Case Report: Biallelic PADI6 frameshift variants contribute to preimplantation embryonic lethality

Preimplantation embryonic lethality (PREMBL) is a major cause of female infertility, characterized by early embryonic arrest. Homozygous or compound heterozygous mutations in PADI6 underlie preimplantation embryonic lethality-2 (PREMBL2). This study aims to conduct a systematic genetic investigation on a case with PADI6 biallelic variants.

A patient clinically diagnosed with PREMBL was systematically evaluated via chromosomal karyotyping analysis, high-resolution chromosomal microarray analysis (CMA), whole-exome sequencing (WES), molecular dynamics analysis (MD), immunofluorescence (IF), and Western blotting (WB) to identify PREMBL-associated variants.

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.

This study implicates a previously unreported compound heterozygous combination of the PADI6 variants c.707dupT and c.2009_2010delAG as the potential genetic basis of PREMBL2 in this individual, based on their predicted disruptive effects. However, as a single-case study, these findings cannot be generalized. Future research should focus on validating these variants in additional patients and functionally characterizing their effects to definitively establish causality and understand their role in early embryonic arrest.