A novel TLE6 mutation, c.541+1G>A, identified using whole‐exome sequencing in a Chinese family with female infertility

Abstract

Background Oocytes have a lot of maternal RNAs and proteins, which are used by the early embryo before zygotic genome activation. Transducin‐like enhancer of split 6 (TLE6) is a component of a subcortical maternal complex which plays a critical role in early embryonic development. Methods The patient had been diagnosed with primary infertility for 6 years and had undergone multiple failed in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles. Genomic DNA samples were extracted from her parents’ peripheral blood as well as hers. Whole‐exome sequencing and Sanger validation were performed to identify candidate variants. Results We identified a novel transducin‐like enhancer of split 6 (TLE6) gene mutations in the female patient with recurrent IVF/ICSI failure. The patient carried a homozygous mutation (NM_001143986.1(TLE6): c.541+1G>A) and had viable but low‐quality embryos. Her parents both had heterozygous mutations at this locus. Conclusion Our study expands the mutational and phenotypic spectrum of TLE6 and suggests the important role of TLE6 during embryonic development. Our findings have implications for the genetic diagnosis of female infertility with recurrent IVF/ICSI failure.

A novel variant in TLE6 is associated with embryonic developmental arrest (EDA) in familial female infertility

“…To date, 13 variants have been identified in TLE6 —associated with EDA characterized by female fertility 34 – 40 . 64% of them were located in the WDR domain.…”

“…variants in the TLE6 gene at the 19p13.3 locus (OMIM * 612399) are responsible for autosomal recessive preimplantation embryonic lethality and EDA. To date, 13 variants have been identified 34 – 40 . The phenotypic spectrum seen in TLE6 mutated patients in these reports suggested sex-associated and genotype–phenotype correlations.…”

Gene mutations associated with fertilization failure after in vitro fertilization/intracytoplasmic sperm injection

“…Functional knockout studies of the TLE6 gene in mice showed the termination of embryo cleavage as the most phenotype (74). Several mutations within the TLE6 gene were shown to be associated with low-quality embryos (39,75,76). In 2015, a homozygous substitution (c.1529C > A) in TLE6 was verified by whole-exome sequencing in three infertile women (77).…”

Roles of transducin-like enhancer of split (TLE) family proteins in tumorigenesis and immune regulation

“…However, many studies have suggested that TLE5 is a multifunctional protein that can positively or negatively modulate the transcriptional activities of many TFs (Tetsuka et al, 2000;Yu et al, 2001;Swingler et al, 2004;Zhang et al, 2008;Beagle and Johnson, 2010;Chanoumidou et al, 2018). TLE6 is highly expressed in the reproductive system, and its mutation is linked to female infertility (Li et al, 2008;Yu et al, 2014;Lin et al, 2020;Mao et al, 2021;Zhang et al, 2021). It possesses a conserved WDR domain and a highly divergent N-terminal region.…”