Candidate gene studies in hypodontia suggest role for FGF3

Abstract

The majority of tooth agenesis cases are mild (hypodontia) and typically not associated with the gene mutations linked to oligodontia. From this, we hypothesize that most cases of tooth agenesis fit a polygenic mode of inheritance, where several genes with small effects cause a variety of varying phenotypes. In this study, we looked at 18 not typically studied genes in this condition, to ascertain their contribution to hypodontia. Our study subjects consisted of 167 patients with hypodontia and their parents from two cohorts (one from Brazil and one from Turkey). An additional 465 DNA samples (93 cases with hypodontia and 372 controls without family history for tooth agenesis or oral clefts) from Brazil were also available for this study. 93 single nucleotide polymorphisms that maximally represent the linkage disequilibrium structure of the genes for the 18 genes were selected and genotyped using Taqman chemistry. Chi-square was used to test if genotype distributions were in Hardy-Weinberg equilibrium, and 24 markers that were in Hardy-Weinberg equilibrium and had allele frequencies higher than 5% in a panel of 50 CEPH samples were further tested. Association between hypodontia and genetic variants was tested with the transmission disequilibrium test within the program Family-Based Association Test (FBAT) and by using chi-square and Fisher’s exact tests. Alpha at a level of 0.05 was used to report results. Results suggest possible associations between several genes and hypodontia in the three populations. In the Turkish cohort (n=51 parent-affected child trios) the most significant results were as follows: FGF3 rs1893047, p=0.08; GLI3 rs929387, p=0.03; GLI3 haplotype rs929387-rs846266, p=0.002; and PAX9 rs2073242, p=0.03. In the Brazilian cohort (n=116 parent-affected child trios), the results were as follows: DLX1 rs788173, p=0.07; FGF3 rs12574452, p=0.03; GLI2 rs1992901, p=0.03; and PITX2 rs2595110, p=0.01. The second Brazilian cohort also suggested that FGF3 (rs12574452, p=0.01) is associated with hypodontia and added EDAR (rs17269487, p=0.04), LHX6 (rs989798, p=0.02), and MSX1 (rs12532, p=0.003). Our results suggest that several genes are potentially associated with hypodontia and their individual contributions may be modest. Hence, these cases may not be explained by inactivating mutations such as many oligodontia cases segregating in a Mendelian fashion but rather are influenced by one or more susceptibility alleles in multiple small effect genes.

Epidemiology and genetics of hypodontia and microdontia: A study of twin families

“…A close relationship between hypodontia and microdontia has been reported, and genetics plays an important role in dental development. 2,3,5,6,14,18,30,31 However, the details differ based on the type of dental anomaly.…”

“…1 Developmental dental anomalies such as hypodontia and microdontia are not uncommon in many populations, but little is known about their underlying causes. 2,3 The prevalence rates of these anomalies varies across populations; previous studies have reported a prevalence as low as 2.3% and as high as 11.3%. [4][5][6] Substantial differences in frequency may at least partly be explained by study design, and a population-based study is more likely to determine the true frequency of these anomalies.…”

Süt Ve Dai̇mi̇ Denti̇syonda Görülen Konjeni̇tal Di̇ş Eksi̇kli̇ği̇ Ve Ai̇le İli̇şki̇si̇: 4 Olgu Sunumu

“…Hipodonti görülen hastalarda estetik sorunların yanı sıra çiğneme ve konuşma bozuklukları da görülebilmektedir. Özellikle bu hastalarda iyi anemnez alınmalı, ailesinde konjenital diş eksikliği varlığı sorulmalıdır 7,10,11 . Konjenital diş eksikliklerinin saptanmasında radyografinin, özellikle panoramik radyografinin önemi büyüktür 3 .…”

“…Bir diğer görüş embriyonik hayatta, kafayüz gelişimi sürerken birleşme bölgelerine denk gelen dişlerde eksikliklerin daha sık görülebildiği şeklindedir. Bir başka görüş ise embriyonik mezenkime gelecek herhangi bir zararın diş gelişimini etkileyebileceği teorisidir 11,16 . Yapılan çalışmalarda, hücrelerin birbiri ile etkileşiminde rol alan çeşitli gen ve gen ürünlerinin diş oluşumunda etkili oldukları belirtilmektedir 7,15,17,18 .…”

“…Günümüzde, diş gelişiminde rol alan yaklaşık 100 genin, diş eksikliğinde de potansiyel aday genler oldukları bildirilmektedir. Son yıllarda yapılan çalışmalarda MSX1, PAX9, FGF3 genlerinde ve 2 (AXIN2) inhibisyon proteininde meydana gelen değişimin, konjenital diş eksikliğinde rol aldığı vurgulanmaktadır 11,17,18 .…”