GENETICS OF SHORT ROOT ANOMALIES

Abstract

GENETICS OF SHORT ROOT ANOMALIES Purpose: The purpose of this study is to define clinical features and identify specific gene mutations that are associated with short root anomalies (SRA) among five affected families. This study aims to determine the potential association between clinical features and genetic mutations in order to provide scientific evidence for oral health providers to enhance diagnosis and management of patients with short root anomalies. Methods: Participants were recruited through the University of Pittsburgh and the University of Michigan. Study explanation, pedigree construction, subject enrollment, clinical examinations and collection of blood or non-stimulated saliva samples were completed under the proper consenting procedure as approved by Institutional Review Board. Each sample was coded and a small aliquot was used for genomic DNA isolation. Samples from parents and proband of each family were selected for whole-exome sequencing. Sequencing results were analyzed according to establish algorism. DNA samples from all other family members were used for confirmation analyses. Prioritized DNA sequence variations and their segregation with short root anomalies within each family were assessed. Phenotypic comparisons of the affected subjects within the five study families were performed to determine whether these families can be considered as having similar if not identical clinical presentation of SRA. Phenotypic features analyzed include root length, root width, taurodontism, missing teeth, whether cases were localized or generalized, and other pertinent dental anomalies. Results: Genomic analyses identified 22 genes with rare and potentially damaging variants in more than one affected individual of the five study families. Four out of five probands have variants in THAP11 gene, three out of five probands have variants in PODXL, NIPA1 and VEZF1 and two out of five probands have variants in additional 18 genes. The role of these gene variants in tooth and root development is not immediately clear. There were no variants involving the same gene present in all five or four families. Given WES data and literature evidence, there were no logical variants or candidate genes that can be targeted for segregation analysis. Phenotypic features documented in the affected study participants include short roots of various types of teeth, wider than normal root widths, taurodontism in both maxillary and mandibular arches, microdontia, ectopic eruption, and pulpal obliteration. Localized and generalized SRA cases showed differences in phenotype features. Conclusion: Phenotypic features of SRA vary from patient to patient. Correlating genotypes and phenotypes of those with short root anomalies may facilitate clinical diagnosis. By determining the genetic etiology of SRA, we may better understand the disease mechanism and be able to make sound decisions on whether applying forces and manipulating the teeth might lead to continued changes in root length and structure. Exploring the molecular mechanisms of SRA allows an understanding of whether the condition is largely a developmental anomaly or a progressive, long-term process. This foundational knowledge is relevant to many facets of dentistry where root to crown ratio must be carefully considered in treatment plan development.