Association between genes and familial mandibular micrognathism in an Eastern Mediterranean population

Abstract

Background: Mandibular micrognathism (MM) is characterized by an underdeveloped mandible leading to a chinless-type face and a convex profile which is characteristic of the Class II/division1 malocclusion. The etiology of MM is multifactorial, where environmental and genetic/familial factors interact over time, thus favoring the polygenic model of inheritance. Only one genome-wide family-based linkage has been carried out in the Hispanic population, exposing that data on the genetic determinants behind MM is nevertheless fragmentary. Aims: 1. Explore the inheritance pattern and identify the candidate genes and loci involved in the development and familial transmission of MM in an Eastern Mediterranean population; 2. Evaluate the skeletal and dento-alveolar cephalometric characteristics of affected individuals compared to a sample of non-affected with normoclusion. Methods: Out of the 11 pedigrees of Eastern Mediterranean families which included probands affected with MM, 5 families (4 Lebanese and 1 Syrian/Jordanian) accepted to undergo a detailed data and biospecimen collection procedure. The diagnosis of the probands was based on a clinical and radiographic (lateral cephalogram) examination. 5cc of blood was collected from both affected and non-affected individuals (as control), and genomic DNA was isolated from blood cells to investigate protein-coding regions via whole exome sequencing (WES) performed on a NovaSeq6000 Illumina platform in Korea. Results: Most of the pedigrees suggest a Mendelian inheritance pattern and segregate in an autosomal-dominant manner, while one family (which underwent biospecimen) displayed an X-linked inheritance pattern of the trait. Pedigree analysis indicated an equal number of reported generations per family (n=3), an equal average number of reported affected males and females (n=2.36) per family and an equal number of families with males and females predominance (n=4). Averaged cephalometric measurements on affected individuals from the 5 families confirmed a reduced mandibular length (mandibular micrognathism), normal maxillary length, a tendency to a hyperdivergent facial pattern, a skeletal Class II malocclusion underlined by an orthognathic maxilla and retrognathic mandible. This was accompanied by dento-alveolar compensations and an increased overjet. Genetic screening didn’t show any aberration in the previously reported genes linked to ClassII/ division1, mandibular retrognathism or MM, but did point out to 8 potentially novel genes (GLUD2, ADGRG4, ARSH, TGIF1, FGFR3, ZNF181, INTS7 and WNT6) that could be implicated in mandibular development and lead mainly to MM. Conclusion: This study reaped its novelty from its design as it is the first genetic study on large families with MM worldwide and more specifically in the Eastern Mediterranean population using NGS to better understand the variations and risks for MM. GLUD2, ADGRG4, ARSH, TGIF1, FGFR3, ZNF181, INTS7 and WNT6 are novel genes discovered to be associated with familial MM, which emphasizes on the complexity of the trait . This exploration will help understand the variation in mandibular growth, potential prediction of the final manifestation of the growth pattern which would help in treatment planning by incorporating such information into clinical-decision making process.