Investigating the Interplay Between Prematurity and Genetic Variation in the Context of Rare Developmental Disorders

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Abstract Rare damaging genetic variation accounts for a substantial proportion of the risk of rare developmental disorders (DDs), but common genetic variants as well as environmental factors, including prematurity, also contribute. Little is known about the interplay between prematurity and genetic variation in influencing phenotypic outcomes in DDs, nor about how genetic factors may contribute to risk of preterm birth in DDs. To address these questions, we leverage phenotypic and genetic data from 21,712 patients with DDs recruited for clinical sequencing, 16% of whom were born prematurely. We find that prematurity is associated with more severe clinical phenotypes amongst these DD patients, including more affected organ systems and more delayed developmental milestones, with prematurity and monogenic diagnoses contributing independently and additively to phenotypic severity. We identify genes and gene sets enriched for diagnostic mutations amongst preterm children with DDs. We also demonstrate an enrichment of de novo mutations (DNMs) in both term and preterm probands; the fraction of cases explained by DNMs in known DD-associated genes is higher in term than preterm cases (25% versus 20%) but DNMs in as-yet-undiscovered genes likely contribute approximately equally to both groups (14% versus 13%). Finally, we show that the positive association between polygenic predisposition to education-related traits and gestational duration is likely to be the result of genetically-influenced parental traits or confounders, rather than direct genetic effects in the child, and that the presence of a monogenic diagnosis modifies this association. Our findings emphasise the importance of considering environmental exposures like prematurity in understanding outcomes in DDs suspected to have a genetic component, and motivate further exploration of the role that genetic variation plays in influencing prematurity.

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