Two Novel Protein-Truncating Variants in NLRP2 and Their Functional Impacts on the Subcortical Maternal Complex

Female infertility is a prevalent reproductive disorder with high genetic heterogeneity. Previous reports have demonstrated the causal role of biallelic pathogenic variants in the Subcortical Maternal Complex (SCMC) genes in female reproductive failure with some leading to infertility, early embryonic loss, and molar pregnancies, while others are compatible with live birth with and without multilocus imprinting disorders (MLID). Here, we report two deleterious protein-truncating variants, c.1326delG, p.Leu443Phefs*78 and c.2802_2803del, p.Arg935Metfs*15, in heterozygous state in the NLRP2 gene of a patient with primary infertility, four early miscarriages, and one failed attempt of intracytoplasmic sperm injection. We show that the two variants mediate mRNA decay in EBV-transformed lymphoblastoid cells from the patient, lead to decreased NLRP2 protein levels, and alter NLRP2 interactions with other members of the SCMC in vitro. This study emphasizes the importance of performing clinical exomes for patients with recurrent reproductive failure and reporting their variants and reproductive histories to improve patient counseling.