Human YTHDC2 mutations disturb RNA homeostasis of oocytes and early embryos.

Oocyte and early embryo competence defects (OECD) are a kind of Mendelian genetic disorder. While numerous pathogenic variants have been identified, the underlying molecular mechanisms remain largely elusive. In this study, through whole-exome sequencing of infertile patients, we identified five novel biallelic mutations in YTHDC2, a locus previously implicated in primary ovarian insufficiency, in four families with OECD. Of note, two affected individuals presented with diminished ovarian reserve. To delineate the functional consequences of these variants, we overexpressed human mutant YTHDC2 in mouse growing oocytes at the GO2 stage (50–55 μm in diameter) with high Ythdc2 expression, and performed transcriptomic profiling. In parallel, we conducted single-cell RNA sequencing of human preimplantation embryo carrying YTHDC2 mutations. By integrating mouse Ythdc2 iCLIP-seq data, transcriptomes of GO2 oocytes, and human embryonic single-cell data, we demonstrate that YTHDC2 mutations disrupt RNA homeostasis, leading to progressive functional abnormalities during oocyte and early embryonic development. Furthermore, mutant YTHDC2 overexpressed in mouse zygotes significantly compromised early embryonic development, characterized by a marked reduction in blastocyst formation rates. Our study identifies YTHDC2 as a critical regulator of oocyte and early embryonic development and provides a novel target for clinical genetic diagnosis.