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A targeted next generation sequencing and gene co-occurrence network analysis revealed the genetic alterations associated with mesiodens patients

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A Targeted Next Generation Sequencing and Gene Co-occurrence Network Analysis Revealed the Genetic Alterations Associated with Mesiodens Patients

Jae Hoon Lee DDS, MS, Ph.D

Associate professor of Department of Prosthodontics, Yonsei University, Seoul, Korea

Hye-Sung Kim, Young Youn Kim, Hee Jun Kwon DDS

234  APPLETREE Dental Hospital, Ilsan, Kyungki-Do, Korea

 

Background and Aim                                     

Mesiodens is the most common type of supernumerary tooth which includes a population prevalence of 0.15-1.9%. Alongside evidence that the condition is heritable, mutations in single genes have been reported in few human supernumerary tooth cases. Gene sequencing methods in tradition way are time-consuming and labor-intensive, whereas next generation sequencing and bioinformatics are cost-effective for large samples and target sizes.

Materials and Methods 

We describe the application of a targeted next generation sequencing (NGS) and bioinformatics approach to samples from 17 mesiodens patients. Subjects were diagnosed on the basis of panoramic radiograph. 101 candidate genes which were captured custom gene were sequenced on the Illumina HiSeq2500. Multistep bioinformatics processing was performed including variant identification, base calling, and in silico analysis of putative disease-causing variants.

Results 

Targeted capture identified 88 non-synonymous, rare, exonic variants involving 42 of the 101 candidate genes. Moreover, we investigated gene co-occurrence relationships between the genomic alterations and identified 88 significant relationships among 18 most recurrent driver alterations.

Conclusions 

Various signaling molecules contribute to the development of teeth with proper number and patterning. Inappropriate regulation of the molecules involved in this process seems to cause mesiodens formation. Mesiodens heritability is complex and polygenic, involving many regulatory signals from several important key molecules and characterized by an abundance of their activators or inhibitors. This study provides key insights into the genetics of mesiodens formation by identifying gene sets associated with the development of supernumerary teeth and providing an analysis implicating the BMP, SHH, and WNT pathways in mesiodens formation. A significant number of putative disease-causing variants in mesiodens patients and related signaling pathways were identified using gene co-occurrence analysis. Given the wide variation and complexity of mesiodens heritability, further research into the detailed interactions between key molecules is of paramount significance.

References

ALBERTI, G., MONDANI, P. M. & PARODI, V. 2006. Eruption of supernumerary permanent teeth in a sample of urban primary school population in Genoa, Italy. Eur J Paediatr Dent, 7, 89-92.

CIRIELLO, G., CERAMI, E., SANDER, C. & SCHULTZ, N. 2012. Mutual exclusivity analysis identifies oncogenic network modules. Genome Res, 22, 398-406.

FERNANDEZ MONTENEGRO, P., VALMASEDA CASTELLON, E., BERINI AYTES, L. & GAY ESCODA, C. 2006. Retrospective study of 145 supernumerary teeth. Med Oral Patol Oral Cir Bucal, 11, E339-44.

GALLAS, M. M. & GARCIA, A. 2000. Retention of permanent incisors by mesiodens: a family affair. British Dental Journal, 188, 63-64.

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