Whole-Exome Sequencing Identifies Novel Variants for Tooth Agenesis.

TitleWhole-Exome Sequencing Identifies Novel Variants for Tooth Agenesis.
Publication TypeJournal Article
Year of Publication2018
AuthorsDinckan, N, Du, R, Petty, LE, Coban-Akdemir, Z, Jhangiani, SN, Paine, I, Baugh, EH, Erdem, AP, Kayserili, H, Doddapaneni, H, Hu, J, Muzny, DM, Boerwinkle, E, Gibbs, RA, Lupski, JR, Uyguner, ZO, Below, JE, Letra, A
JournalJ Dent Res
Date Published2018 Jan
KeywordsAnodontia, Exome Sequencing, Female, Genetic Linkage, Genetic Variation, Humans, Intercellular Signaling Peptides and Proteins, Laminin, Low Density Lipoprotein Receptor-Related Protein-6, Male, Membrane Proteins, Mutation, Missense, Pedigree, Real-Time Polymerase Chain Reaction, Turkey, Wnt Proteins

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.

Alternate JournalJ Dent Res
PubMed ID28813618
PubMed Central IDPMC6728545
Grant ListR03 DE024596 / DE / NIDCR NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States

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