Uncovering the Genetic Architecture of NSCPO in Chinese via Subtype GWAS

Nonsyndromic cleft palate only (NSCPO) significantly impairs swallowing and speech, reducing quality of life. While surgical interventions offer some improvement, full recovery remains challenging, underscoring the need for a deeper understanding of its etiology. This study aimed to investigate the genetic architecture of nonsyndromic cleft palate only (NSCPO) in the Han Chinese population, focusing on identifying novel susceptibility loci by leveraging data from previous genome-wide association studies and functional genomic datasets from the ENCODE project. We identified significant associations between NSCPO subtypes (incomplete cleft palate and hard and soft cleft palate) and variants such as rs660975 in <i>IRF6</i>, rs3758244 in <i>CDC37L1</i>, and rs4880224 in <i>BNIP3</i>. Functional validation studies, including chromatin conformation capture and dual-luciferase assays, demonstrated that these single-nucleotide polymorphisms influence enhancer activity, thereby affecting gene expression. In addition, subtype-specific analyses revealed novel associations that may be obscured in mixed phenotypic cohorts. The findings highlight the importance of investigating genetic contributions at the subtype level to elucidate the complex etiology of cleft palate and demonstrate that the associated variants have functional effects in vitro, suggesting their roles in the pathogenesis of NSCPO.