Genetic landscape of preterm birth due to cervical insufficiency: Comprehensive gene analysis and patient next-generation sequencing data interpretation

Abstract

Preterm delivery is both a traumatizing experience for the patient and a burden on the healthcare system. A condition distinguishable by its phenotype in prematurity is cervical insufficiency, where certain cases exhibit a strong genetic component. Despite genomic advancements, little is known about the genetics of human cervix remodeling during pregnancy. Using selected gene approaches, a few studies have demonstrated an association of common gene variants with cervical insufficiency. However, until now, no study has employed comprehensive methods to investigate this important subject matter. In this study, we asked: i) are there genes reliably linked to cervical insufficiency and, if so, what are their roles? and ii) what is the proportion of cases of non-syndromic cervical insufficiency attributable to these genetic variations? We performed next-generation sequencing on 21 patients with a clinical presentation of cervical insufficiency. To assist the sequencing data interpretation, we retrieved all known genes implicated in cervical functioning through a systematic literature analysis and additional gene searches. These genes were then classified according to their relation to the questions being posed by the study. Patients' sequence variants were filtered for pathogenicity and assigned a likelihood of being contributive to phenotype development. Gene extraction and analysis revealed 12 genes primarily linked to cervical insufficiency, the majority of which are known to cause collagenopathies. Ten patients carried disruptive variants potentially contributive to the development of non-syndromic cervical insufficiency. Pathway enrichment analysis of variant genes from our cohort revealed an increased variation burden in genes playing roles in tissue mechanical and biomechanical properties, i.e. collagen biosynthesis and cell-extracellular matrix communications. Consequently, the proposed idea of cervical insufficiency being a subtle form of collagenopathy, now strengthened by our genetic findings, might open up new opportunities for improved patient evaluation and management.

Development and validation of a model for individualized prediction of cervical insufficiency risks in patients undergoing IVF/ICSI treatment

“…In 2011, routine cervical ripening recording was recommended by the Global Alliance to Prevent Prematurity and Stillbirth, [ 8 ] where a cervix shorter than 25 mm was regarded as the best predictor of PTB due to the inverse relationship between mid-trimester cervical length and gestational age at delivery [ 9 , 10 ]. However, in the preterm prediction study, among all the women with a short cervix, only 27% of them delivered before 37 weeks, and less than 18% women delivered before 35 weeks [ 10 ].…”

Protein interaction networks define the genetic architecture of preterm birth

“…They showed the heritability of gestationalduration was enriched for functional annotations in decidual stromal cells 54 . Volozanoka recently carried out targeted sequencing of genes shown to be related to cervical insufficiency following a systematic literature analysis similar to that underlying this study 9,55 . They identified 12 genes that were normally linked to cervical insufficiency.…”

Protein Interaction Networks Define the Genetic Architecture of Preterm Birth

“…They showed the heritability of gestational-duration was enriched for functional annotations in decidual stromal cells(59). Volozanoka recently carried out targeted sequencing of genes shown to be related to cervical insufficiency following a systematic literature analysis similar to that underlying this study(11, 60). They identified 12 genes that were normally linked to cervical insufficiency.…”