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A targeted next-generation sequencing assay for the molecular diagnosis of genetic disorders with orodental involvement

Background Orodental diseases include several clinically and genetically heterogeneous disorders that can present in isolation or as part of a genetic syndrome. Due to the vast number of genes implicated in these disorders, establishing a molecular diagnosis can be challenging. We aimed to develop a...

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Main Authors: Prasad, Megana K. (Author) , Geoffroy, Véronique (Author) , Vicaire, Serge (Author) , Jost, Bernard (Author) , Dumas, Michael (Author) , Gras, Stéphanie Le (Author) , Switala, Marzena (Author) , Gasse, Barbara (Author) , Laugel-Haushalter, Virginie (Author) , Paschaki, Marie (Author) , Leheup, Bruno (Author) , Droz, Dominique (Author) , Dalstein, Amelie (Author) , Loing, Adeline (Author) , Grollemund, Bruno (Author) , Muller-Bolla, Michèle (Author) , Lopez-Cazaux, Séréna (Author) , Minoux, Maryline (Author) , Jung, Sophie (Author) , Obry, Frédéric (Author) , Vogt, Vincent (Author) , Davideau, Jean-Luc (Author) , Davit-Beal, Tiphaine (Author) , Kaiser, Ann-Sophie (Author) , Moog, Ute (Author) , Richard, Béatrice (Author) , Morrier, Jean-Jacques (Author) , Duprez, Jean-Pierre (Author) , Odent, Sylvie (Author) , Bailleul-Forestier, Isabelle (Author) , Rousset, Monique Marie (Author) , Merametdijan, Laure (Author) , Toutain, Annick (Author) , Joseph, Clara (Author) , Giuliano, Fabienne (Author) , Dahlet, Jean-Christophe (Author) , Courval, Aymeric (Author) , Alloussi, Mustapha El (Author) , Laouina, Samir (Author) , Soskin, Sylvie (Author) , Guffon, Nathalie (Author) , Dieux, Anne (Author) , Doray, Bérénice (Author) , Feierabend, Stephanie (Author) , Ginglinger, Emmanuelle (Author) , Fournier, Benjamin (Author) , Molla, Muriel de la Dure (Author) , Alembik, Yves (Author) , Tardieu, Corinne (Author) , Clauss, François (Author) , Berdal, Ariane (Author) , Stoetzel, Corinne (Author) , Manière, Marie Cécile (Author) , Dollfus, Hélène (Author) , Bloch-Zupan, Agnès (Author)
Format: Article (Journal)
Language:English
Published: 2016
In: Journal of medical genetics
Year: 2015, Volume: 53, Issue: 2, Pages: 98-110
ISSN:1468-6244
DOI:10.1136/jmedgenet-2015-103302
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1136/jmedgenet-2015-103302
Verlag, lizenzpflichtig, Volltext: https://jmg.bmj.com/content/53/2/98
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Author Notes:Megana K. Prasad, Véronique Geoffroy, Serge Vicaire, Bernard Jost, Michael Dumas, Stéphanie Le Gras, Marzena Switala, Barbara Gasse, Virginie Laugel-Haushalter, Marie Paschaki, Bruno Leheup, Dominique Droz, Amelie Dalstein, Adeline Loing, Bruno Grollemund, Michèle Muller-Bolla, Séréna Lopez-Cazaux, Maryline Minoux, Sophie Jung, Frédéric Obry, Vincent Vogt, Jean-Luc Davideau, Tiphaine Davit-Beal, Anne-Sophie Kaiser, Ute Moog, Béatrice Richard, Jean-Jacques Morrier, Jean-Pierre Duprez, Sylvie Odent, Isabelle Bailleul-Forestier, Monique Marie Rousset, Laure Merametdijan, Annick Toutain, Clara Joseph, Fabienne Giuliano, Jean-Christophe Dahlet, Aymeric Courval, Mustapha El Alloussi, Samir Laouina, Sylvie Soskin, Nathalie Guffon, Anne Dieux, Bérénice Doray, Stephanie Feierabend, Emmanuelle Ginglinger, Benjamin Fournier, Muriel de la Dure Molla, Yves Alembik, Corinne Tardieu, François Clauss, Ariane Berdal, Corinne Stoetzel, Marie Cécile Manière, Hélène Dollfus, Agnès Bloch-Zupan
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Summary:Background Orodental diseases include several clinically and genetically heterogeneous disorders that can present in isolation or as part of a genetic syndrome. Due to the vast number of genes implicated in these disorders, establishing a molecular diagnosis can be challenging. We aimed to develop a targeted next-generation sequencing (NGS) assay to diagnose mutations and potentially identify novel genes mutated in this group of disorders. - Methods We designed an NGS gene panel that targets 585 known and candidate genes in orodental disease. We screened a cohort of 101 unrelated patients without a molecular diagnosis referred to the Reference Centre for Oro-Dental Manifestations of Rare Diseases, Strasbourg, France, for a variety of orodental disorders including isolated and syndromic amelogenesis imperfecta (AI), isolated and syndromic selective tooth agenesis (STHAG), isolated and syndromic dentinogenesis imperfecta, isolated dentin dysplasia, otodental dysplasia and primary failure of tooth eruption. - Results We discovered 21 novel pathogenic variants and identified the causative mutation in 39 unrelated patients in known genes (overall diagnostic rate: 39%). Among the largest subcohorts of patients with isolated AI (50 unrelated patients) and isolated STHAG (21 unrelated patients), we had a definitive diagnosis in 14 (27%) and 15 cases (71%), respectively. Surprisingly, COL17A1 mutations accounted for the majority of autosomal-dominant AI cases. - Conclusions We have developed a novel targeted NGS assay for the efficient molecular diagnosis of a wide variety of orodental diseases. Furthermore, our panel will contribute to better understanding the contribution of these genes to orodental disease. - Trial registration numbers NCT01746121 and NCT02397824.
Item Description:Published online first 26 October 2015
Gesehen am 09.07.2020
Physical Description:Online Resource
ISSN:1468-6244
DOI:10.1136/jmedgenet-2015-103302

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