Identification of likely pathogenic and known variants in TSPEAR, LAMB3, BCOR, and WNT10A in four Turkish families with tooth agenesis.

TitleIdentification of likely pathogenic and known variants in TSPEAR, LAMB3, BCOR, and WNT10A in four Turkish families with tooth agenesis.
Publication TypeJournal Article
Year of Publication2018
AuthorsDu, R, Dinckan, N, Song, X, Coban-Akdemir, Z, Jhangiani, SN, Guven, Y, Aktoren, O, Kayserili, H, Petty, LE, Muzny, DM, Below, JE, Boerwinkle, E, Wu, N, Gibbs, RA, Posey, JE, Lupski, JR, Letra, A, Z Uyguner, O
JournalHum Genet
Date Published2018 Sep
KeywordsAnodontia, Cell Adhesion Molecules, Child, Child, Preschool, Female, Genetic Markers, Humans, Kalinin, Male, Mutation, Pedigree, Phenotype, Proteins, Proto-Oncogene Proteins, Repressor Proteins, Turkey, Wnt Proteins

Tooth agenesis (TA), the failure of development of one or more permanent teeth, is a common craniofacial abnormality observed in different world populations. The genetic etiology of TA is heterogeneous; more than a dozen genes have been associated with isolated or nonsyndromic TA, and more than 80 genes with syndromic forms. In this study, we applied whole exome sequencing (WES) to identify candidate genes contributing to TA in four Turkish families. Likely pathogenic variants with a low allele frequency in the general population were identified in four disease-associated genes, including two distinct variants in TSPEAR, associated with syndromic and isolated TA in one family each; a variant in LAMB3 associated with syndromic TA in one family; and a variant in BCOR plus a disease-associated WNT10A variant in one family with syndromic TA. With the notable exception of WNT10A (Tooth agenesis, selective, 4, MIM #150400), the genotype-phenotype relationships described in the present cohort represent an expansion of the clinical spectrum associated with these genes: TSPEAR (Deafness, autosomal recessive 98, MIM #614861), LAMB3 (Amelogenesis imperfecta, type IA, MIM #104530; Epidermolysis bullosa, junctional, MIMs #226700 and #226650), and BCOR (Microphthalmia, syndromic 2, MIM #300166). We provide evidence supporting the candidacy of these genes with TA, and propose TSPEAR as a novel nonsyndromic TA gene. Our data also suggest potential multilocus genomic variation, or mutational burden, in a single family, involving the BCOR and WNT10A loci, underscoring the complexity of the genotype-phenotype relationship in the common complex trait of TA.

Alternate JournalHum Genet
PubMed ID30046887
PubMed Central IDPMC6165673
Grant ListUM1 HG006542 / HG / NHGRI NIH HHS / United States
R03 DE024596 / DE / NIDCR NIH HHS / United States
CRANIRARE-2, grant number: SBAG-112S398 / / TUBITAK-ERA NET /
K08 HG008986 / HG / NHGRI NIH HHS / United States
48398 / / Istanbul University Research Fund /
U24 HG008956 / HG / NHGRI NIH HHS / United States
R03-DE024596 / DE / NIDCR NIH HHS / United States

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