Genetic and Molecular Determinants of Familial Transmission of Skeletal Malocclusions

Families studies conducted in different ethnic populations worldwide have helped elucidate the molecular and genetic factors involved in the development of skeletal class III malocclusion. Therefore, the aim of this study is to provide an updated summary. The study followed the JBI Manual for Evidence Synthesis and PRISMA-scR guidelines. PubMed, Scopus, WOS, Google Scholar and DANS databases were explored using specific strategies. Eligible studies included linkage and genome-wide analyses, while association studies, case reports and in vivo/in vitro research were excluded. The included studies must have involved at least one family with one or more members exhibiting the skeletal malocclusion phenotypes. An autosomal dominant inheritance pattern with variable penetrance for skeletal class III malocclusions across East Asian, Southeast Asian, Middle Eastern, European and South American populations was identified. In contrast, skeletal class II malocclusions exhibited autosomal dominant and X-linked inheritance patterns, with a higher prevalence in Eastern Mediterranean and South American populations. Key molecular findings include missense mutations in DUSP6 (c.545C>T and c.1094C>T), which affect mandibular prognathism and maxillary deficiency via the FGF/FGFR and MAPK/ERK pathways. Additionally, mutations in ADAMTS1 (c.742I>T), ADAMTS2 (c.3506G>T) and ADAMTSL1 (c.176G>A) impact mandibular growth through aggrecan metabolism and osteogenesis, disrupting bone remodelling via the EGFR/ErbB signalling pathway. This comprehensive review highlights the complex genetic basis of skeletal malocclusions, provides insights into the underlying molecular mechanisms, suggests potential targets for therapeutic intervention, and contributes to our understanding of the genetic architecture of these conditions.