A human CEP120 gene variant impairs meiotic spindle building causing aneuploidy†

Infertility is increasing, leading more women to seek assisted reproduction treatments than ever before. One of the main causes of infertility and pregnancy loss is aneuploidy, an incorrect number of chromosomes in the embryo or developing fetus, which hinders normal development. Aneuploidy overwhelmingly arises from the missegregation of chromosomes during the maternal meiotic divisions that produce haploid oocytes (or eggs). Variants of genes involved in spindle building are of primary interest when searching for genetic causes of aneuploidy because the oocyte meiotic spindle is responsible for faithful chromosome segregation. We previously identified a genetic variant in a human centrosome gene, CEP120, as associated with high embryonic aneuploidy. To evaluate the functional significance of this genetic variant, we generated a knock-in mouse model and found that female mice had reduced fertility and increased egg aneuploidy. By assessing microtubule re-establishment after cold temperature exposure and warming after vitrification, we found that oocytes from mice harboring the genetic variant had reduced microtubule nucleation efficiency. Because mouse and human oocytes present differences in spindle building mechanism, we modified mouse oocyte spindle building assembly by pericentrin depletion to better mimic human oocytes and found that aneuploidy levels significantly increase in CEP120 variant eggs. Although PGT-A allows the deselection of aneuploid embryos, the development of biomarkers for predisposition to aneuploidy could be used to identify subfertile patients and model their aneuploid risk. Therefore, our data indicate that patients harboring common genetic variants in CEP120 may require additional counseling when considering egg cryopreservation procedures.