KCTD1 plays crucial roles in regulating both the SHH and WNT/β-catenin signaling pathways, which are essential for tooth development. The objective of this study was to investigate if genetic variants in KCTD1 might also be associated with isolated dental anomalies. We clinically and radiographically investigated 362 patients affected with isolated dental anomalies. Whole exome sequencing identified two unrelated families with rare (p.Arg241Gln) or novel (p.Pro243Ser) variants in KCTD1. The variants segregated with the dental anomalies in all nine patients from the two families. Clinical findings of the patients included taurodontism, unseparated roots, long roots, tooth agenesis, a supernumerary tooth, torus palatinus, and torus mandibularis. The role of Kctd1 in root development is supported by our immunohistochemical study showing high expression of Kctd1 in Hertwig epithelial root sheath. The KCTD1 variants in our patients are the first variants found to be located in the C-terminal domain, which might disrupt protein-protein interactions and/or SUMOylation and subsequently result in aberrant WNT-SHH-BMP signaling and isolated dental anomalies. Functional studies on the p.Arg241Gln variant are consistent with an impact on β-catenin levels and canonical WNT signaling. This is the first report of the association of KCTD1 variants and isolated dental anomalies.

OBJECTIVE: Molar incisor malformation (MIM) is a dental anomaly rendering first permanent molar pulps inflamed/necrotic at a young age. It often affects permanent incisors, primary second molars and less frequently other teeth. The purpose of this study was to investigate the anatomy and histology of MIM in seeking insight into its pathogenesis.
METHODS: Five MIM first permanent molars were examined with micro-computed tomography (micro-CT) for 3D morphology, with scanning electron microscopy for microanatomy, with energy-dispersive X-ray spectrometer (EDS) for chemical composition and for histology with optical microscopy. Composition differences were statistically determined using one-way ANOVA.
RESULTS: Micro-CT confirmed dentin abnormalities in the middle and cervical third of the crown in the form of the radiodense \'cervical mineralized diaphragm\' (CMD). This was peripherally intertwined with enamel fjords and projections severely disrupting the integrity of pulp chamber and its continuity with root canals. EDS showed increased Ca in CMD compared to dentin. The histological examination revealed anomalous osteodentin-like hard tissue with denticles in the CMD.
CONCLUSIONS: An interconnection of anomalous cervical enamel with crown CMD dentin preceded to the severe pulp chamber and root dysplasias in MIM molar teeth.