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Nuriye Dinckan - One of the best experts on this subject based on the ideXlab platform.
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identification of likely pathogenic and known variants in tspear lamb3 bcor and wnt10a in four turkish families with tooth agenesis
Human Genetics, 2018Co-Authors: Renqian Du, Nuriye Dinckan, Zeynep Cobanakdemir, Hulya Kayserili, Shalini N Jhangiani, Yeliz Guven, Oya Aktoren, Xiaofei Song, Lauren E PettyAbstract: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.
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a biallelic antxr1 variant expands the anthrax toxin receptor associated phenotype to tooth agenesis
American Journal of Medical Genetics Part A, 2018Co-Authors: Nuriye Dinckan, Harsha Vardhan Doddapaneni, Renqian Du, Shalini N Jhangiani, Zeynep Coban Akdemir, Yavuz Bayram, Jianhong Hu, Donna M Muzny, Yeliz Guven, Oya AktorenAbstract:Tooth development is regulated by multiple genetic pathways, which ultimately drive the complex interactions between the oral epithelium and mesenchyme. Disruptions at any time point during this process may lead to failure of tooth development, also known as tooth agenesis (TA). TA is a common Craniofacial Abnormality in humans and represents the failure to develop one or more permanent teeth. Many genes and potentially subtle variants in these genes contribute to the TA phenotype. We report the clinical and genetic impact of a rare homozygous ANTXR1 variant (c.1312C>T), identified by whole exome sequencing (WES), in a consanguineous Turkish family with tooth agenesis. Mutations in ANTXR1 have been associated with GAPO (growth retardation, alopecia, pseudoanodontia, and optic atrophy) syndrome and infantile hemangioma, however no clinical characteristics associated with these conditions were observed in our study family. We detected the expression of Antxr1 in oral and dental tissues of developing mouse embryos, further supporting a role for this gene in tooth development. Our findings implicate ANTXR1 as a candidate gene for isolated TA, suggest the involvement of specific hypomorphic alleles, and expand the previously known ANTXR1-associated phenotypes.
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whole exome sequencing identifies novel variants for tooth agenesis
Journal of Dental Research, 2018Co-Authors: Nuriye Dinckan, Lauren E Petty, Ingrid S Paine, Evan H Baugh, A P Erdem, Zeynep Cobanakdemir, Renqian Du, Hulya Kayserili, Shalini N Jhangiani, Harsha Vardhan DoddapaneniAbstract:Tooth agenesis is a common Craniofacial Abnormality in humans and represents failure to develop 1 or more permanent teeth. Tooth agenesis is complex, and variations in about a dozen genes have been...
Harsha Vardhan Doddapaneni - One of the best experts on this subject based on the ideXlab platform.
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a biallelic antxr1 variant expands the anthrax toxin receptor associated phenotype to tooth agenesis
American Journal of Medical Genetics Part A, 2018Co-Authors: Nuriye Dinckan, Harsha Vardhan Doddapaneni, Renqian Du, Shalini N Jhangiani, Zeynep Coban Akdemir, Yavuz Bayram, Jianhong Hu, Donna M Muzny, Yeliz Guven, Oya AktorenAbstract:Tooth development is regulated by multiple genetic pathways, which ultimately drive the complex interactions between the oral epithelium and mesenchyme. Disruptions at any time point during this process may lead to failure of tooth development, also known as tooth agenesis (TA). TA is a common Craniofacial Abnormality in humans and represents the failure to develop one or more permanent teeth. Many genes and potentially subtle variants in these genes contribute to the TA phenotype. We report the clinical and genetic impact of a rare homozygous ANTXR1 variant (c.1312C>T), identified by whole exome sequencing (WES), in a consanguineous Turkish family with tooth agenesis. Mutations in ANTXR1 have been associated with GAPO (growth retardation, alopecia, pseudoanodontia, and optic atrophy) syndrome and infantile hemangioma, however no clinical characteristics associated with these conditions were observed in our study family. We detected the expression of Antxr1 in oral and dental tissues of developing mouse embryos, further supporting a role for this gene in tooth development. Our findings implicate ANTXR1 as a candidate gene for isolated TA, suggest the involvement of specific hypomorphic alleles, and expand the previously known ANTXR1-associated phenotypes.
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whole exome sequencing identifies novel variants for tooth agenesis
Journal of Dental Research, 2018Co-Authors: Nuriye Dinckan, Lauren E Petty, Ingrid S Paine, Evan H Baugh, A P Erdem, Zeynep Cobanakdemir, Renqian Du, Hulya Kayserili, Shalini N Jhangiani, Harsha Vardhan DoddapaneniAbstract:Tooth agenesis is a common Craniofacial Abnormality in humans and represents failure to develop 1 or more permanent teeth. Tooth agenesis is complex, and variations in about a dozen genes have been...
Renqian Du - One of the best experts on this subject based on the ideXlab platform.
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identification of likely pathogenic and known variants in tspear lamb3 bcor and wnt10a in four turkish families with tooth agenesis
Human Genetics, 2018Co-Authors: Renqian Du, Nuriye Dinckan, Zeynep Cobanakdemir, Hulya Kayserili, Shalini N Jhangiani, Yeliz Guven, Oya Aktoren, Xiaofei Song, Lauren E PettyAbstract: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.
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a biallelic antxr1 variant expands the anthrax toxin receptor associated phenotype to tooth agenesis
American Journal of Medical Genetics Part A, 2018Co-Authors: Nuriye Dinckan, Harsha Vardhan Doddapaneni, Renqian Du, Shalini N Jhangiani, Zeynep Coban Akdemir, Yavuz Bayram, Jianhong Hu, Donna M Muzny, Yeliz Guven, Oya AktorenAbstract:Tooth development is regulated by multiple genetic pathways, which ultimately drive the complex interactions between the oral epithelium and mesenchyme. Disruptions at any time point during this process may lead to failure of tooth development, also known as tooth agenesis (TA). TA is a common Craniofacial Abnormality in humans and represents the failure to develop one or more permanent teeth. Many genes and potentially subtle variants in these genes contribute to the TA phenotype. We report the clinical and genetic impact of a rare homozygous ANTXR1 variant (c.1312C>T), identified by whole exome sequencing (WES), in a consanguineous Turkish family with tooth agenesis. Mutations in ANTXR1 have been associated with GAPO (growth retardation, alopecia, pseudoanodontia, and optic atrophy) syndrome and infantile hemangioma, however no clinical characteristics associated with these conditions were observed in our study family. We detected the expression of Antxr1 in oral and dental tissues of developing mouse embryos, further supporting a role for this gene in tooth development. Our findings implicate ANTXR1 as a candidate gene for isolated TA, suggest the involvement of specific hypomorphic alleles, and expand the previously known ANTXR1-associated phenotypes.
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whole exome sequencing identifies novel variants for tooth agenesis
Journal of Dental Research, 2018Co-Authors: Nuriye Dinckan, Lauren E Petty, Ingrid S Paine, Evan H Baugh, A P Erdem, Zeynep Cobanakdemir, Renqian Du, Hulya Kayserili, Shalini N Jhangiani, Harsha Vardhan DoddapaneniAbstract:Tooth agenesis is a common Craniofacial Abnormality in humans and represents failure to develop 1 or more permanent teeth. Tooth agenesis is complex, and variations in about a dozen genes have been...
Shalini N Jhangiani - One of the best experts on this subject based on the ideXlab platform.
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identification of likely pathogenic and known variants in tspear lamb3 bcor and wnt10a in four turkish families with tooth agenesis
Human Genetics, 2018Co-Authors: Renqian Du, Nuriye Dinckan, Zeynep Cobanakdemir, Hulya Kayserili, Shalini N Jhangiani, Yeliz Guven, Oya Aktoren, Xiaofei Song, Lauren E PettyAbstract: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.
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a biallelic antxr1 variant expands the anthrax toxin receptor associated phenotype to tooth agenesis
American Journal of Medical Genetics Part A, 2018Co-Authors: Nuriye Dinckan, Harsha Vardhan Doddapaneni, Renqian Du, Shalini N Jhangiani, Zeynep Coban Akdemir, Yavuz Bayram, Jianhong Hu, Donna M Muzny, Yeliz Guven, Oya AktorenAbstract:Tooth development is regulated by multiple genetic pathways, which ultimately drive the complex interactions between the oral epithelium and mesenchyme. Disruptions at any time point during this process may lead to failure of tooth development, also known as tooth agenesis (TA). TA is a common Craniofacial Abnormality in humans and represents the failure to develop one or more permanent teeth. Many genes and potentially subtle variants in these genes contribute to the TA phenotype. We report the clinical and genetic impact of a rare homozygous ANTXR1 variant (c.1312C>T), identified by whole exome sequencing (WES), in a consanguineous Turkish family with tooth agenesis. Mutations in ANTXR1 have been associated with GAPO (growth retardation, alopecia, pseudoanodontia, and optic atrophy) syndrome and infantile hemangioma, however no clinical characteristics associated with these conditions were observed in our study family. We detected the expression of Antxr1 in oral and dental tissues of developing mouse embryos, further supporting a role for this gene in tooth development. Our findings implicate ANTXR1 as a candidate gene for isolated TA, suggest the involvement of specific hypomorphic alleles, and expand the previously known ANTXR1-associated phenotypes.
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whole exome sequencing identifies novel variants for tooth agenesis
Journal of Dental Research, 2018Co-Authors: Nuriye Dinckan, Lauren E Petty, Ingrid S Paine, Evan H Baugh, A P Erdem, Zeynep Cobanakdemir, Renqian Du, Hulya Kayserili, Shalini N Jhangiani, Harsha Vardhan DoddapaneniAbstract:Tooth agenesis is a common Craniofacial Abnormality in humans and represents failure to develop 1 or more permanent teeth. Tooth agenesis is complex, and variations in about a dozen genes have been...
Michael K. Richardson - One of the best experts on this subject based on the ideXlab platform.
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Large-Scale Analysis of Acute Ethanol Exposure in Zebrafish Development: A Critical Time Window and
2013Co-Authors: Shaukat Ali, Danielle L. Champagne, Alia Alia, Michael K. RichardsonAbstract:Background: In humans, ethanol exposure during pregnancy causes a spectrum of developmental defects (fetal alcohol syndrome or FAS). Individuals vary in phenotypic expression. Zebrafish embryos develop FAS-like features after ethanol exposure. In this study, we ask whether stage-specific effects of ethanol can be identified in the zebrafish, and if so, whether they allow the pinpointing of sensitive developmental mechanisms. We have therefore conducted the first large-scale (.1500 embryos) analysis of acute, stage-specific drug effects on zebrafish development, with a large panel of readouts. Methodology/Principal Findings: Zebrafish embryos were raised in 96-well plates. Range-finding indicated that 10% ethanol for 1 h was suitable for an acute exposure regime. High-resolution magic-angle spinning proton magnetic resonance spectroscopy showed that this produced a transient pulse of 0.86 % concentration of ethanol in the embryo within the chorion. Survivors at 5 days postfertilisation were analysed. Phenotypes ranged from normal (resilient) to severely malformed. Ethanol exposure at early stages caused high mortality ($88%). At later stages of exposure, mortality declined and malformations developed. Pharyngeal arch hypoplasia and behavioral impairment were most common after prim-6 and prim-16 exposure. By contrast, microphthalmia and growth retardation were stage-independent. Conclusions: Our findings show that some ethanol effects are strongly stage-dependent. The phenotypes mimic key aspects of FAS including Craniofacial Abnormality, microphthalmia, growth retardation and behavioral impairment. We als
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large scale analysis of acute ethanol exposure in zebrafish development a critical time window and resilience
PLOS ONE, 2011Co-Authors: Shaukat Ali, Danielle L. Champagne, Alia Alia, Michael K. RichardsonAbstract:Background In humans, ethanol exposure during pregnancy causes a spectrum of developmental defects (fetal alcohol syndrome or FAS). Individuals vary in phenotypic expression. Zebrafish embryos develop FAS-like features after ethanol exposure. In this study, we ask whether stage-specific effects of ethanol can be identified in the zebrafish, and if so, whether they allow the pinpointing of sensitive developmental mechanisms. We have therefore conducted the first large-scale (>1500 embryos) analysis of acute, stage-specific drug effects on zebrafish development, with a large panel of readouts. Methodology/Principal Findings Zebrafish embryos were raised in 96-well plates. Range-finding indicated that 10% ethanol for 1 h was suitable for an acute exposure regime. High-resolution magic-angle spinning proton magnetic resonance spectroscopy showed that this produced a transient pulse of 0.86% concentration of ethanol in the embryo within the chorion. Survivors at 5 days postfertilisation were analysed. Phenotypes ranged from normal (resilient) to severely malformed. Ethanol exposure at early stages caused high mortality (≥88%). At later stages of exposure, mortality declined and malformations developed. Pharyngeal arch hypoplasia and behavioral impairment were most common after prim-6 and prim-16 exposure. By contrast, microphthalmia and growth retardation were stage-independent. Conclusions Our findings show that some ethanol effects are strongly stage-dependent. The phenotypes mimic key aspects of FAS including Craniofacial Abnormality, microphthalmia, growth retardation and behavioral impairment. We also identify a critical time window (prim-6 and prim-16) for ethanol sensitivity. Finally, our identification of a wide phenotypic spectrum is reminiscent of human FAS, and may provide a useful model for studying disease resilience.