Identification of likely pathogenic and known variants in TSPEAR, LAMB3, BCOR, and WNT10A in four Turkish families with tooth agenesis.

Tooth agenesis (TA), the failure of development of one or more permanent teeth, is a common craniofacial abnormality observed in different world populations. The genetic etiology of TA is heterogeneous; more than a dozen genes have been associated with isolated or nonsyndromic TA, and more than 80 genes with syndromic forms. In this study, we applied whole exome sequencing (WES) to identify candidate genes contributing to TA in four Turkish families. Likely pathogenic variants with a low allele frequency in the general population were identified in four disease-associated genes, including two distinct variants in TSPEAR, associated with syndromic and isolated TA in one family each; a variant in LAMB3 associated with syndromic TA in one family; and a variant in BCOR plus a disease-associated WNT10A variant in one family with syndromic TA. With the notable exception of WNT10A (Tooth agenesis, selective, 4, MIM #150400), the genotype-phenotype relationships described in the present cohort represent an expansion of the clinical spectrum associated with these genes: TSPEAR (Deafness, autosomal recessive 98, MIM #614861), LAMB3 (Amelogenesis imperfecta, type IA, MIM #104530; Epidermolysis bullosa, junctional, MIMs #226700 and #226650), and BCOR (Microphthalmia, syndromic 2, MIM #300166). We provide evidence supporting the candidacy of these genes with TA, and propose TSPEAR as a novel nonsyndromic TA gene. Our data also suggest potential multilocus genomic variation, or mutational burden, in a single family, involving the BCOR and WNT10A loci, underscoring the complexity of the genotype-phenotype relationship in the common complex trait of TA.

A biallelic ANTXR1 variant expands the anthrax toxin receptor associated phenotype to tooth agenesis.

Tooth development is regulated by multiple genetic pathways, which ultimately drive the complex interactions between the oral epithelium and mesenchyme. Disruptions at any time point during this process may lead to failure of tooth development, also known as tooth agenesis (TA). TA is a common craniofacial abnormality in humans and represents the failure to develop one or more permanent teeth. Many genes and potentially subtle variants in these genes contribute to the TA phenotype. We report the clinical and genetic impact of a rare homozygous ANTXR1 variant (c.1312C>T), identified by whole exome sequencing (WES), in a consanguineous Turkish family with TA. Mutations in ANTXR1 have been associated with GAPO (growth retardation, alopecia, pseudoanodontia, and optic atrophy) syndrome and infantile hemangioma, however no clinical characteristics associated with these conditions were observed in our study family. We detected the expression of Antxr1 in oral and dental tissues of developing mouse embryos, further supporting a role for this gene in tooth development. Our findings implicate ANTXR1 as a candidate gene for isolated TA, suggest the involvement of specific hypomorphic alleles, and expand the previously known ANTXR1-associated phenotypes.

Colorectal Cancer-Associated Genes Are Associated with Tooth Agenesis and May Have a Role in Tooth Development.

Previously reported co-occurrence of colorectal cancer (CRC) and tooth agenesis (TA) and the overlap in disease-associated gene variants suggest involvement of similar molecular pathways. Here, we took an unbiased approach and tested genome-wide significant CRC-associated variants for association with isolated TA. Thirty single nucleotide variants (SNVs) in CRC-predisposing genes/loci were genotyped in a discovery dataset composed of 440 individuals with and without isolated TA. Genome-wide significant associations were found between TA and ATF1 rs11169552 (P = 4.36 × 10-10) and DUSP10 rs6687758 (P = 1.25 × 10-9), and positive association found with CASC8 rs10505477 (P = 8.2 × 10-5). Additional CRC marker haplotypes were also significantly associated with TA. Genotyping an independent dataset consisting of 52 cases with TA and 427 controls confirmed the association with CASC8. Atf1 and Dusp10 expression was detected in the mouse developing teeth from early bud stages to the formation of the complete tooth, suggesting a potential role for these genes and their encoded proteins in tooth development. While their individual contributions in tooth development remain to be elucidated, these genes may be considered candidates to be tested in additional populations.

Cleidocranial dysplasia: Clinical, endocrinologic and molecular findings in 15 patients from 11 families.

Cleidocranial dysplasia (CCD) is an autosomal dominant disorder characterized by skeletal anomalies such as delayed closure of the cranial sutures, underdeveloped or absent clavicles, multiple dental abnormalities, short stature and osteoporosis. RUNX2, encoding Runt DNA-binding domain protein important in osteoblast differentiation, is the only known gene related to the disease and identified as responsible in 70% of the cases. Our clinical evaluations revealed that short stature present at a rate of 28.6%, osteoporosis at a rate of 57.1% and osteopenia at 21.4%. In this study, RUNX2 sequencing revealed nine different variations in 11 families, eight being pathogenic of which one was novel gross insertion (c.1271_1272ins20) and one other being predicted benign in frame gross deletion (c.241_258del).

A novel c.1255G>T (p.D419Y) mutation in SH3BP2 gene causes cherubism in a Turkish family.

Cherubism (MIM no. 118400) is a rare autosomal dominant disorder characterized by bilateral multilocular lesions of the upper and lower jaws. The lesions usually manifest clinically during early childhood, progress until puberty, and regress in adulthood. SH3BP2 is the only gene currently known to be associated with cherubism. This study began with an 8-year-old boy who was referred owing to overgrowth of mandible. A panoramic radiograph revealed multilocular radiolucent lesions of the upper/lower jaws, suggestive of cherubism. Sequence analysis of SH3BP2 revealed a novel c.G1255T change in exon 9 of the gene where 80% of the disease-causing mutations were observed. We report here the clinical and molecular findings of a family with 3 affected members in two generations showing variable clinical expressivity with the regression of symptoms with advancing age and the lack of penetrance.

Down syndrome diagnosis based on Gabor Wavelet Transform.

Down syndrome is a chromosomal condition caused by the presence of all or part of an extra 21st chromosome. It has different facial symptoms. These symptoms contain distinctive information for face recognition. In this study, a novel method is developed to distinguish Down Syndrome in a custom face database. Gabor Wavelet Transform (GWT) is used as a feature extraction method. Dimension reduction is performed with Principal Component Analysis (PCA). New dimension which has most valuable information is derived with Linear Discriminant Analysis (LDA). Classification process is implemented with k-nearest neighbor (kNN) and Support Vector Machine (SVM) methods. The classification accuracy is carried out 96% and 97,34% with kNN and SVM methods, respectively. Different from the studies related with the Down Sydrome, feature selection process is applied before PCA according to the correlation between components of feature vectors. Best results are achieved with euclidean distance metric for kNN and linear kernel type for SVM. In this way, we developed an efficient system to recognize Down syndrome.