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J Dent Res. 2018 Jan;97(1):49-59. doi: 10.1177/0022034517724149. Epub 2017 Aug 16.

Whole-Exome Sequencing Identifies Novel Variants for Tooth Agenesis.

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1 Department of Medical Genetics, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey.
2 Department of Diagnostic and Biomedical Sciences and Center for Craniofacial Research, University of Texas Health Science Center at Houston School of Dentistry, Houston, TX, USA.
3 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
4 Human Genetics Center, University of Texas Health Science Center at Houston School of Public Health, Houston, TX, USA.
5 Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
6 Department of Biology, New York University, New York, NY, USA.
7 Department of Pedodontics, Faculty of Dentistry, Istanbul University, Capa, Istanbul, Turkey.
8 Department of Medical Genetics, Koc University, School of Medicine (KUSOM), Istanbul, Turkey.
9 Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
10 Texas Children's Hospital, Houston, TX, USA.
11 Pediatric Research Center, University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX, USA.


Tooth agenesis is a common craniofacial abnormality in humans and represents failure to develop 1 or more permanent teeth. Tooth agenesis is complex, and variations in about a dozen genes have been reported as contributing to the etiology. Here, we combined whole-exome sequencing, array-based genotyping, and linkage analysis to identify putative pathogenic variants in candidate disease genes for tooth agenesis in 10 multiplex Turkish families. Novel homozygous and heterozygous variants in LRP6, DKK1, LAMA3, and COL17A1 genes, as well as known variants in WNT10A, were identified as likely pathogenic in isolated tooth agenesis. Novel variants in KREMEN1 were identified as likely pathogenic in 2 families with suspected syndromic tooth agenesis. Variants in more than 1 gene were identified segregating with tooth agenesis in 2 families, suggesting oligogenic inheritance. Structural modeling of missense variants suggests deleterious effects to the encoded proteins. Functional analysis of an indel variant (c.3607+3_6del) in LRP6 suggested that the predicted resulting mRNA is subject to nonsense-mediated decay. Our results support a major role for WNT pathways genes in the etiology of tooth agenesis while revealing new candidate genes. Moreover, oligogenic cosegregation was suggestive for complex inheritance and potentially complex gene product interactions during development, contributing to improved understanding of the genetic etiology of familial tooth agenesis.


WNT signaling pathway; array genotyping; gene; hypodontia; next generation sequencing; oligodontia

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