Expanding the genetic and phenotypic spectrum of the subcortical maternal complex genes in recurrent preimplantation embryonic arrest

Abstract

The subcortical maternal complex (SCMC) is an oocyte‐to‐embryo‐specific maternal functional module. Some variants of SCMC genes that contribute to preimplantation embryonic arrest have been identified. However, more novel variants should be identified to broaden the genetic and phenotypic spectrum of SCMC genes and establish their roles in embryonic development. We identified 13 novel variants in the SCMC genes, TLE6, NLRP5, NLRP2, and PADI6, from 10 of a total of 50 infertile females with recurrent preimplantation embryonic arrest. Six variants in TLE6 were found in five patients with embryonic arrest, accompanied by direct cleavage and severe fragmentation at the cleavage stage. Three patients carried NLRP5 variants, and one patient each who carried NLRP2 and PADI6 variants had subsequent poor or failed fertilization and cleavage arrest with a relatively lower ratio of severely fragmented embryos. Our findings expand the genetic and phenotypic spectrum of SCMC genes associated with human embryogenesis and might help lay the foundation for the genetic diagnosis of female infertility.

Novel Biallelic TLE6 Variants Induce Preimplantation Embryonic Lethality That Cannot be Rescued by IVF or ICSI

“…Phenotypes of infertile women harboring biallelic TLE6 variants in this study are similar to the previously reported clinical cases [14,[23][24][25]. These four patients underwent a total of nine IVF/ICSI attempts in which the number of retrieved oocytes and frequency of oocyte maturity were not clearly abnormal; however, the fertilization rate and blastocyst development rate were very low.…”

“…Two of them obtained a very low number of low-quality embryos but failed to establish pregnancy [24]. Recently, using time-lapse imaging, Zheng et al found that the TLE6 missense variant c.1564G > C (p.Asp522His) is associated with direct cleavage (zygotes directly cleaved into more than two blastomeres) [25].…”

Identification of Novel Biallelic TLE6 Variants in Female Infertility With Preimplantation Embryonic Lethality

“…Therefore, the incidence of TEL6 variants in our study is higher than other studies (Lin et al, 2020;Maddirevula et al, 2020). Furthermore, phenotypes of infertile women harboring biallelic TLE6 variants in this study are similar to the previously reported clinical cases (Alazami et al, 2015;Wang et al, 2018;Lin et al, 2020;Zheng et al, 2021). These four patients underwent a total of nine IVF/ICSI attempts in which the number and morphology of retrieved MII oocytes were not clearly abnormal.…”

“…Two of them obtained a very low number of low-quality embryos but failed to establish pregnancy (Lin et al, 2020). Recently, using timelapse imaging, Zheng et al (2021) found that the TLE6 missense variant c.1564G > C (p.Asp522His) is associated with direct cleavage (zygotes directly cleaved into more than two blastomeres).…”

Biallelic variants in ZFP36L2 cause female infertility characterised by recurrent preimplantation embryo arrest

“…Cytoplasmic maturation involves the occurrence of microscopic molecular processes, such as spindle assembly, organelle distribution and maternal mRNA decay 6–8. Several genetic factors associated with RPEA have been identified, such as spindle assembly molecular TUBB8 (MIM: 616768),9 10 subcortical maternal complex (SCMC) members, PADI6 (MIM: 610363),3 11 TLE6 (MIM: 612399)12 13 and NLRP5 (MIM: 609658) 14 15. However, pathogenic variants in the above-mentioned genes only account for approximately 20%–30% of the RPEA population,13 16 and the underlying genetic causes for other affected individuals remain largely unknown.…”