Association between genes and familial mandibular prognathism in the Mediterranean population

Abstract

Mandibular prognathism (MP) is a dentofacial phenotype characterized by overgrowth and-or prognathism of the mandible with or without maxillary retrognathism, leading to esthetic and functional impairments. While MP segregates within families in an autosomal-dominant manner with incomplete penetrance, environmental factors remain involved in its etiology. Only a few genome-wide family-based linkages have been done in different ethnic populations to identify the gene(s) involved in the trait, showing that the genetic determinants of MP remain unclear. Aims: 1. Explore the inheritance pattern and identify the candidate genes and loci involved in the development and familial transmission of MP in Mediterranean families; 2. Evaluate the skeletal and dento-alveolar cephalometric characteristics of affected individuals. Methods: Pedigrees of 51 Mediterranean families known to include individuals affected by MP were drawn. 14 of them, including several affected subjects, underwent a detailed data and biospecimen collection procedure. This consisted of a clinical examination followed by a lateral cephalometric radiograph on subjects where features of a Class III malocclusion were noted clinically and 5cc of blood collection from the affected and some non-affected relatives. Genetic screening was performed on 8 families (7 Lebanese; 1 Lebanese-Syrian), including the largest number of affected individuals over many generations and the most severe conditions, using Next Generation Sequencing (NGS) technology by application of a Whole Exome Sequencing (WES). Results: Most of the pedigrees suggest a Mendelian inheritance pattern and segregate in an autosomal-dominant manner. Pedigree analysis showed an average of 3 reported generations per family, equal number of reported affected males and females (n=2) and more families with male predominance. Cephalometric analysis on affected individuals denoted long mandibular length (mandibular macrognathism), normal maxillary length, tendency to a hyperdivergent facial pattern,