Mandibular retrognathism (MR), commonly recognized as a skeletal malocclusion, manifests through the backward positioning of the mandible relative to the frontal portion of the skull base(Balkhande, Lakkakula, & Chitharanjan, 2018; Bell, 1966). It can present as a component of a broader syndrome or as an isolated anomaly. Non-syndromic MR, predominantly characterized by three-dimensional mandibular hypoplasia, affects both facial aesthetics and oral function(Huo, Che, & Li, 2023; Lavigne et al., 2020; Paul, Simon, Issac, & Kumar, 2015). It represents the prevalent type of skeletal class II malocclusion, affecting approximately 23 %-29 % of the global population(Ferrazzano et al., 2019).

Attributed to craniofacial growth and developmental issues, MR is shaped by both genetic and environmental influences(Telatar, Telatar, & Saydam, 2023). A particular study (Lundström, 1984) revealed that genetic factors contribute to about 40 % of malocclusion cases, exerting a stronger influence on skeletal rather than dental patterns. Earlier research indicated a polygenic etiological basis for MR (Arun, Lakkakula, & Chitharanjan, 2016; Balkhande et al. 2018; Küchler, Reis, Carelli, et al., 2021), with genetic influences varying significantly among ethnic groups(Gershater et al., 2021). Additionally, environmental factors such as lip and tongue functions, localized dental disturbances, poor oral habits, and airway obstruction also play roles in MR’s development(Ngan & Fields, 1997; Nielsen, 1991). Importantly, the interaction between genetic predisposition and environmental exposures may significantly contribute to the phenotypic variability observed in MR patients. Recent studies have highlighted the role of gene-environment interactions in shaping craniofacial development (Shull & Artinger, 2023). Environmental factors may influence the genome and epigenome, induce epigenetic modifications (e.g., DNA methylation, histone acetylation) in genes involved in mandibular growth, thereby modulating their expression (Shull & Artinger, 2023). In zebrafish models, interactions between alcohol, piperonyl butoxide (PBO), and Sonic Hedgehog A gene (shha) was observed, indicating multifactorial environmental and genetic interactions in the pathogenesis of craniofacial defects(Everson, Batchu, & Eberhart, 2020).

Currently, predicting mandibular development and the success of clinical intervention remains challenging, primarily due to a lack of comprehensive understanding of its etiology (Gershater et al., 2021). Genome-wide association studies (GWASs) have revealed a multitude of single nucleotide polymorphisms (SNPs) associated with various human diseases and traits (Gorlova, Xiao, Tsavachidis, Amos, & Gorlov, 2022). SNPs in certain regions may alter gene expression, thereby influencing individual variability and predisposition to complex traits, including malocclusion (Küchler et al., 2022). Related to maxillofacial growth and development, some SNPs might lead to skeletal malocclusion, affecting sagittal, lateral, and vertical growth patterns (Telatar et al. 2023). Consequently, the investigation of candidate genes for MR has intensified recently, offering insights into its pathogenesis and clarifying its underlying causes. These efforts could enable orthodontists to develop preventive measures, and devise personalized therapeutic interventions and more precise treatment strategies that benefit MR patients (Claes et al., 2018; Jheon, Oberoi, Solem, & Kapila, 2017). However, comprehensive insights and a global perspective on the genes and signaling pathways linked to MR are still lacking.

Therefore, the primary goal of this review is to compile the available scientific evidence on genetic association studies pertaining to MR. We aim for our findings to contribute a novel perspective on the etiology of MR and provide a detailed understanding of the genetic factors involved.