Genetic basis of familial oligo-hypo-hyperdontia in eastern Mediterranean families

Abstract

Background: Tooth agenesis is one of the most common congenital malformations in humans. This may affect either the primary or permanent dentition and can range from 5 or fewer missing teeth (hypodontia), 6 or more (oligodontia), to complete absence of teeth (anodontia). Tooth agenesis may originate from either genetic or environmental factors. Hypodontia as genetically determined can either occur as an isolated condition (non-syndromic hypodontia) involving 4 common genes types: MSX1, PAX9, WINT10A and AXIN2 or can be associated with a syndrome (syndromic hypodontia). Early tooth development can lead also to supernumerary teeth known for “hyperdontia” which refers to the presence of extra teeth compared to a normal dentition. Genetic factors play a role in the occurrence of hyperdontia, but the isolated condition (non-syndromic hyperdontia) is rare compared to the syndromic condition. Objective: 1. To gain more insight into the prevalence of dental agenesis and dental excess. 2. Clarify the inheritance pattern of dental agenesis and dental excess. 3. Highlight the concomitance of hypodontia/hyperdontia in one family. Methods: An initial cohort of 16 patients seeking orthodontic treatment at AUBMC will be recruited for the study. The patients were from different families affected by hypodontia, oligodontia, and hyperdontia. Inclusion criteria were: at least two generations affected in each family; agenesis ranging from 1 to ≥ 6 teeth, hyperdontia ≥ 1 tooth; no genetic syndromes or systemic conditions, no history of facial trauma, previous extractions, or orthodontic treatment. Tooth agenesis and hyperdontia were evaluated on panoramic radiographs and pedigrees were established using the progeny software. Whole exome sequencing will be performed on all family members and variants would be analyzed using the Illumina variant studio based on minor allele frequency of <1% concomitant with a segregation of the genotype with the underlying phenotype. A second cohort study will be conducted on the affected members (with dental agenesis) of the included families and their relatives to evaluate the dental and arches dimensions compared to control groups. The group are as follow: group 1 (affected patients N=18); group 2 (control of group 1 N=18); group 3 (relatives of group 1: non affected N=10) and group 4 (control of group 3 N=10). The inclusion criteria for the control groups are: no dental extractions or implant restorations; no genetic syndromes or systemic conditions, no history of facial trauma and no orthodontic treatment. Variables assessed were: dental crown width and length; root length; maxillary/ mandibular arch perimeters: arch circumference available, required and deficiency; maxillary/ mandibular inter-molar and inter-canine widths.

Results: Most of the pedigrees suggest a Mendelian inheritance pattern and segregate in an autosomal-dominant manner. Pedigree analysis indicated an equal number of reported generations per family (n=3-4), number of families with female predominance (n=11), number of families with male predominance (n=4) and families with equal number of reported affected males and females (n=1). Genetic screening did not show any aberration in the previously reported genes linked to hypodontia/hyperdontia, but did point out to 14 potential candidate novel genes (CRACR2A, PER3, NOV/CCN3, EDAR, APCDD1, CDH26, NME8, LAMC2, LIMD1, WNT10A, FGFBP1, DFFA, OR10A6 and DYRK1A) that could be implicated in hypodontia/hyperdontia. Dental evaluation through panoramic x-ray and intra-oral 3D scans from the 8 families having hypodontia, confirmed a reduced arch dimension, less crowding and smaller teeth with shorter roots in the affected group compared to the control and to their relatives. In addition, dental evaluation confirmed as well that the relative group have smaller arch and dental dimensions compared to the control group and larger compared to the affected group. Conclusion: This study gains its strength and novelty from its design as it is the first genetic study on large families having hypodontia alone (n=5), hyperdontia alone (n=1) and combined hypo and hyperdontia (n=3) in the Eastern Mediterranean population using the NGS/WES. An “accordion pattern” exists between the two phenotypes: Hypodontia is an evolutionary effect and hyperdontia is a compensatory effect. A “continuum pattern” exists between all groups for all dental variables: Teeth crowns tend to get thinner and shorter, and root length tend to get shorter as we move from control to non-affected to agenesis group.