Our results provide for the first time evidence implicating FGF1 in the occurrence of CL/P, and support TIMP2 and WNT9B as novel loci predisposing to CL/P. We have also replicated recently reported significant associations between variants in or near FOXE1 and CL/P. It is likely that variation in FOXE1, TIMP2, and the FGF and Wnt signaling pathway genes confers susceptibility to nonsyndromic CL/P in Northeastern European populations.

This study provides for the first time evidence of the implication of IRF6, COL2A1, and WNT3 in the occurrence of NSCP. It is likely that variation in cartilage collagen II and XI genes, IRF6, and the Wnt and FGF signaling pathway genes contributes susceptibility to nonsyndromic cleft palate in Northeastern European populations.

Recent studies suggest that multiple interacting loci, with possible additional environmental factors, influence the risk for nonsyndromic oral clefts, one of the most common birth defects in humans. Advances in high-throughput genotyping technology allow the testing of multiple markers, simultaneously, in many candidate genes. We tested for associations between 176 haplotype-tagging single nucleotide polymorphisms (SNPs) in 18 candidate genes/loci and nonsyndromic clefts in a case-control study in an Estonian sample (153 patients, 205 controls). The most significant associations with nonsyndromic cleft lip with or without cleft palate (CL/P) were found for SNPs in MSX1, MTHFR, and PVRL2, including several common haplotypes in the MTHFR and MSX1 genes. The strongest association was observed for rs6446693 in the MSX1 region, which remained statistically significant after Bonferroni correction. The strongest association with nonsyndromic cleft palate (CP) was found for the SNP rs11624283 in the JAG2 gene. Epistatic interactions were observed for SNPs within PVRL2, between BCL3 and EDN1, and between IRF6 and MSX1 genes. This study provides further evidence implicating MSX1 and MTHFR in the etiology of nonsyndromic CL/P across different populations.

Class III malocclusion is a common dentofacial phenotype with a variable prevalence according to ethnic background. The etiology of Class III malocclusion has been attributed mainly to interactions between susceptibility genes and environmental factors during the morphogenesis of the mandible and maxilla. Class III malocclusion shows familial recurrence, and family-based studies support a predominance of an autosomal-dominant mode of inheritance. We performed whole-exome sequencing on five siblings from an Estonian family affected by Class III malocclusion. We identified a rare heterozygous missense mutation, c.545C>T (p.Ser182Phe), in the DUSP6 gene, a likely causal variant. This variant co-segregated with the disease following an autosomal-dominant mode of inheritance with incomplete penetrance. Transcriptional activation of DUSP6 has been presumed to be regulated by FGF/FGFR and MAPK/ERK signaling during fundamental processes at early stages of skeletal development. Several candidate genes within a linkage region on chromosome 12q22-q23--harboring DUSP6--are implicated in the regulation of maxillary or mandibular growth. The current study reinforces that the 12q22-q23 region is biologically relevant to craniofacial development and may be genetically linked to the Class III malocclusion.

The aim of the study was to (a) analyse dental occlusion and determine the need for orthodontic treatment of persons with osteogenesis imperfecta (OI) in comparison with the healthy population and (b) investigate the associations between OI and malocclusion. A case‐control study included 26 OI persons and 400 healthy participants (control group). Occlusal features and the need for orthodontic treatment were defined according to Dental Health Component‐Index of Orthodontic Treatment Need and Dental Aesthetic Index. Results showed that Angle Class I, II, and III relationship was found in 23.1%, 3.8%, and 73.1% of OI group, and in the control group, it was 67%, 17.5%, and 15.5%, respectively. OI group had significantly higher prevalence of reverse overjet >1 mm (76.9%), missing teeth (42.3%), posterior crossbite (34.6%), and open bite >2 mm (19.2%) compared to the control group (8.5%, 2.2%, 6.2%, and 3.5%, respectively). OI group had less incisal segment crowding and more incisal segment spacing than the control group (p < 0.05). The need for orthodontic treatment of OI group according to Dental Health Component‐Index of Orthodontic Treatment Need and Dental Aesthetic Index was 88.5% and 61.5%, respectively, while in the control group, it was 24.8% and 51.8%. The malocclusion in OI persons was associated with reverse overjet > 1 mm (OR = 13.3, 95% CI = 3.9–44.7, p < .001), Angle Class III malocclusion (OR = 8.0, 95% CI = 2.0–30.8, p = .003), and missing teeth (OR = 4.7, 95% CI = 1.0–22.4, p = .049). In conclusion, there is the high probability of malocclusion in OI persons. Persons with OI require early orthodontic treatment because of significant correlation of OI disease with Angle Class III malocclusion, reverse overjet, and missing teeth.