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Human Genetics

, Volume 137, Issue 9, pp 689–703 | Cite as

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

  • Renqian Du
  • Nuriye Dinckan
  • Xiaofei Song
  • Zeynep Coban-Akdemir
  • Shalini N. Jhangiani
  • Yeliz Guven
  • Oya Aktoren
  • Hulya Kayserili
  • Lauren E. Petty
  • Donna M. Muzny
  • Jennifer E. Below
  • Eric Boerwinkle
  • Nan Wu
  • Richard A. Gibbs
  • Jennifer E. Posey
  • James R. Lupski
  • Ariadne LetraEmail author
  • Z. Oya UygunerEmail author
Original Investigation

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.

Notes

Acknowledgements

We appreciate the participation of the patients and their families in this project. We also thank Dr. Ousheng Liu and Dr. Davut Pehlivan for helpful discussions. This work was supported in part by the Scientific and Technological Research Institution of Turkey, TUBITAK-ERA NET (CRANIRARE-2, grant number: SBAG-112S398), Istanbul University Research Fund (Project No: 48398), National Institute of Dental and Craniofacial Research (NIDCR) R03-DE024596 (to AL) and the Baylor-Hopkins Center for Mendelian Genomics, BHCMG (UM1 HG006542, to JRL). The BHCMG is jointly funded by the National Human Genome Research Institute (NHGRI) and National Heart Lung and Blood Institute (NHLBI). The GSP Coordinating Center (U24 HG008956) contributed to cross-program scientific initiatives and provided logistical and general study coordination. JEP was supported by NHGRI K08 HG008986. NW was supported by 2016 Milstein Medical Asian American Partnership Foundation Fellowship Award in Translational Medicine.

Compliance with ethical standards

Conflict of interest

JRL has stock ownership in 23andMe and Lasergen, is a paid consultant for Regeneron, and a co-inventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases and bacterial genomic fingerprinting. Other authors declare that they have no conflict of interest.

Supplementary material

439_2018_1907_MOESM1_ESM.pdf (103 kb)
Supplementary material 1 (PDF 103 KB)
439_2018_1907_MOESM2_ESM.pdf (98 kb)
Supplementary material 2 (PDF 98 KB)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Renqian Du
    • 1
  • Nuriye Dinckan
    • 2
    • 3
  • Xiaofei Song
    • 1
  • Zeynep Coban-Akdemir
    • 1
  • Shalini N. Jhangiani
    • 4
  • Yeliz Guven
    • 5
  • Oya Aktoren
    • 5
  • Hulya Kayserili
    • 6
  • Lauren E. Petty
    • 7
  • Donna M. Muzny
    • 4
  • Jennifer E. Below
    • 7
  • Eric Boerwinkle
    • 4
    • 7
  • Nan Wu
    • 1
    • 8
  • Richard A. Gibbs
    • 1
    • 4
  • Jennifer E. Posey
    • 1
  • James R. Lupski
    • 1
    • 4
    • 9
    • 10
  • Ariadne Letra
    • 3
    • 11
    • 12
    • 13
    Email author
  • Z. Oya Uyguner
    • 2
    Email author
  1. 1.Department of Molecular and Human GeneticsBaylor College of MedicineHoustonUSA
  2. 2.Department of Medical Genetics, Istanbul Medical FacultyIstanbul UniversityIstanbulTurkey
  3. 3.Center for Craniofacial ResearchUniversity of Texas Health Science Center at Houston School of DentistryHoustonUSA
  4. 4.Human Genome Sequencing CenterBaylor College of MedicineHoustonUSA
  5. 5.Department of Pedodontics, Faculty of DentistryIstanbul UniversityIstanbulTurkey
  6. 6.Department of Medical GeneticsKoc University, School of Medicine (KUSOM)IstanbulTurkey
  7. 7.Human Genetics CenterUniversity of Texas Health Science Center at Houston School of Public HealthHoustonUSA
  8. 8.Department of Orthopedic SurgeryPeking Union Medical College HospitalBeijingChina
  9. 9.Department of PediatricsBaylor College of MedicineHoustonUSA
  10. 10.Texas Children’s HospitalHoustonUSA
  11. 11.Department of Diagnostic and Biomedical SciencesUniversity of Texas Health Science Center at Houston School of DentistryHoustonUSA
  12. 12.Pediatric Research CenterUniversity of Texas Health Science Center at Houston McGovern Medical SchoolHoustonUSA
  13. 13.Department of Diagnostic and Biomedical Sciences, Center for Craniofacial ResearchUniversity of Texas Health Science Center at Houston School of DentistryHoustonUSA

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