Investigating the interplay between prematurity and genetic variation in the context of rare developmental disorders

TL;DR

This study explores how prematurity interacts with genetic factors to affect the severity of rare developmental disorders.

Contribution

The study is the first to systematically analyze the interplay between prematurity and genetic variation in rare developmental disorders.

Findings

Prematurity is linked to more severe clinical phenotypes in developmental disorders.

Genes associated with fetal anomalies are enriched for mutations in preterm individuals.

De novo mutations contribute similarly to both term and preterm cases in undiscovered genes.

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.

We leveraged phenotypic and genetic data from 21,712 patients with DDs recruited for clinical sequencing, 16% of whom were born prematurely. Using multivariable regression models, we compared phenotypic features and the prevalence of diagnostic genetic variation in specific genes between preterm and term individuals with DDs. We tested whether the fraction of cases attributable to de novo mutations differed between term and preterm probands. Additionally, we assessed whether associations between common variant contributions to education-related traits and prematurity are explained by direct genetic effects.

Prematurity was associated with more severe clinical phenotypes among these DD patients, including more affected organ systems and more delayed developmental milestones. Prematurity and the presence of a monogenic diagnosis contributed additively to severity. We found that genes associated with fetal anomalies were enriched for diagnostic mutations among preterm individuals (p = 7.83 × 10−5). We also demonstrated an exome-wide enrichment of de novo mutations (DNMs) in both term and preterm probands; the fraction of cases explained by DNMs in known DD-associated genes was 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 showed 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 a monogenic diagnosis modifies this association.

Our findings emphasise the importance of considering environmental factors 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.

The online version contains supplementary material available at 10.1186/s13073-025-01560-3.

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