Biallelic variants in ZFP36L2 cause female infertility characterised by recurrent preimplantation embryo arrest
- J Med Genet. 2022 Sep;59(9):850-857. doi: 10.1136/jmedgenet-2021-107933.
- 1. Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-XIANGYA, Changsha, Hunan, China.
- 2. Labortatory of Reproductive and Stem Cell Engineering, NHC Key Laboratory of Human Stem and Reproductive Engineering, Central South University, Changsha, Hunan, China.
- 3. Fertility Preservation Laboratory, Reproductive Medicine Center, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong, China.
- 4. Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China [email protected] [email protected].
- 5. Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-XIANGYA, Changsha, Hunan, China [email protected] [email protected].
- # Contributed equally.
Background: Recurrent preimplantation embryo developmental arrest (RPEA) is the most common cause of assisted reproductive technology treatment failure associated with identified genetic abnormalities. Variants in known maternal genes can only account for 20%-30% of these cases. The underlying genetic causes for the Other affected individuals remain unknown.
Methods: Whole exome Sequencing was performed for 100 independent infertile females that experienced RPEA. Functional characterisations of the identified candidate disease-causative variants were validated by Sanger Sequencing, bioinformatics and in vitro functional analyses, and single-cell RNA Sequencing of zygotes.
Results: Biallelic variants in ZFP36L2 were associated with RPEA and the recurrent variant (p.Ser308_Ser310del) prevented maternal mRNA decay in zygotes and HeLa cells.
Conclusion: These findings emphasise the relevance of the relationship between maternal mRNA decay and human preimplantation embryo development and highlight a novel gene potentially responsible for RPEA, which may facilitate genetic diagnoses.