Novel mutations in LRP6 highlight the role of WNT signaling in tooth agenesis

Charlotte W. Ockeloen; Kriti D. Khandelwal; Karoline Dreesen; Kerstin U. Ludwig; Robert Sullivan; Iris A L M Van Rooij; Michelle Thonissen; Steven Swinnen; Milien Phan; Federica Conte; Nina Ishorst; Christian Gilissen; Laury Roa Fuentes; Maartje Van De Vorst; Arjen Henkes; Marloes Steehouwer; Ellen Van Beusekom; Marjon Bloemen; Bruno Vankeirsbilck; Stefaan Bergé; Greet Hens; Joseph Schoenaers; Vincent Vander Poorten; Jasmien Roosenboom; An Verdonck; Koen Devriendt; Nel Roeleveldt; Shalini N. Jhangiani; Lisenka E L M Vissers; James R. Lupski; Joep De Ligt; Johannes W. Von Den Hoff; Rolph Pfundt; Han G. Brunner; Huiqing Zhou; Jill Dixon; Elisabeth Mangold; Hans Van Bokhoven; Michael J. Dixon; Tjitske Kleefstra; Alexander Hoischen; Carine E L Carels

doi:10.1038/gim.2016.10

Novel mutations in LRP6 highlight the role of WNT signaling in tooth agenesis

Charlotte W. Ockeloen, Kriti D. Khandelwal, Karoline Dreesen, Kerstin U. Ludwig, Robert Sullivan, Iris A L M Van Rooij, Michelle Thonissen, Steven Swinnen, Milien Phan, Federica Conte, Nina Ishorst, Christian Gilissen, Laury Roa Fuentes, Maartje Van De Vorst, Arjen Henkes, Marloes Steehouwer, Ellen Van Beusekom, Marjon Bloemen, Bruno Vankeirsbilck, Stefaan BergéGreet Hens, Joseph Schoenaers, Vincent Vander Poorten, Jasmien Roosenboom, An Verdonck, Koen Devriendt, Nel Roeleveldt, Shalini N. Jhangiani, Lisenka E L M Vissers, James R. Lupski, Joep De Ligt, Johannes W. Von Den Hoff, Rolph Pfundt, Han G. Brunner, Huiqing Zhou, Jill Dixon, Elisabeth Mangold, Hans Van Bokhoven, Michael J. Dixon, Tjitske Kleefstra, Alexander Hoischen^*, Carine E L Carels

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

2 Citations (Scopus)

Abstract

Purpose:We aimed to identify a novel genetic cause of tooth agenesis (TA) and/or orofacial clefting (OFC) by combining whole-exome sequencing (WES) and targeted resequencing in a large cohort of TA and OFC patients.Methods:WES was performed in two unrelated patients: one with severe TA and OFC and another with severe TA only. After deleterious mutations were identified in a gene encoding low-density lipoprotein receptor-related protein 6 (LRP6), all its exons were resequenced with molecular inversion probes in 67 patients with TA, 1,072 patients with OFC, and 706 controls.Results:We identified a frameshift (c.4594delG, p.Cys1532fs) and a canonical splice-site mutation (c.3398-2A>C, p.?) in LRP6, respectively, in the patient with TA and OFC and in the patient with severe TA only. The targeted resequencing showed significant enrichment of unique LRP6 variants in TA patients but not in nonsyndromic OFC patients. Of the five variants in patients with TA, two affected the canonical splice site and three were missense variants; all variants segregated with the dominant phenotype, and in one case the missense mutation occurred de novo.Conclusion:Mutations in LRP6 cause TA in humans.

Original language	English
Pages (from-to)	1158-1162
Number of pages	5
Journal	Genetics in Medicine
Volume	18
Issue number	11
DOIs	https://doi.org/10.1038/gim.2016.10
Publication status	Published - 1 Nov 2016

Keywords

LRP6
molecular inversion probes
tooth agenesis
Wnt/β-catenin canonical signaling pathway

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10.1038/gim.2016.10

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Ockeloen, C. W., Khandelwal, K. D., Dreesen, K., Ludwig, K. U., Sullivan, R., Van Rooij, I. A. L. M., Thonissen, M., Swinnen, S., Phan, M., Conte, F., Ishorst, N., Gilissen, C., Roa Fuentes, L., Van De Vorst, M., Henkes, A., Steehouwer, M., Van Beusekom, E., Bloemen, M., Vankeirsbilck, B., ... Carels, C. E. L. (2016). Novel mutations in LRP6 highlight the role of WNT signaling in tooth agenesis. Genetics in Medicine, 18(11), 1158-1162. https://doi.org/10.1038/gim.2016.10

@article{17fae01fa5874a84b76222feb673be1e,

title = "Novel mutations in LRP6 highlight the role of WNT signaling in tooth agenesis",

abstract = "Purpose:We aimed to identify a novel genetic cause of tooth agenesis (TA) and/or orofacial clefting (OFC) by combining whole-exome sequencing (WES) and targeted resequencing in a large cohort of TA and OFC patients.Methods:WES was performed in two unrelated patients: one with severe TA and OFC and another with severe TA only. After deleterious mutations were identified in a gene encoding low-density lipoprotein receptor-related protein 6 (LRP6), all its exons were resequenced with molecular inversion probes in 67 patients with TA, 1,072 patients with OFC, and 706 controls.Results:We identified a frameshift (c.4594delG, p.Cys1532fs) and a canonical splice-site mutation (c.3398-2A>C, p.?) in LRP6, respectively, in the patient with TA and OFC and in the patient with severe TA only. The targeted resequencing showed significant enrichment of unique LRP6 variants in TA patients but not in nonsyndromic OFC patients. Of the five variants in patients with TA, two affected the canonical splice site and three were missense variants; all variants segregated with the dominant phenotype, and in one case the missense mutation occurred de novo.Conclusion:Mutations in LRP6 cause TA in humans.",

keywords = "LRP6, molecular inversion probes, tooth agenesis, Wnt/β-catenin canonical signaling pathway",

author = "Ockeloen, {Charlotte W.} and Khandelwal, {Kriti D.} and Karoline Dreesen and Ludwig, {Kerstin U.} and Robert Sullivan and {Van Rooij}, {Iris A L M} and Michelle Thonissen and Steven Swinnen and Milien Phan and Federica Conte and Nina Ishorst and Christian Gilissen and {Roa Fuentes}, Laury and {Van De Vorst}, Maartje and Arjen Henkes and Marloes Steehouwer and {Van Beusekom}, Ellen and Marjon Bloemen and Bruno Vankeirsbilck and Stefaan Berg{\'e} and Greet Hens and Joseph Schoenaers and {Vander Poorten}, Vincent and Jasmien Roosenboom and An Verdonck and Koen Devriendt and Nel Roeleveldt and Jhangiani, {Shalini N.} and Vissers, {Lisenka E L M} and Lupski, {James R.} and {De Ligt}, Joep and {Von Den Hoff}, {Johannes W.} and Rolph Pfundt and Brunner, {Han G.} and Huiqing Zhou and Jill Dixon and Elisabeth Mangold and {Van Bokhoven}, Hans and Dixon, {Michael J.} and Tjitske Kleefstra and Alexander Hoischen and Carels, {Carine E L}",

year = "2016",

month = nov,

day = "1",

doi = "10.1038/gim.2016.10",

language = "English",

volume = "18",

pages = "1158--1162",

journal = "Genetics in Medicine",

issn = "1098-3600",

publisher = "Lippincott Williams & Wilkins",

number = "11",

}

Ockeloen, CW, Khandelwal, KD, Dreesen, K, Ludwig, KU, Sullivan, R, Van Rooij, IALM, Thonissen, M, Swinnen, S, Phan, M, Conte, F, Ishorst, N, Gilissen, C, Roa Fuentes, L, Van De Vorst, M, Henkes, A, Steehouwer, M, Van Beusekom, E, Bloemen, M, Vankeirsbilck, B, Bergé, S, Hens, G, Schoenaers, J, Vander Poorten, V, Roosenboom, J, Verdonck, A, Devriendt, K, Roeleveldt, N, Jhangiani, SN, Vissers, LELM, Lupski, JR, De Ligt, J, Von Den Hoff, JW, Pfundt, R, Brunner, HG, Zhou, H, Dixon, J, Mangold, E, Van Bokhoven, H, Dixon, MJ, Kleefstra, T, Hoischen, A & Carels, CEL 2016, 'Novel mutations in LRP6 highlight the role of WNT signaling in tooth agenesis', Genetics in Medicine, vol. 18, no. 11, pp. 1158-1162. https://doi.org/10.1038/gim.2016.10

TY - JOUR

T1 - Novel mutations in LRP6 highlight the role of WNT signaling in tooth agenesis

AU - Ockeloen, Charlotte W.

AU - Khandelwal, Kriti D.

AU - Dreesen, Karoline

AU - Ludwig, Kerstin U.

AU - Sullivan, Robert

AU - Van Rooij, Iris A L M

AU - Thonissen, Michelle

AU - Swinnen, Steven

AU - Phan, Milien

AU - Conte, Federica

AU - Ishorst, Nina

AU - Gilissen, Christian

AU - Roa Fuentes, Laury

AU - Van De Vorst, Maartje

AU - Henkes, Arjen

AU - Steehouwer, Marloes

AU - Van Beusekom, Ellen

AU - Bloemen, Marjon

AU - Vankeirsbilck, Bruno

AU - Bergé, Stefaan

AU - Hens, Greet

AU - Schoenaers, Joseph

AU - Vander Poorten, Vincent

AU - Roosenboom, Jasmien

AU - Verdonck, An

AU - Devriendt, Koen

AU - Roeleveldt, Nel

AU - Jhangiani, Shalini N.

AU - Vissers, Lisenka E L M

AU - Lupski, James R.

AU - De Ligt, Joep

AU - Von Den Hoff, Johannes W.

AU - Pfundt, Rolph

AU - Brunner, Han G.

AU - Zhou, Huiqing

AU - Dixon, Jill

AU - Mangold, Elisabeth

AU - Van Bokhoven, Hans

AU - Dixon, Michael J.

AU - Kleefstra, Tjitske

AU - Hoischen, Alexander

AU - Carels, Carine E L

PY - 2016/11/1

Y1 - 2016/11/1

N2 - Purpose:We aimed to identify a novel genetic cause of tooth agenesis (TA) and/or orofacial clefting (OFC) by combining whole-exome sequencing (WES) and targeted resequencing in a large cohort of TA and OFC patients.Methods:WES was performed in two unrelated patients: one with severe TA and OFC and another with severe TA only. After deleterious mutations were identified in a gene encoding low-density lipoprotein receptor-related protein 6 (LRP6), all its exons were resequenced with molecular inversion probes in 67 patients with TA, 1,072 patients with OFC, and 706 controls.Results:We identified a frameshift (c.4594delG, p.Cys1532fs) and a canonical splice-site mutation (c.3398-2A>C, p.?) in LRP6, respectively, in the patient with TA and OFC and in the patient with severe TA only. The targeted resequencing showed significant enrichment of unique LRP6 variants in TA patients but not in nonsyndromic OFC patients. Of the five variants in patients with TA, two affected the canonical splice site and three were missense variants; all variants segregated with the dominant phenotype, and in one case the missense mutation occurred de novo.Conclusion:Mutations in LRP6 cause TA in humans.

AB - Purpose:We aimed to identify a novel genetic cause of tooth agenesis (TA) and/or orofacial clefting (OFC) by combining whole-exome sequencing (WES) and targeted resequencing in a large cohort of TA and OFC patients.Methods:WES was performed in two unrelated patients: one with severe TA and OFC and another with severe TA only. After deleterious mutations were identified in a gene encoding low-density lipoprotein receptor-related protein 6 (LRP6), all its exons were resequenced with molecular inversion probes in 67 patients with TA, 1,072 patients with OFC, and 706 controls.Results:We identified a frameshift (c.4594delG, p.Cys1532fs) and a canonical splice-site mutation (c.3398-2A>C, p.?) in LRP6, respectively, in the patient with TA and OFC and in the patient with severe TA only. The targeted resequencing showed significant enrichment of unique LRP6 variants in TA patients but not in nonsyndromic OFC patients. Of the five variants in patients with TA, two affected the canonical splice site and three were missense variants; all variants segregated with the dominant phenotype, and in one case the missense mutation occurred de novo.Conclusion:Mutations in LRP6 cause TA in humans.

KW - LRP6

KW - molecular inversion probes

KW - tooth agenesis

KW - Wnt/β-catenin canonical signaling pathway

UR - http://www.scopus.com/inward/record.url?scp=84994106572&partnerID=8YFLogxK

U2 - 10.1038/gim.2016.10

DO - 10.1038/gim.2016.10

M3 - Article

C2 - 26963285

AN - SCOPUS:84994106572

SN - 1098-3600

VL - 18

SP - 1158

EP - 1162

JO - Genetics in Medicine

JF - Genetics in Medicine

IS - 11

ER -

Novel mutations in LRP6 highlight the role of WNT signaling in tooth agenesis

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Keywords

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