Researchers identified a novel homozygous mutation in the TLE6 gene (NM001143986.1: exon7: c.286-7G > A) in a patient with recurrent IVF failure and embryonic arrest, with the parents being heterozygous carriers. TLE6 is an essential component of the subcortical maternal complex (SCMC) that controls early embryogenesis and cytoskeleton dynamics. A minigene assay showed aberrant RNA editing with a 5-nucleotide insertion, frameshift, and premature truncation of the protein. Structural modeling predicted loss of the C-terminal domain essential for SCMC integrity. In the CRISPR/Cas9 mouse model, mutant Tle6 caused fission arrest and reduced blastocyst formation. Microinjection of wild-type Tle6 mRNA into zygotes produced only limited developmental improvement. The findings broaden the spectrum of pathogenic TLE6 variants that cause loss of function and disruption of SCMCs and highlight the need for alternative interventions and genetic counseling.