Biallelic PADI6 Frameshift Variants Contribute to Preimplantation Embryonic Lethality

A patient clinically diagnosed with PREMBL was systematically evaluated via chromosomal karyotyping analysis, high-resolution chromosomal microarray (CMA), whole-exome sequencing (WES), molecular dynamics analysis (MD), immunofluorescence (IF), and Western blotting (WB) to identify pathogenic variants and establish causal links.WES identified two biallelic frameshift variants in PADI6: c.707dupT (L237Afs*24) and c.2009_2010delAG (E670Gfs*48). MD, IF, and WB analyses demonstrated that: The L237A variant generates a 259-aa truncated protein lacking the essential C-terminal domain. The E670G variant produces a 716-aa elongated protein with significant C-terminal structural alterations. Both variants cause complete loss of protein function and markedly reduced abundance.