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Hum Genet. 2018 Sep;137(9):689-703. doi: 10.1007/s00439-018-1907-y. Epub 2018 Jul 26.

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

Author information

1
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
2
Department of Medical Genetics, Istanbul Medical Faculty, Istanbul University, Millet Cad., Capa, Fatih, 34093, Istanbul, Turkey.
3
Center for Craniofacial Research, University of Texas Health Science Center at Houston School of Dentistry, Houston, TX, USA.
4
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
5
Department of Pedodontics, Faculty of Dentistry, Istanbul University, Capa, Istanbul, Turkey.
6
Department of Medical Genetics, Koc University, School of Medicine (KUSOM), Istanbul, Turkey.
7
Human Genetics Center, University of Texas Health Science Center at Houston School of Public Health, Houston, TX, USA.
8
Department of Orthopedic Surgery, Peking Union Medical College Hospital, Beijing, China.
9
Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
10
Texas Children's Hospital, Houston, TX, USA.
11
Center for Craniofacial Research, University of Texas Health Science Center at Houston School of Dentistry, Houston, TX, USA. ariadne.m.letra@uth.tmc.edu.
12
Department of Diagnostic and Biomedical Sciences, University of Texas Health Science Center at Houston School of Dentistry, Houston, TX, USA. ariadne.m.letra@uth.tmc.edu.
13
Pediatric Research Center, University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX, USA. ariadne.m.letra@uth.tmc.edu.
14
Department of Diagnostic and Biomedical Sciences, Center for Craniofacial Research, University of Texas Health Science Center at Houston School of Dentistry, 1941 East Road, BBSB Room 4210, Houston, TX, 77054, USA. ariadne.m.letra@uth.tmc.edu.
15
Department of Medical Genetics, Istanbul Medical Faculty, Istanbul University, Millet Cad., Capa, Fatih, 34093, Istanbul, Turkey. o.uyguner@istanbul.edu.tr.

Abstract

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.

PMID:
30046887
PMCID:
PMC6165673
[Available on 2019-09-01]
DOI:
10.1007/s00439-018-1907-y
[Indexed for MEDLINE]

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