Three novel genes tied to mandibular prognathism in eastern Mediterranean families

• Published in: American journal of orthodontics and dentofacial orthopedics 2019-07, Vol.156 (1), p.104-112.e3
• Main Authors: Genno, Pamela G., Nemer, Georges M., Zein Eddine, Savo Bou, Macari, Anthony T., Ghafari, Joseph G.
• Format: Article
• Language: English
• Subjects: Adult; Asian Continental Ancestry Group; Cephalometry; Chromosomes, Human, Pair 1 - genetics; Dentistry; Female; Genetic Association Studies; Genetic Predisposition to Disease - genetics; Genome, Human; Humans; Lebanon; Male; Malocclusion, Angle Class III - blood; Malocclusion, Angle Class III - diagnostic imaging; Malocclusion, Angle Class III - genetics; Malocclusion, Angle Class III - pathology; Middle Aged; Pedigree; Prognathism - blood; Prognathism - diagnostic imaging; Prognathism - genetics; Prognathism - pathology; Sequence Analysis, DNA; Syria; Young Adult
• ISSN: 0889-5406; 1097-6752
• DOI: 10.1016/j.ajodo.2018.08.020

Mandibular prognathism (MP) is subject to major polygenic influence and segregates within families in autosomal dominance with variable expressivity and incomplete penetrance. We aimed to identify the inheritance pattern and genes and loci involved in the development of MP in Mediterranean families and to evaluate the dentoskeletal characteristics of affected individuals. Fifty-one eastern Mediterranean families with individuals affected by MP were identified. Data and biospecimens were collected from 14 of the families, including clinical examination, lateral cephalography (on subjects with Class III malocclusion), and 5 mL blood drawn from consenting affected and nonaffected relatives. Next-generation sequencing (NGS) was performed on 8 families (7 Lebanese, 1 Lebanese/Syrian), including large numbers of affected individuals over many generations and severe conditions, with the use of whole-exome sequencing. Most pedigrees suggested autosomal-dominant inheritance with an equal number of affected male and female individuals. Affected individuals had macrognathic and prognathic mandibles with dentoalveolar compensation. Genetic screening did not correspond with previously reported MP-linked genes, but yielded 3 novel genes (C1orf167, NBPF8, NBPF9) on chromosome 1 potentially responsible for mandibular development and macrognathism. In this first genetic study with the use of NGS on the largest reported number of families with MP, novel genes (C1orf167, NBPF8, NBPF9) were associated with familial MP in the eastern Mediterranean population. •Most pedigrees showed that MP has an autosomal-dominant mendelian inheritance.•Subjects affected by MP had macrognathic mandibles with dentoalveolar compensation.•NGS was done on 8 eastern Mediterranean families including subjects affected by MP.•Three novel genes on chromosome 1 were linked to familial MP in these families.