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.
Highlights
In order to carry a successful term pregnancy, different organs such as the uterus, cervix, placenta, and amniotic membranes as well as the fetus itself must cohesively interact and create a healthy symbiotic relationship with each other and the rest of the female body [1]
A common phenotype of spontaneous preterm birth (PTB) is primarily characterized by progressive cervical effacement, after which preterm premature rupture of membranes (PPROM), persistent uterine contractions, prolapsed fetal membranes, or uterine bleeding may be the reason for acute care seeking
Out of 105 eligible studies selected for the gene extraction (S1 Fig; S2 Table), 51 were solely association studies with the majority focusing on the analysis of common genetic variants in a limited number of candidate genes
Summary
In order to carry a successful term pregnancy, different organs such as the uterus, cervix, placenta, and amniotic membranes as well as the fetus itself must cohesively interact and create a healthy symbiotic relationship with each other and the rest of the female body [1]. Preterm birth (PTB) remains the leading cause of perinatal morbidity, mortality, and hospitalization in the first year of life in the developed world. 5–12% of newborns worldwide are born preterm (
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