Identification of a novel TLE6 mutation linked to embryonic arrest and limited rescue by mRNA supplementation
In this study, we report a patient who underwent two in vitro fertilization (IVF) cycles with no usable day-3 embryos. Whole-exome sequencing identified a homozygous splice-region variant in TLE6 (NM_001143986.1: exon7: c.286-7G > A) that was absent from population and clinical variant databases (e.g., gnomAD and ClinVar).We expand the TLE6 variant spectrum and interrogate pathogenicity through a tiered approach combining minigene splicing analysis and structural inference with a CRISPR/Cas9 mouse model. Finally, we evaluate an RNA add-back strategy in mutant zygotes to probe the feasibility, constraints, and timing of intervention for maternal-effect gene defects.