletions) were identified in 13 (2.7%) infants; one infant possessing two de novo deletions. Some of these CNVs were causal for developmental syndromes (including Charcot Marie Tooth Type 1A, Prader Willi/Angelman and Wolf-Hirschorn syndromes) or were associated with neurodevelopmental disorders (NRXN1 and CNTN4 genes). The frequencies of pathogenic CNVs were 4.3% (n=21) in VPT infants, 2.7% (n=13) in mothers and 2.0% (n=10) in fathers. 
A large-scale prospective genetic cohort study of VPT families in the UK is feasible and acceptable to parents. The rate of de novo CNVs is likely elevated in those born VPT and pathogenic CNVs may play a role. 
[1] Li et al. Fetal de novo mutations and preterm birth. PLoS Genet 13(4):e1006689. [2] Crawford et al. Medical consequences of pathogenic CNVs in adults: analysis of the UK Biobank. J Med Genet 2019;56:131. 

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