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

Megana K. Prasad 1 Véronique Geoffroy 1 Serge Vicaire 1 Bernard Jost 1, 2 Michael Dumas 1 Stéphanie Le Gras 1 Marzena Switala Barbara Gasse 3 Virginie Laugel-Haushalter 1 Marie Paschaki 1 Bruno Leheup 4, 5 Dominique Droz 6 Amelie Dalstein Adeline Loing Bruno Grollemund 7 Michèle Muller-Bolla 8 Serena Lopez-Cazaux 9 Maryline Minoux 10 Sophie Jung Frédéric Obry Vincent Vogt Jean-Luc Davideau 11 Tiphaine Davit-Béal 3 Anne-Sophie Kaiser Ute Moog 12 Béatrice Richard 13 Jean-Jacques Morrier 13 Jean-Pierre Duprez 13 Sylvie Odent 14, 15, 16 Isabelle Bailleul-Forestier 17 Monique Marie Rousset Laure Merametdijan Annick Toutain 18 Clara Joseph Fabienne Giuliano 19 Jean-Christophe Dahlet Aymeric Courval Mustapha El Alloussi Samir Laouina Sylvie Soskin Nathalie Guffon 20 Anne Dieux 21 Bérénice Doray 22 Stephanie Feierabend Emmanuelle Ginglinger 23 Benjamin Fournier 24 Muriel de la Dure Molla 24 Yves Alembik 25 Corinne Tardieu 26, 27 François Clauss 28, 29 Ariane Berdal 24, 30 Corinne Stoetzel 31 Marie Cécile Manière Hélène Dollfus 32 Agnès Bloch-Zupan 33, 34, 1
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 : Thursday, February 11, 2016 - 3:33:50 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⟩