[Research progress in regulatory variants in non-coding regions in non-syndromic cleft lip with or without cleft...

Non-syndromic cleft lip with or without cleft palate (NSCL/P) is one of the most common congenital craniofacial malformations, characterized by significant genetic heterogeneity and polygenic features. Historically, genetic studies of NSCL/P have primarily focused on coding region variants. However, only approximately 2% of the human genome consists of coding sequences, with the majority of variants located in non-coding regions. Recent large-scale genome-wide association studies have indicated that risk loci associated with NSCL/P are predominantly enriched in regulatory elements within non-coding regions of the genome. These non-coding variants, while not directly altering protein structures, can influence gene expression patterns in specific tissues or developmental spatiotemporal contexts by affecting the function of regulatory elements, thereby contributing to disease phenotypes. With the continuous advancement of functional genomics and bioinformatics methodologies, the identification, functional annotation, and mechanistic analysis of regulatory variants in non-coding regions have become critical directions in NSCL/P genetic research. This review systematically summarizes the research progress in identification methods, functional annotation strategies, and functional validation techniques for non-coding variants in NSCL/P patients. It elaborates on the significant role of non-coding regulatory elements in the pathogenesis of NSCL/P, aiming to provide new perspectives for understanding the functional significance of non-coding regions in NSCL/P and other complex diseases.