Large-scale analysis of de novo mutations identifies risk genes for female infertility characterized by oocyte and early embryo defects

Abstract

Background Oocyte maturation arrest and early embryonic arrest are important reproductive phenotypes resulting in female infertility and cause the recurrent failure of assisted reproductive technology (ART). However, the genetic etiologies of these female infertility-related phenotypes are poorly understood. Previous studies have mainly focused on inherited mutations based on large pedigrees or consanguineous patients. However, the role of de novo mutations (DNMs) in these phenotypes remains to be elucidated. Results To decipher the role of DNMs in ART failure and female infertility with oocyte and embryo defects, we explore the landscape of DNMs in 473 infertile parent–child trios and identify a set of 481 confident DNMs distributed in 474 genes. Gene ontology analysis reveals that the identified genes with DNMs are enriched in signaling pathways associated with female reproductive processes such as meiosis, embryonic development, and reproductive structure development. We perform functional assays on the effects of DNMs in a representative gene Tubulin Alpha 4a (TUBA4A), which shows the most significant enrichment of DNMs in the infertile parent–child trios. DNMs in TUBA4A disrupt the normal assembly of the microtubule network in HeLa cells, and microinjection of DNM TUBA4A cRNAs causes abnormalities in mouse oocyte maturation or embryo development, suggesting the pathogenic role of these DNMs in TUBA4A. Conclusions Our findings suggest novel genetic insights that DNMs contribute to female infertility with oocyte and embryo defects. This study also provides potential genetic markers and facilitates the genetic diagnosis of recurrent ART failure and female infertility.

The Global Decline in Human Fertility: The Post-Transition Trap Hypothesis

“…As well as facilitating the vertical transmission of infertility-inducing mutations, ICSI may also result in the creation of de novo mutations in the offspring due to the aberrant repair of sperm DNA damage in the newly formed zygote [ 88 , 97 ]. Such de novo mutations may then result in compromised fertility in the offspring affecting oocyte maturation, embryo development and normal testicular function [ 98 , 99 , 100 , 101 ].…”

Need for larger cohorts and standardized tools to study diseases in newborn infants

“…1,2 Genetic variations can alter the development of primordial structures during embryonic and early fetal periods. [3][4][5] In the more mature fetus, the perinatal period, and during early infancy, infections and consequent systemic inflammatory response syndrome can cause organ damage. [5][6][7] Later, various infectious and noninfectious, ischemic, and mechanical injuries can disrupt many of these growing structures.…”