Identification of CASKIN2 as a Novel Candidate Gene for Müllerian Duct Anomalies in Humans.

Objective: The aim of this study was to explore potential novel genes associated with Müllerian duct anomalies (MDAs) through next-generation sequencing techniques. Materials and Methods: Whole-exome sequencing (WES) was conducted for 5 unrelated patients of Chinese Han ethnicity diagnosed with congenital absence of the uterus and vagina (CAUV), alongside 10 unaffected women. Genomic data were sourced from a public database. Diagnosis and classification of the anomalies were based on findings from ultrasound imaging, hysterosalpingography, and hysteroscopy. A previously unreported candidate gene, CASKIN2, was identified. Subsequently, 120 unrelated patients with MDAs, who sought infertility treatment at the Center for Reproductive Medicine, The First Affiliated Hospital of Anhui Medical University between January 2008 and December 2011, were included for targeted analysis of candidate genes and variants detected through WES. Results: Two novel heterozygous missense variants in the CASKIN2 gene (NM_020753: c.969C>A, p.H323Q; c.1228G>A, p.V410M) were identified in two unrelated patients with CAUV through WES. Further direct sequencing of all coding exons of CASKIN2 in the cohort of 120 patients with MDA revealed three additional missense variants (c.1128G>A, p.V410M; c.2816C>T, p.T939M; c.3377G>A, p.R1126H). No pathogenic variants were detected among individuals in the control group. Conclusion: The CASKIN2 gene, which is evolutionarily conserved across multiple species and known to interact with CASK, may represent a novel candidate gene associated with MDAs in people of Chinese Han ethnicity. The CASKIN2-CASK signaling axis appears to play an evolutionarily conserved and indispensable role during human Müllerian-duct development.