Identification of Novel SCMC Gene Variants Associated With Early Embryonic Arrest

Abstract

The subcortical maternal complex (SCMC) is crucial for the oocyte-to-embryo transition, and genetic variants in SCMC genes have been associated with early embryonic arrest (EEA). In this study, we performed whole-exome sequencing on 303 independent females with EEA and identified 16 patients with biallelic pathogenic variants in SCMC genes (NLRP2, NLRP5, PADI6, and TLE6), accounting for 5.3% of EEA cases. NLRP5 had the highest prevalence, with 7 out of 16 cases (43.8%). A total of 23 novel variants were identified, including 13 missense, eight loss-of-function, one in-frame insertion, and one large 6.9 kb deletion. Functional predictions using mCSM indicated that nine missense variants destabilize SCMC structure. Additionally, RT-PCR and cDNA sequencing demonstrated that the synonymous variant in TLE6 (c.180G>A) impacts splicing and induces nonsense-mediated decay. Taken together, our findings revealed that novel biallelic variants in SCMC genes were associated with human EEA, which expands the spectrum of genetic causes and facilitates the genetic diagnosis of female infertility with EEA.