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

Megana K. Prasad 1, 2 Véronique Geoffroy 1, 2 Serge Vicaire 3 Bernard Jost 3 Michael Dumas 3 Stéphanie Le Gras 3 Marzena Switala 4, 5 Barbara Gasse 6 Virginie Laugel-Haushalter 3 Marie Paschaki 3, 1, 2 Bruno Leheup 7 Dominique Droz 7 Amelie Dalstein 7 Adeline Loing 4 Bruno Grollemund 5 Michèle Muller-Bolla 8, 9 Serena Lopez-Cazaux 10 Maryline Minoux 4, 5 Sophie Jung 5, 4 Frédéric Obry 5, 4 Vincent Vogt 5, 4 Jean-Luc Davideau 5 Tiphaine Davit-Béal 6 Anne-Sophie Kaiser 11 Ute Moog 11 Béatrice Richard 12, 13 Jean-Jacques Morrier 12, 13 Jean-Pierre Duprez 12, 13 Sylvie Odent 14 Isabelle Bailleul-Forestier 15, 16 Monique Marie Rousset 17 Laure Merametdijan 18, 19 Annick Toutain 20 Clara Joseph 21, 8 Fabienne Giuliano 8 Jean-Christophe Dahlet 4 Aymeric Courval 22, 23 Mustapha El Alloussi 24 Samir Laouina 24 Sylvie Soskin 23 Nathalie Guffon 25 Anne Dieux 17 Bérénice Doray 26 Stephanie Feierabend 27 Emmanuelle Ginglinger 28 Benjamin Fournier 29, 30, 31 Muriel de La Dure Molla 29, 30, 31 Yves Alembik 26 Corinne Tardieu 32, 33 François Clauss 5, 4 Ariane Berdal 30, 29, 31 Corinne Stoetzel 1, 2 Marie Cécile Manière 5, 4 Hélène Dollfus 34, 1, 2 Agnès Bloch-Zupan 35, 3, 4 
Abstract : 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
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Submitted on : Friday, June 17, 2022 - 3:14:24 PM
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Megana K. Prasad, Véronique Geoffroy, Serge Vicaire, Bernard Jost, Michael Dumas, et al.. A targeted next-generation sequencing assay for the molecular diagnosis of genetic disorders with orodental involvement. Journal of Medical Genetics, BMJ Publishing Group, 2016, 53 (2), pp.98--110. ⟨10.1136/jmedgenet-2015-103302⟩. ⟨hal-01272929⟩



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