Novel genes linked to Class II Division 1 malocclusion with mandibular micrognathism

• Published in: American journal of orthodontics and dentofacial orthopedics 2023-05, Vol.163 (5), p.667-676.e3
• Main Authors: El Chekie, Michelle R., Nemer, Georges, Khalil, Athar, Macari, Anthony T., Ghafari, Joseph G.
• Format: Article
• Language: English
• Subjects: Homeodomain Proteins; Humans; Malocclusion; Malocclusion, Angle Class II; Mandible; Micrognathism; Pedigree; Phenotype; Repressor Proteins
• ISSN: 0889-5406; 1097-6752
• DOI: 10.1016/j.ajodo.2022.04.020

Mandibular micrognathism (MM) is an underdeveloped mandible resulting from complex interactions between genetic and environmental factors. Prior research focused mainly on the genetic determinants of mandibular retrognathism, not necessarily reflecting micrognathism, thus supporting the need to study MM. This study aimed to explore the inheritance pattern and identify the candidate genes involved in the development and familial transmission of MM. Diagnosing probands with MM was based on clinical and lateral cephalometric data. The pedigrees were drawn for 11 identified families, 5 of whom accepted to undergo detailed data and biospecimen collection. These families included 15 MM and 13 non-MM subjects over 2-3 generations. The procedure involved the withdrawal of 5 mL of blood. Genomic DNA was isolated from blood cells to investigate protein-coding regions via whole exome sequencing. Standardized filtering steps were employed, and candidate genes were identified. Most of the pedigrees suggested a Mendelian inheritance pattern and segregated in an autosomal-dominant manner. One of the families, which also underwent biospecimen, displayed an X-linked inheritance pattern of the trait. Genetic screening disclosed 8 potentially novel genes (GLUD2, ADGRG4, ARSH, TGIF1, FGFR3, ZNF181, INTS7, and WNT6). None of the recognized exonic regions were previously reported. Eight novel genes were identified in association with MM in the largest number of families reported to date. The genes were X-linked in 1 family, a finding previously not observed in mandibular genetics. •MM segregated over 2 to 3 generations in 5 families (Mendelian inheritance).•Autosomal dominance was observed in 4 families.•One family displayed an X-linked pattern, a unique finding to date.•Eight genes harboring potentially novel variants were identified.