Rare and Common Variants Conferring Risk of Tooth Agenesis

Jönsson, Lina; Magnusson, Thordur Eydal; Thordarson, Arni; Jónsson, Þorvaldur; Geller, Frank; Feenstra, Bjarke; Melbye, Mads; Nøhr, Ellen A.; Vučić, Strahinja; Dhamo, Brunilda; Rivadeneira, Fernando; Ongkosuwito, Edwin M.; Wolvius, Eppo B.; Leslie, Elizabeth J.; Marazita, Mary L.; Howe, Brian J; Uribe, Lina M. Moreno; Alonso, Isabel; Santos, Mariana; Pinho, Teresa; Jónsson, Rafn; Audolfsson, G; Gudmundsson, Larus J.; Nawaz, Muhammad Sulaman; Ólafsson, Sigurgeir; Gústafsson, Ómar; Ingason, Andrés; Unnsteinsdóttir, Unnur; Björnsdóttir, Gyða; Walters, G. Bragi; Zervas, Mark; Oddsson, Ásmundur; Guðbjartsson, Daníel F.; Steinberg, Stacy; Stefánsson, Hreinn; Stefánsson, Kāri

doi:10.1177/0022034517750109

Cited by 44 publications

(52 citation statements)

References 40 publications

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“…Additional genetic studies of both syndromic and nonsyndromic tooth agenesis have reported mutations in WNT10A as pathogenic for the condition and suggested that this gene is responsible for over 50% of the cases of tooth agenesis, with multiple variants accounting for the variable phenotypes . A recent genome‐wide study of isolated tooth agenesis also reported significant associations with two common variants in WNT10A (rs121908120; p.Phe228Ile and rs121908119; p.Cys107Ter) . These two variants have been frequently found in both syndromic and isolated tooth agenesis, and often as biallelic variants, in combinations with additional variants in WNT10A or other genes .…”

Section: Discussionmentioning

confidence: 99%

Further evidence for the role of WNT10A, WNT10B and GREM2 as candidate genes for isolated tooth agenesis

Magruder

Carter

Williams

et al. 2018

Orthod Craniofacial Res

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Objective: To investigate the association of single nucleotide variants in the candidate genes WNT10A, WNT10B and GREM2 with isolated tooth agenesis. Setting and sample population:A total of 435 Caucasian individuals (88 cases with isolated tooth agenesis and 347 unrelated controls) were ascertained at the University of Texas Health Science Center at Houston School of Dentistry. Clinical and radiographic examination by orthodontists confirmed the diagnosis of tooth agenesis. Genetic evaluation excluded syndromic forms of tooth agenesis. Materials and methods: Saliva samples were collected as source of genomic DNA.Fourteen variants in/nearby WNT10A, WNT10B and GREM2 were genotyped to test for association with tooth agenesis. Genotyping was performed using TaqMan chemistry in a real-time polymerase chain reaction assay. Allelic and haplotype frequencies were compared among cases and controls using chi-square tests as implemented in PLINK v.1.06. Bonferroni correction was used and P ≤ 0.004 indicates statistical differences between groups.Results: Significant associations were found between individual SNPs and SNP combinations in WNT10A, WNT10B and GREM2 SNPs with isolated tooth agenesis (P < 0.004). Conclusion:Our findings further support a role for variants in WNT10A, WNT10Band GREM2 genes in the aetiology of isolated tooth agenesis. Functional studies are necessary to investigate the biological effects of these gene variants in tooth agenesis phenotypes. K E Y W O R D S association, GREM2, tooth agenesis, WNT10A, WNT10B S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section at the end of the article. How to cite this article: Magruder S, Carter E, Williams MA, English J, Akyalcin S, Letra A. Further evidence for the role of WNT10A, WNT10B and GREM2 as candidate genes for isolated tooth agenesis. Orthod Craniofac Res. 2018;21:258-263. https://doi.

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Section: Discussionmentioning

confidence: 99%

Further evidence for the role of WNT10A, WNT10B and GREM2 as candidate genes for isolated tooth agenesis

Magruder

Carter

Williams

et al. 2018

Orthod Craniofacial Res

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“…1 The reported incidence of tooth agenesis is 3%-10% depending on the population being studied. [2][3][4] The incidence is higher in females, and 60% of individuals exhibit unilateral tooth agenesis. 3 Third molars are the most commonly missing permanent teeth; 23% is the often-cited incidence rate.…”

Section: Introductionmentioning

confidence: 99%

“…[2][3][4] The incidence is higher in females, and 60% of individuals exhibit unilateral tooth agenesis. 3 Third molars are the most commonly missing permanent teeth; 23% is the often-cited incidence rate. 3 The next most prevalent missing teeth are mandibular second premolars, followed by maxillary lateral incisors.…”

Section: Introductionmentioning

confidence: 99%

Diagnosis of Tooth Agenesis in Childhood and Risk for Neoplasms in Adulthood

Ritwik

Patterson

2018

TOJ

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Background: Tooth agenesis, the congenital absence of one or more teeth, can be diagnosed in children in the first decade of life. Tooth agenesis is a phenotypic feature of conditions such as ectodermal dysplasia, cleft lip, cleft palate, Down syndrome, and Van der Woude syndrome. Tooth agenesis can also be nonsyndromic. Studies have shown an association between the genetic determinants of nonsyndromic tooth agenesis and neoplasms in adulthood. Methods: This review of the implications of tooth agenesis as a risk indicator for neoplasms in adulthood is based on a search of PubMed to identify published case series, case reports, and review articles. The reference articles were manually searched. The search was limited to articles published in the English language. Results: Neoplasms reported in patients with tooth agenesis include colorectal neoplasms and epithelial ovarian cancer, as well as family histories of breast cancer, prostate cancer, and cancers of the brain and nervous system. Conclusion: Although odontogenesis and tumorigenesis may seem to be unrelated processes, the clinical association between the two highlights the overlap of genetic determinants and molecular pathways. Tooth agenesis can be diagnosed during childhood and should be considered a marker for risk of neoplasms in adulthood. Healthcare providers should identify tooth agenesis and provide appropriate anticipatory guidance.Tooth agenesis can be classified based on the number of congenitally missing teeth. Hypodontia refers to the absence of fewer than 6 teeth (not including third molars). 5,6

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“…EDAR variant c.1258C>T (p.Arg420Trp) has so far been reported only in a recent Icelandic publication referring to a genome-wide association study for tooth agenesis. 11 Our protein binding assays elucidated that this variant caused a complete abrogation of the interaction between the death domains of EDAR and EDARADD. Downstream NF-κB signaling was found to be reduced.…”

Section: Discussionmentioning

confidence: 86%

Variants of the ectodysplasin A1 receptor gene underlying homozygous cases of autosomal recessive hypohidrotic ectodermal dysplasia

Wohlfart

Schneider

2019

Clinical Genetics

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Hypohidrotic ectodermal dysplasia (HED) is a rare genetic condition resulting from defective development of ectodermal derivatives, such as hair, teeth, and sweat glands. Autosomal recessive (AR) forms of HED may be caused by pathogenic variants of the ectodysplasin A1 receptor (EDAR) gene that encodes a receptor involved in the NF‐κB signaling pathway. Here, we describe three cases of AR‐HED in families of Turkish, Austrian, and German‐American origin (with or without known consanguinity). In these cases, two out‐of‐frame deletions and a pathogenic missense variant of EDAR were found to be disease‐causing due to reduced availability of the respective messenger RNA or impaired interaction of the encoded protein with its binding partner leading to diminished signal transduction. The same missense variant, c.1258C>T (p.Arg420Trp), has actually been reported to be restricted to the Icelandic population and to be associated with non‐syndromic tooth agenesis but not HED. As our patient has no known relationship to Icelandic individuals and displays a rather severe HED phenotype, we suggest that EDAR‐Arg420Trp is a more widespread variant, possibly with variable clinical expressivity.

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Rare and Common Variants Conferring Risk of Tooth Agenesis

Cited by 44 publications

References 40 publications

Further evidence for the role of WNT10A, WNT10B and GREM2 as candidate genes for isolated tooth agenesis

Further evidence for the role of WNT10A, WNT10B and GREM2 as candidate genes for isolated tooth agenesis

Diagnosis of Tooth Agenesis in Childhood and Risk for Neoplasms in Adulthood

Variants of the ectodysplasin A1 receptor gene underlying homozygous cases of autosomal recessive hypohidrotic ectodermal dysplasia

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