Recurrent spontaneous oocyte activation causes female infertility.

PURPOSE: Spontaneous oocyte activation (SOA) is a recently classified phenomenon characterized by the presence of a single pronucleus immediately following oocyte retrieval, without the apparent involvement of sperm. SOA currently remains poorly understood in humans, with no clear genetic or pathological factor(s). Herein, we report two separate cases of recurrent spontaneous oocyte activation, investigating potential avenues to identify causative etiology. METHODS: Two patients with several cycles with SOA have undergone further genetic and embryologic investigation to reveal underlying causes for SOA and provide a treatment if possible. RESULTS: One case was a patient with recurrent pregnancy loss and the other was diagnosed as unexplained infertility. In the first case, 61 out of 69 oocytes retrieved exhibited SOA in five cycles while in the second case 44 out of 49 oocytes exhibited SOA in five cycles. Oocytes were injected with sperm; embryo development and presence of paternal contribution were investigated. No pregnancy is ensued following embryo transfer in both patients. Time-lapse imaging of embryogenesis from the second case did not reveal even momentary second pronucleus appearance. We also performed clinical whole exome sequencing for both patients but did not identify any disease-causing variant. CONCLUSION: Patients with SOA suffer from infertility. Our results indicate that more investigation is required to understand the etiology of SOA in humans concentrating on the molecular mechanisms that underpin regulation of oocyte activation and calcium dynamics need to be investigated to fully understand, and perhaps in the future rectify, recurrent SOA.

ASTL is mutated in female infertility.

Female infertility is a relatively common phenotype with a growing number of single gene causes although these account for only a minority of cases. Here, we report a consanguineous family in which adult females who are homozygous for a truncating variant in ASTL display markedly reduced fertility in a pattern strikingly similar to Astl-/- female mice. ASTL encodes ovastacin, which is known to trigger zona pellucida hardening (ZPH) as part of the cortical reaction upon fertilization. ZPH is required for normal early embryonic development and its absence can be caused by pathogenic variants in other zona pellucida proteins that result in a similar infertility phenotype in humans and mouse. This is the first report of ASTL-related infertility in humans and suggests that the inclusion of ASTL in female infertility gene panels is warranted.