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

Abstract

Preimplantation embryonic lethality is a rare cause of primary female infertility. It has been reported that variants in the transducin-like enhancer of split 6 (TLE6) gene can lead to preimplantation embryonic lethality. However, the incidence of TLE6 variants in patients with preimplantation embryonic lethality is not fully understood. In this study, we identified four patients carrying novel biallelic TLE6 variants in a cohort of 28 patients with preimplantation embryonic lethality by whole-exome sequencing and bioinformatics analysis, accounting for 14.29% (4/28) of the cohort. Immunofluorescence showed that the TLE6 levels in oocytes from patients were much lower than in normal control oocytes, suggesting that the variants result in the lower expression of the TLE6 protein in oocytes. In addition, a retrospective analysis showed that the four patients underwent a total of nine failures of in vitro fertilization and intracytoplasmic sperm injection attempts, and one of them became pregnant on the first attempt using donated oocytes. Our study extends the genetic spectrum of female infertility caused by variants in TLE6 and further confirms previously reported findings that TLE6 plays an essential role in early embryonic development. In such case, oocyte donation may be the preferred treatment.

Genetics of Oocyte Maturation Defects and Early Embryo Development Arrest

“…In mouse models, the knockout of the Tle6 gene has no effect on oogenesis but results in embryonic developmental arrest at the 2-cell stage, leading to female mouse infertility [ 48 , 67 ]. Homozygous and compound-heterozygous variants in the TLE6 gene are associated with various phenotypes, including fertilization failure, early cleavage failure, embryonic developmental arrest on day 3, and a high rate of embryo fragmentation due to the disruption of F-actin and spindle assembly [ 14 , 66 , 68 , 69 ]. A woman with a heterozygous variant in TLE6 had normal fertility and two healthy children [ 69 ].…”

“…Homozygous and compound-heterozygous variants in the TLE6 gene are associated with various phenotypes, including fertilization failure, early cleavage failure, embryonic developmental arrest on day 3, and a high rate of embryo fragmentation due to the disruption of F-actin and spindle assembly [ 14 , 66 , 68 , 69 ]. A woman with a heterozygous variant in TLE6 had normal fertility and two healthy children [ 69 ]. In men with homozygous variants in TLE6 fertility is preserved [ 14 ].…”

Nlrp5 and Tle6 expression patterns in buffalo oocytes and pre‐implantation embryos

“…Increasing evidence indicates additional functions of SCMCs, including mitochondrial distribution and translational regulation (Bebbere et al., 2016; Lu et al., 2017). Recently, several MEGs were identified in human by whole‐exome sequencing (Alazami et al., 2015; M. Zhang et al., 2021). For domestic animals, Bebbere et al first reported expression of SCMC genes in ovine oocytes and pre‐implantation embryos, representing the first expression profiles for a large mammalian species (Bebbere et al., 2014).…”

“…SCMCs, which appear to be functionally conserved across many mammalian species, include eight proteins: oocyte‐expressed protein, zinc finger BED domain‐containing protein 3, KH domain‐containing protein 3, protein‐arginine deiminase type 6 (PADI6), transducin‐like enhancer protein 6 (TLE6), NOD‐like receptor family pyrin domain‐containing 2 (NLRP2), NLRP5 and NLRP7 (Mahadevan et al., 2017; Monk et al., 2017; Xu et al., 2016; M. Zhang et al., 2021; Zhu et al., 2015). The study of MEGs has mainly focused on humans and mice.…”

“…Increasing evidence indicates additional functions of SCMCs, including mitochondrial distribution and translational regulation (Bebbere et al, 2016;Lu et al, 2017). Recently, several MEGs were identified in human by whole-exome sequencing (Alazami et al, 2015;M. Zhang et al, 2021).…”